key: cord-1008989-6s5ehycc authors: Marley, J. C.; Marley, N. title: Characterising COVID-19 as a Viral Clotting Fever: A Mixed-Methods Scoping Review date: 2020-11-13 journal: nan DOI: 10.1101/2020.11.10.20228809 sha: 97e8d0151666d29f23ec69745c7f8e1f00a4bd2f doc_id: 1008989 cord_uid: 6s5ehycc Background: The COVID-19 pandemic has claimed over 1 million lives globally and results from the SARS-COV2 virus. COVID-19 is associated with a coagulopathy. In this mixed-methods PRISMA-compliant scoping review, we set out to determine if ARDS, sepsis and DIC could account for the coagulopathy and if there were any other features of the coagulopathy we could determine so as to inform future research. Methods: We used a search strategy to identify papers with clinically relevant thromboembolic events in COVID-19. We then developed a technique referred to as an Abridged Thematic Analysis (ATA) to quickly identify themes in the papers so as to increase the yield of clinically relevant information. We further developed Validated Abridged Thematic Analysis (VATA) to validate the resulting taxonomy of themes. Finally we developed a number of methods that can be used by other researchers to take forwards this work. Results: We identified 56 studies with 10,523 patients, 456 patients with COVID-19 and thromboembolic events (TBE's) and 586 thrombembolic events. There were an average of 1.3 TBE's per patient. There were five main arterial territories with corresponding clinical sequelae: Acute limb ischaemia, myocardial infarcts, strokes, mesenteric ischaemia and pulmonary embolism. We also identified DVT's. There were two further groups: medical-device-related coagulopathy and dermal lesions. In a subgroup of 119 patients we found mortality ranged from 26% in DVT to 79% in acute limb ischaemia although there was evidence of selection bias in the latter group. All patients were hospitalised and the average age of survivors was 63 versus 73 for those who died. 91/150 patients with TE's had fever. From the ATA, we identified 16 characteristics of the clotting pathology in COVID-19. From the VATA, we identified 34 mechanisms leading to coagulopathy and grouped them according to Virchow's triad of vascular damage, stasis and hypercoagulability. Coagulopathy occurred with and without each of ARDS, Sepsis and DIC. We conclude that COVID-19 leads to the syndrome of a viral clotting fever in a subgroup of patients and that the presentation of coagulopathy and fever should raise the possibility of COVID-19 as a differential. We make recommendations for future research studies. evidence of selection bias in the latter group. All patients were hospitalised and the average age of survivors was 63 versus 73 for those who died. 91/150 patients with TE's had fever. From the ATA, we identified 16 characteristics of the clotting pathology in COVID- 19 . From the VATA, we identified 34 mechanisms leading to coagulopathy and grouped them according to Virchow's triad of vascular damage, stasis and hypercoagulability. Coagulopathy occurred with and without each of ARDS, Sep- sis and DIC. We conclude that COVID-19 leads to the syndrome of a viral clotting fever in a subgroup of patients and that the presentation of coagulopathy and fever should raise the possibility of COVID-19 as a differential. We make recommendations for future research studies. On December 1 st 2019, the first patient with Pneumonia of unknown origin was reported in Wuhan, China followed by several cases associated with the Huanan seafood market reported by the Health Commission of Hubei province on December 31st 2019 (Gralinksi and Menachery, 2020)(Habibzadeh and Stoneman, 2020) . The illness was associated with a novel Coronavirus, SARS-COV2 which was isolated and characterised . The resulting infection has been termed COVID-19. Asymptomatic presentation has been well described (Oran and Topol, 2020) and is essential in understanding transmission dynamics but fever is recognised as a prominent clinical feature occurring in 98.6% of 138 symptomatic patients in an early study . Other studies have confirmed the significance of fever which has been reported in 83-98% of symptomatic cases (Wiersinga et al, 2020) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint manifestations have been described including neurological, renal, dermatological, cardiac and gastrointestinal symptoms (Gupta et al, 2020) (Elmunzer et al, 2020) (Adukia et al, 2020) . Silent hypoxia has been described in COVID-19 (Wilkerson et al, 2020) and can present a clinical challenge in routine practice. An abnormal coagulation state is an important finding in COVID-19 with similarities to other coronavirus infections including MERS (Mackay and Arden, 2015) and SARS . D-Dimer levels were found to be elevated in a study of 1099 patients with COVID-19 and other coagulation abnormalities have been identified (Boccia et al, 2020) . In this scoping review we focus on the COVID-19-related coagulopathy and it is necessary to set the scene in this introduction. We firstly provide an overview of SARS-COV2 and the pathological findings identified in COVID-19. We then outline the typical host response to a viral infection before moving on to discuss the clotting cascade and then Virchow's triad which we have used as a framework for our analysis. We then consider three important pathologies in COVID-19 which have featured in the early discussions around the COVID-19related coagulopathy -ARDS, DIC and septicaemia and which form a basis for our initial analysis of the literature. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. Coronaviruses are single-stranded RNA viruses (V'kovski et al, 2020) and are positive sense which means they can be read as mRNA by the ribosomes in the host cell and then translated into proteins. Taxonomically SARS-COV2 is a member of the suborder Coronoavirineae and the genus Betacoronaviridae which specifically infect mammals (V'kovski et al, 2020) . Although viruses are not classified as living organisms, the sequence of events leading to replication is described as a life cycle (Ryu, 2017) . (Ryu, 2017) outlines six steps in the virus life cycle: Attachment, penetration, uncoating, gene expression and genome replication, assembly and release. During attachment, the virus attaches to the surface of the host cell followed by entry into the cytoplasm (penetration) and shedding of the viral capsid (uncoating). The viral RNA is then read (gene expression and genome replication) and then the gene products are assembled into a virion (assembly) and released from the cell (release). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 Turning to coronaviruses there are four main structural proteins -spike, envelope, membrane and nucleocapsid (V'kovski et al, 2020)(see also Figure 1 ). The SARS-COV2 spike protein is divided into two functional components: S1 binds the receptor on the host cell and S2 facilitates the fusion of the virus with the host cell membrane. Like SARS, SARS-COV2 binds the ACE-2 receptor on the host cell. The ACE-2 receptor is found in tissues throughout the body (Hikmet et al, 2020) . SARS-COV2 also requires the priming action of trans- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Bösmüller et al, 2020) in a post-mortem series (n=4) found evidence of progression of pulmonary pathology with findings typical of ARDS in the more severe cases of pathology. In milder pathology they found evidence of increased mRNA expression of IL-1 beta and IL-6 as well as capillaritis with the presence of neutrophils and also microthromboses in the capillaries. (Tabary et al, 2020) review the pathological findings in COVID-19 and summarise the findings in the lungs, gastrointestinal tract, liver, kidney, skin, heart blood, spleen and lymph nodes, brain, blood vessels and placenta. Hepatocyte degeneration is noted in the liver as well as an altered vascular structure. Diffuse alveolar damage and lymphocyte infiltration is found in the lungs. Intramural non-occlusive thrombi and fibrin deposition are found in the placenta. Necrosis of the keratinocytes and Langerhans cell nests are found in the skin. Inflammatory cell infiltrates and endotheliitis are found in the blood vessels. Sinus fibrosis and white pulp atrophy are found in the spleen. Axonal injuries and leukocyte infiltration are found in the CNS. Proximal acute tubule injury, tubular necrosis and interstitial fibrosis are found in the kidneys. The post-mortem findings will represent the more severe end of COVID-19 in general depending on the cause of death and so there are limitations on the generalisation to the milder course of the illness. The human immune system is broadly divided into the adaptive and innate immune response and what follows is a simplified account of their function so as to contextualise subsequent material in this paper. The innate immune system responds to novel microbes in the early phase of an infection in contrast with the adaptive immune system which predominantly recognises and responds to a previously encountered microbe. The is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint lymphocytes. The T-lymphocytes recognise antigens on microbes, referred to as epitopes upon which the T-cell will clone itself to increase the number of circulating T-cells capable of recognising the antigen (Abbas et al, 2018) . In this case the T-cell has not previously encountered the microbe and is thus referred to as a naieve T-cell although any subsequent encounters will result in a more effective initial adaptive immune response. T-cells are fur- Coagulation is the process by which a liquid changes to a solid or semisolid state. Coagulation of blood is essential in haemostasis, the process which prevents blood leaking from damaged blood vessels. The haemostatic system is a balance between procoagulant and anticoagulant mechanisms (Konkle, 2017). On the one hand the platelets adhere to damaged surfaces and aggregate whilst fibrin forms a clot. Fibrin has complex physical properties and the conditions in which fibrin clots are formed determine the structure of the clot which in turn influences the fibrinolytic susceptibility (Wolberg et al, 2012 ). There are a number of anticoagulant mechanisms that provide a counterbalance. There are four main antithrombotic systemsthe fibrinolytic system and the systems involving protein C & S, tissue factor pathway inhibitor (TFPI) and antithrombin. The fibrinolytic system degrades fibrin clots in a complex interplay which features the activation of plasminogen to plasmin which then acts on fibrin. Tissue plasminogen activator activates plasminogen. The clotting cascade is the mechanism by which clotting is initiated and amplified in response to triggers. The clotting cascade can in the simplest form be divided into the intrinsic pathway, the extrinsic pathway and the common pathway (see . The clotting cascade consists of a number of clotting factors. Historically the clotting factors received many names with one factor receiving 14 different names (Giangrande, 2003) . The nomenclature of the clotting factors was rationalised in a series of meetings of the International Committee for the Nomenclature of Blood Clotting Factors between 1955 and 1958 and resulted in the use of Roman numerals. A selection of clotting factors with Roman numeral equivalents is shown in Table 1 and (Palta et al, 2014) note that the first four factors are referred to by the clotting factor names rather than the Roman numerals. The extrinsic pathway (see Figure 2 ) is initiated with the exposure of Factor VII to Tissue Factor. Tissue Factor is expressed on circulating particles released by monocytes and platelets and components of the vascular subendothelium including smooth muscle cells and fibroblasts (Konkle, 2017). Expression of Tissue Factor results from damage to the blood vessel walls. The exposure of Factor VII to Tissue Factor leads to activation of Factor VII (Factor VIIa). Factor VIIa then activates Factor X in the common pathway. . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. The intrinsic pathway (see Figure 3 ) is also known as the contact pathway (Smith et al, 2015) . The intrinsic pathway is initiated in vivo by the inflammatory response. The intrinsic pathway in vitro can be initiated when the blood comes into contact with glass and other artificial surfaces. In the intrinsic pathway, Factor XII is activated to Factor XIIa. Factor XIIa then activates Factor XI to Factor XIa which in turn activates Factor IX to Factor IXa. Factor IXa then activates Factor VIII to Factor VIIIa. The intrinsic and extrinsic pathways both act on the common pathway (see Figure 4 ) via activation of Factor X to Factor Xa. Factor Xa then activates Factor V to Factor Va. Finally Factor Va activates Prothrombin (formerly known as Factor II). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint There is evidence to suggest that the intrinsic pathway's role is to amplify the extrinsic pathway (Palta et al, 2014) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Virchow's triad is a well-established model of coagulation and provides a central framework for the interpretation of the data in this paper. Virchow's triad is named after the 19 th century physician Dr Rudolph Virchow. Prior to Virchow there were different explanations for coagulation. Hippocrates advocated the model of the four humors (Yapijakis, 2009 ) which was further refined by Galen (Neder, 2020) Virchow focused on pulmonary emboli and viewed them as originating in the deep veins. Rather than accounting for the process of thrombogenesis, Virchow identified a triad of effects resulting from the thrombus (Bagot and Arya, 2008) as well as explaining the propagation of the thrombus. Over the next one hundred and sixty-five years, the meaning of Virchow's triad has been reworked and this interpretation is supported by accumulating evidence. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In areas of low shear (post-stenotic), viscosity increases and many factors predispose to thrombosis (Lowe, 2003) . The white platelet-rich head of the arterial thrombi in the highshear region is contrasted with the red tail of the thrombus in the low-shear region which is rich in red-cells. In summary, Virchow's triad involves a complex interplay between three factors that can each predispose to coagulation but together form a potent combination. Three possible aetiologies for a hypercoagulable state in Covid-19 are listed in Table 2 and were used in the initial examination of the literature in this paper. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Table 2 Organ dysfunction in sepsis has been assessed using the SOFA score and in the sepsis-3 definition an increase of at least 2 points is used as a threshold for organ failure. The SOFA score has been specifically developed for the evaluation of organ failure in severe sepsis (Vincent et al, 1996) . A number of practical drawbacks with the use of the SOFA score led to the development of the qSOFA score which is simpler to use in clinical practice (Singer et al, 2020) and also referenced in the sepsis-3 definition. (Giesen and Singer, 2018) suggest that organ dysfunction is functional rather than structural and may reflect an adaptive hibernation-like mechanism. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 Sepsis commonly leads to coagulation with elevated D-Dimers, fibrinolysis and turnover of thrombin markers (Hunt, 2009 ). Clinically significant haemostatic changes have been identified in up to 70% of patients with sepsis (Levi, 2018) . (Levi, 2018 ) describes a central role for cytokines in sepsis-related coagulopathy with IL-1, IL-6 and Tumour Necrosis Factor having a prominent role. (Levi, 2018 ) also notes that fibrinolysis may be downregulated and there is a reduction in the levels of Protein C/S, TFPI and antithrombin all of which may contribute to a coagulopathy. (Levi, 2018 ) also notes the important balance between inflammation and sepsis-related coagulopathy. (Iba et al, 2017) published their findings from the development of the sepsis-induced coagulopathy scoring system which has been widely used. The importance of sepsis in COVID-19 has been recognised with the development of consensus guidelines for the management of sepsis in a critical care setting (Alhazzani et al, 2020) . (Dumitrascu et al, 2020) provide an example of COVID-19-related coagulopathy with sepsis in a case where ophthalmic artery occlusion developed despite thromboprophylaxis. In summary the definition of sepsis has been through several iterations, sepsis is generally associated with coagulopathy and the importance of managing sepsis in COVID-19 has been recognised. Acute Respiratory Distress Syndrome (ARDS) is a syndrome of respiratory failure that is predominantly diagnosed and managed in an ICU setting. ARDS was first described in 1967 (Ashbaugh, 1967 and the definition has changed in response to practical and prognostic challenges (Moss and Thompson, 2009) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint threshold value for the pulmonary arterial pressure and an acute onset. ARDS was graded into mild, moderate and severe and requirements were made for PEEP or CPAP thresholds. A number of treatment approaches have been developed for ARDS including prone positioning (Anzueto and Gattinoni, 2009 ), mechanical ventilation (Brower and Brochard, 2009 ), fluid therapy (Calfee et al, 2009 ), cell-based therapy ) and surfactant therapy (Spragg and Lewis, 2009 ) although some are experimental. The consensus guidelines for treatment of sepsis in a critical care setting includes the management of ARDS (Alhazzani et al, 2020) . (Mitchell, 2020) reviews the relationship of thromboinflammation to acute lung injury in There is noted to be damage to the endothelium and thrombosis in the perialveolar capillaries. (Mitchell, 2020) notes the antithrombotic and anti-inflammatory mechanisms of the vascular endothelium and that in COVID-19 there is loss of the contact with the basement membrane, exposing procoagulant factors. (Mitchell, 2020) also notes the influx of neutrophils and macrophages seen in COVID-19 in response to acute lung injury and their role in promoting thrombosis and inhibiting fibrinolysis. The Berlin definition does not include the construct of acute lung injury (ALI) due to inconsistencies in the use of the terminology (Fanelli et al, 2013) although this is referenced in the older literature and refers to a milder form of lung injury. (Wheeler and Rice, 2009 ) outline a number of relationships that are relevant to the question of COVID-19-related coagulopathy. They note that up to 50% of cases of acute lung injury result from sepsis but also patients with acute lung injury may be more likely to develop sepsis. (Wheeler and Rice, 2009 ) also note that there is increased tissue factor expression, fibrin generation and impaired fibrinolysis sharing similarities to the pathology seen in is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint sepsis. (Wheeler and Rice, 2009 ) note that in more severe cases of sepsis, the lung is usually involved and they suggest that this may be related to the extensive capillary network with exposure to the endothelial cells. The relationship between sepsis and ARDS is important not just in terms of coagulation but also for the risk of sepsis with prolonged ventilation (Valenza et al, 2009) ARDS has been identified in COVID-19 but the utility of the syndrome has been questioned (Tobin, 2020) . COVID-19-related ARDS may arise in multiple non-specialist settings which together with the silent hypoxia associated with COVID-19 has potential implications for the early recognition of ARDS in COVID- 19 . The association of ARDS with coagulopathy means that this is an important consideration in the aetiology of COVID-19-related coagulopathy. Disseminated intravascular coagulation (DIC) is an excessive activation of coagulation that can lead to significant mortality and morbidity. The 2001 definition by the International Society on Thrombosis and Haemostasis (ISTH) describes DIC as an acquired and generalised intravascular activation of coagulation (Taylor et al, 2001) . DIC is associated with many diseases and conditions (see Table 3 ). Activation of coagulation is recognised as a part of the host response to infection in sepsis (Okamoto, 2016) . In DIC, the coagulation response is pathological and can result from the host response to infection. (Semeraro et al, 2014) describe the mechanisms of sepsis-related coagulopathy including disseminated intravascular coagulation. One of the mediators of the relationship between the host response to infection and coagulopathy is complement and (Kurosawa et al, 2014) review the complex relationship between complement and coagulation. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Iba et al, 2019) distinguish between the microthrombosis that occurs predominantly in capillary venules in DIC and in arterioles in thrombotic microangiopathy. The distinction between thrombotic microangiopathy and DIC is also covered by (Wada et al, 2018) . (Toh et al, 2017) note the importance of the multidisciplinary team in decision making with DIC as well as the nuances of interpretation of the haematological parameters. (Wada et al, 2014) distinguish four types of DIC according to their characteristics and recommend stratifying DIC according to these types when undertaking diagnosis and treatment. (Papageorgiou et al, 2018) review the treatments approaches for DIC. There is an emerging evidence base for DIC in COVID- 19 . In a position statement by the Italian Haematology Society (Marietta et al, 2020) , DIC was suggested as a cause of the hypercoagulable state in COVID-19. (Levi, 2020) argues that COVID-19-related coagulopathy is distinct from DIC and notes that the thrombocytopenia is not as profound as expected in DIC, that most patients with COVID-19 would not reach the criteria for overt DIC and that there isn't evidence for excessive thrombin production. (Lillicrap, 2020) on the other hand cites the evidence that the criteria for overt DIC are more likely in non-survivors of COVID-19. (Joob and Wiwanitkit, 2020) describe a case of COVID-19 with petechial rashes and low platelet count, initially diagnosed as Dengue fever. Dengue fever is also associated with DIC which in turn can result in petechial rashes. This case highlights the diagnostic challenges in COVID-19. The primary aim of this study was to determine if clotting pathology in COVID-19 occurs in the presence or absence of sepsis, disseminated intravascular coagulopathy and ARDS. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 The secondary aims of this study were to use an iterative approach within the scoping review to: Characterise the clotting pathology in COVID-19 with reference to the literature 2. To utilise the identified characteristics to develop a testable model. To identify knowledge gaps To make recommendations on research methodology based on the findings To generate testable hypotheses in addition to those in the model. The PRISMA extension for scoping reviews checklist was used for this paper (Tricco et al, 2018) and was a key framework for this paper. Additionally we developed a number of the methods used in this scoping review which we outline below. To test the hypothesis that there was a clotting mechanism independent of ARDS, sepsis and DIC we used a simple search strategy to identify the main papers. We described the quantitative findings and also applied a thematic analysis to identify themes both for the clinical findings in relation to the coagulopathy as well as the suggested explanatory mechanisms. We then utilised an iterative (Brunton et al, 2017) semi-structured search strategy to identify further papers relevant to the results of the thematic analysis for explanatory mechanisms. These papers were utilised in the development of a theoretical framework for the characterisation of the COVID-19-related coagulopathy. There was no protocol due to the exploratory and iterative nature of the scoping review and no registration given the need to avoid a delay due to the COVID-19 pandemic. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Whilst there is evidence to suggest that COVID-19 is associated with a coagulopathy, there are diverse views on this coagulopathy and a number of potential mediators as above. COVID-19 has only recently been described and the evidence base is developing. Given the above, a scoping review was selected in favour of a meta-analysis or systematic review where the research questions are clearer and the research evidence base may be more well-developed. A mixed methods approach was used to maximise the yield from the identified studies. As this is a scoping review, broad search terms were used to identify evidence of clinically significant clotting disorders. The search terms used in the Pubmed database (Pubmed, 2020) are shown in Table 4 . The inclusion and exclusion criteria are shown in Table 5 . The COVID-19 initiative has made COVID-19 related papers available during the pandemic (GPMB, 2020). We therefore included only papers that were freely available including through the COVID-19 initiative as this review did not receive any external funding. The abstracts were evaluated and after exclusions, the remaining papers were examined in detail and further exclusions took place. We excluded papers that did not present any of the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint We used Microsoft Excel® for Windows 365 to store and analyse the data. We used Microsoft PowerPoint for the Diagrammatic Mapping. A template was created using an Excel spreadsheet and the data was filled on analysing the papers. Several columns were used to describe the pathology where more than one pathology existed in the same patient. We utilised reports of pathology, descriptions of imaging findings, operative findings, autopsy and biopsy evidence. In cases where there was clear evidence of end-organ ischaemia, we counted this as an thromboembolic event and have grouped this together with clotting episodes where thromboembolism was identified or inferred from the evidence (e.g. loss of patency of a blood vessel on imaging). For each of the studies we collected information on the number of cases, individual thromboembolic complications, sex, mortality, number of non-COVID-19 or non-thromboembolic cases and whether information was recorded on D-Dimers, fibrinogen, platelet count, prothrombin time, PaO2/FiO2, bilateral chest infiltrates evident on chest imaging, an absence of atrial hypertension or a threshold value for the pulmonary arterial pressure, acuteness of . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint onset, confirmation of ARDS, sepsis, DIC, antithrombin, Protein C, whether respiratory rate or blood pressure were recorded, whether qSofa or SOFA score were recorded, mental status, main country of authors. We looked for evidence of randomisation or blinding as well as a power analysis. Whilst the analysis was underway we identified a further potential mediator of the COVID-19-related coagulopathy -activation of the alternative complement pathway and added this to the analysis of the 56 papers. Where clarification was needed, we contacted the authors of the papers. A subset of 34 papers was identified in which individual patient data was available including sex, age and pathology. This enabled us to look at sex as a biological variable. The data was aggregated and analysed, further separated according to outcome and sex and comparisons between groups based was undertaken. We utilised a two proportion Z-test to determine the statistical significance of the difference in proportions between various sample proportions. We used the Benjamini and Hochberg procedure to correct for multiple comparisons using a false discovery rate of 0. 25 (McDonald, 2014) (Benjamini and Hochberg, 1995) . A qualitative analysis was undertaken, using what we refer to as an abridged thematic analysis which we extended by adding(see Figure 5 ). The 56 main papers are classed as a secondary source for the purposes of thematic analysis (Braun and Clarke, 2006) . We abridged the thematic analysis by removing the coding process and working out the themes as we moved through the papers. We have outlined the process in figure 6 to enable this to be reproduced. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 The application of the abridged thematic analysis was two-fold. 1. Firstly we looked for any characterisation of the coagulopathy. We identified any distinct characteristics reported by the authors based on their clinical findings and determined if they qualified as a theme and if so which theme. When we had identified all of the themes, we then quantified the frequency of the theme in the papers. 2. Secondly we looked for explanatory mechanisms for the COVID-19-related coagulopathy. The authors were clinicians providing a specialised expert perspective on their clinical experience with patients with COVID-19 and bringing their expert knowledge to bear on the question of aetiology. Again we identified the themes and organised them into an initial structure. We then undertook a validation process utilising an exploratory literature search (detailed below). We then analysed the identified papers and determined if there was sufficient evidence to confirm or refute the identified aetiological mechanisms. After this subsequent analysis, we were able to remove certain aetiologies and restructure the taxonomy of the aetiologies. We referred to this extended process as validated abridged thematic analysis (VATA). The exploratory literature search involved using specified search terms in Pubmed and selecting English language articles that were freely available including under the COVID-19 agreement and which were predominantly meta-analyses or systematic reviews in order to gain a rapid overview of the subject. We used these together with case studies or case series. We also used 'forward searching' from within the citations index of identified papers (Petticrew and Roberts, 2006) as well as personal knowledge of papers we were already familiar with (Grewal et al, 2020) . For more selective questions we used additional resources including MedRxiv (RRID:SCR_018222), bioRxiv (RRID:SCR_003933), DOAJ -Directory of Open Access Journals (RRID:SCR_004521) and AMEDEO: The Medical is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Literature Guide ( RRID:SCR_002284). We thus used a combination of primary, secondary and tertiary literature (Grewal et al, 2020) . We have included search terms used in the exploratory literature search as part of the VATA as open data in the supplemental data. After validating the identified themes against the clinical literature, we then reorganised the themes and documented a justification for the final taxonomy of themes. We used alphanumeric identifiers to label the themes. We also utilised the resulting taxonomy to generate a narrative summary which is presented at the end of the paper. We mapped the final taxonomy of themes onto corresponding diagrams using the alphanumeric identifiers and a set of rules which we outline below. 1. Each diagram is labelled with an alphanumeric identifier which maps onto the taxon- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The initial results of the literature search are shown in Figure 6 and includes the dates of the searches. The searches identified a total of 608 papers which were reduced to 71 papers after a review of the abstracts and finally 56 papers after inspection of the full text and application of the inclusion/exclusion criteria. A number of the papers reported on mixed clotting/ischaemic pathologies (e.g. stroke and lower limb deep vein thrombosis) and so the final 56 papers are pooled. The final papers are listed in Table 6 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The countries of publication are shown in Figure 7 . There were no authors based in Africa, Oceania or South America. The authors of 84% of the papers included in the analysis were based in five countries (Italy, USA, France, Spain and China). The descriptive statistics for thromboembolic/ischaemic events in the 56 papers are shown in Table 7 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The analysis shows that just over 4% of the total number of patients in all the studies had a combination of COVID-19 and thromboembolic/ischaemic events. Furthermore the average number of thromboembolic/ischaemic events was above 1. The distribution of the average number of ischaemic/clotting events per patient is illustrated in Figure 8 . The spread of the data was not normally distributed but instead was skewed towards the mode which was one thromboembolic/ischaemic event per patient. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The number of thromboembolic/ischaemic events is categorised in Table 8 . Strokes are differentiated according to the description. Where the occluded artery/arteries are not identified, the pathology has been identified through the infarcted regions. Several infarcted regions may result from the occlusion of a single artery but the location is not predictable due to anatomical variants and collateral circulation and therefore in these cases the distinct regions are counted. Skin livedo and necrosis are counted as thromboembolic/ischaemic events although data was not available in these cases on the potentially relevant arterial patency (e.g. acute limb ischaemia). Upper limb DVT was differentiated according to the absence or presence of a catheter with the latter group being included with medical deviceassociated clotting. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Table 9 shows the number and percentage of papers reporting a range of syndromes, diagnoses and blood test results relevant to COVID-19-related coagulopathy. The D-Dimers and platelet count were the two most frequently reported parameters in the 56 papers. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint likelihood of thrombotic events in the patients with COVID-19 (Odds Ratio 2.6 [1.1-6.1], p=0.035). The SOFA scores did not differ between the two groups. In the 56 main papers, two of the papers provide evidence of sepsis and are shown in Ta There are other papers where sepsis is discussed but the confirmation is less clear. (Barrios Lopez et al, 2020) report on 4 cases of ischaemic stroke with COVID-19 and suggest septic shock as a cause. Other papers mention the use of the SOFA or qSOFA score which are intended for use in sepsis although they have been used for critically ill patients more generally and are shown in is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Helms et al, 2020) is on ARDS although they exclude DIC (depending on the scoring system) and have included aggregated SOFA scores. DIC was specifically confirmed or excluded in four papers which are shown in Table 13 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint (Helms et al, 2020) investigated DIC as a secondary outcome and used various scoring methods to ascertain caseness. No patients were identified with DIC using the ISTH "overt" score, 6 cases of DIC were identified using the JAAM-DIC score and 22 patients were identified using the SIC score indicating those at risk of DIC. Thus there was evidence of thromboembolic complications in patients with COVID-19 and where DIC had both been confirmed or excluded. We identified a subset of 34 studies which contained individual information on the age and gender of the patient as well as the corresponding pathology, enabling a more detailed characterisation of the pathology. The 34 studies are listed in Table 14 . In the 34 studies, the distribution of thromboembolic/ischaemic events per patient was similar to Figure 7 , being skewed towards the mode value of 1 thromboembolic/ischaemic event per patient with a range of 1-8. The results are shown in Tables 8-12. In the limb ischaemia group, eight of the patients had been reported from one study where the data had been published selectively for patients that had died (i.e. individual data was not available for patients that had not died). . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The results from the analysis of the female cases in the 34 papers is shown in Table 16 . 32% of the patients in this group died. The deaths associated with each type of thromboembolic/ischaemic event ranged from 21% with cardiac thromboembolic/ischaemic events to 100% with acute limb ischaemia. The results from the analysis of the male cases in the 34 papers is shown in Table 17 . There were just over twice as many males as females in the 34 papers and 40% of the patients in this group died. There were eight deaths reported in one of the studies where the data was not available for those who survived. The deaths associated with each type of thromboembolic/ischaemic event ranged from 18% with pulmonary emboli to 75% with acute limb ischaemia. We also compared the results in the 34 papers for those who died and those who survived. The results for the cases of those who died are shown in Table 18 where the average age is 73. The four main types of thromboembolic/ischaemic events in this group in increasing percentages were thromboembolic/ischaemic events in the splanchnic arteries (20%), . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint stroke-related events including the carotid arteries (24%), acute limb ischaemia (24%) and cardiac thromboembolic/ischaemic events (33%). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The results of the analysis of the patients that survived in the 34 papers is shown in Table 20 . The average age in this group was 74 and there were twice as many men as women in this group. The four main types of thromboembolic/ischaemic events in this group in increasing percentages were pulmonary emboli (16%), venous thromboembolic events not including pulmonary emboli (19%), cardiac thromboembolic/ischaemic events (26%) and stroke-related events including the carotid arteries (32%). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Table 22 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The papers in which the confirmation or exclusion of fever were reported are shown in Table 26 . From these papers we identified 150 patients and these are summarised in Table 25 . The results show that there were 1.5 times as many patients with COVID-19 and thromboembolic events that were reported to have fever compared to those without fever. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint The 56 identified papers were analysed and a thematic analysis was undertaken relating to the clinical thromboembolic/ischaemic features reported in patients with COVID-19. The themes are summarised in Table 27 . This was the most commonly reported characteristic of thromboembolic events in COVID- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Cui et al, 2020) report 40% mortality in twenty patients with COVID-19 and lower limb deep vein thrombosis. (Bellosta et al, 2020) report 40% mortality in their series of twenty patients with acute limb ischaemia. (Kaafarani et al, 2020) report on 141 critically ill patients with COVID-19 of which there were four cases of mesenteric ischaemia and one case of hepatic necrosis. Although they do not distinguish between the ischaemia and non-ischaemic pathology in the mortality, overall they report a mortality of 40% in those requiring surgery. They also report a man in his 80's who was on aspirin but developed multiple ischaemic strokes and in hospital whilst receiving treatment with aspirin, clopidogrel and enoxaparin he developed another stroke. They further report on a lady in her 70's who despite treatment with aspirin and warfarin develops multiple ischaemic strokes. They report on a man in his late fifties who despite treatment with Enoxaparin develops a dural sinus thrombosis but also a cerebral haemmorhage. (Barrios Lopez et al, 2020) report on a patient who develops ischaemic stroke whilst on bemiparin (a low weight molecular heparin) and another patient with known atrial fibrillation taking acenocoumarol prior to an ischaemic stroke. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In their case series, (Escalard et al, 2020) report that fifty-percent of the patients with COVID-19 and stroke had multi-territory stroke involving the middle cerebral artery plus posterior or anterior cerebral artery involvement. (Zayet et al, 2020) describe two cases with ischaemic strokes affecting multiple vascular territories. report one case with both anterior and posterior circulation ischaemic stroke. (Morassi et al, 2020) report multiple bilateral ischaemic strokes and suggest an embolic aetiology. (Escalard et al, 2020) report four patients (40%) with reocclusion within twenty-four hours in their case series of ischaemic stroke. describe their experience with mechanical thrombectomy in ischaemic stroke patients with COVID-19. They report two cases in which recanalisation with a stent retriever was followed by reocclusion within minutes and which they attributed to a hypercoagulable state. (Bellosta et al, 2020) report twenty cases is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint of acute limb ischaemia with revascularisation. They identify a high rate of technical and clinical failure and attribute this to a hypercoagulable state. (Escalard et al, 2020) report fifty percent of patients in their case series as presenting with mild symptoms at stroke onset. (Fara et al, 2020) present one case of a lady who was coughing prior to stroke but otherwise had no symptoms. (Escalard et al, 2020) report no significant neurological improvement in any of their patients 24 hours after mechanical thrombectomy for stroke. (Benussi et al, 2020) reported worse neurological outcome for COVID-19 patients with stroke compared to a control group without COVID-19. The ability to recanalise an occluded blood vessel at first pass is associated with better outcome. (Escalard et al, 2020) reported an absence of first-pass effect for recanalisation in their series of ten patients with COVID-19 and ischaemic stroke. report an average of just under three passes with the stent-retriever to achieve recanalisation. report on the fragmentation of clots with intervention in a case series of patients with ischaemic strokes. They report on the intervention in one patient where aspiration was used initially with resulting embolisation from the carotid bulb thrombus distally. After using a stent-aspiration approach there was further embolisation of the thrombus into the middle cerebral artery. They report another case involving stent-aspiration of a thrombus in the internal carotid artery which embolised to the anterior cerebral artery. They report on another patient where a thrombus in the basilar artery was treated with a combination of is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint balloon-guide catheter and aspiration resulting in embolisation to the posterior cerebral arteries. In another case they describe embolisation of fragments of a thrombus from the middle cerebral artery following stent-aspiration.The authors confirmed distant emboli in 100% of their cases. They also confirm embolisation into a different vascular territory in 40% of their cases which they contrast with a rate of 4.5% in a study involving patients without COVID-19 (Jovin et al, 2015) . (Vigueir et al, 2020) report a case of a floating thrombus in the common carotid artery. They note that this is an unusual location for strokes resulting from occlusion within the cervicocephalic arteries and particularly in the absence of atheroma or dissection. They cite evidence that this location occurs in less than 1% of strokes involving the cervico-cephalic arteries . (Bellosta et al, 2020) describe the need for an additional surgical procedure in the treatment of acute limb ischaemia due to the occurrence of residual non-detachable clots. Desert foot refers to the occlusion of all of the main arteries of the foot. (Bellosta et al, 2020) refer to several cases of desert foot in their case series of 20 patients with acute limb ischaemia. (Bellosta et al, 2020) report a low rate of successful revascularisation in their case series of acute limb ischaemia. They note that patients receiving intravenous heparin did not undergo reintervention and a low oxygen saturation was significantly associated with unsuccessful revascularisation. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint P. Thrombosis of a Graft (Giacomelli et al, 2020) report on a case of a man in his late sixties with an abdominal aortic aneurysm that had been repaired with an aortic graft six years previously. At admission to hospital, the graft was patent. His overall condition deteriorated and nine days after admission, the graft was completed occluded with a thrombus and the patient died before revascularisation was possible. (Helms et al, 2020) report on 150 patients with COVID-19 who were admitted to four intensive care units in France. They report circuit clotting with the use of renal replacement therapy. They also report the thrombotic occlusion of the centrifugal pumps in patients receiving extracorporeal membrane oxygenation (ECMO). The centrifugal pump needed replacing after between 4 and 7 days. They also report that the average lifespan of the renal replacement therapy circuit was reduced by 50%. The authors hypothesised that the occlusion of the centrifugal pumps was due to a combination of ultrafiltration and high fibrinogen levels. We screened over 12,000 references from the clinical and scientific literature (see supplementary data) as well as references from prior and successive searches. The search strategy was determined from the specified aetiology unless there was sufficient evidence from the existing material. We identified 50 COVID-19 coagulopathy-related mechanisms suggested in the 56 main papers and have listed them in Table 28 . Some of the mechanisms were mentioned by single authors whilst others such as a hypercoagulable state were mentioned by most of the authors. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; In most of the main papers, the authors suggest that the coagulopathy results from a hypercoagulable state. Also termed a thrombophilic state, the hypercoagulable state is one which there is an increased likelihood of clotting or else a severe clotting response (Senst et al, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint into the aetiology. Thus there is the possibility that these changes are secondary to the vascular pathology including endothelial involvement that would that would form another aspect of Virchow's triad. Increased levels of tissue factor in the blood in response to endothelial damage would fit with both mechanisms and is just one example of mediators of hypercoagulability in response to endothelial damage. We will consider other components of the blood and plasma that may contribute to hypercoagulability in subsequent sections. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; In terms of ACE-2 receptors, a recent NICE review found no evidence to suggest that ACEinhibitors or Angiotensin Receptor Blockers either increased the risk of contracting COVID-19 or else lead to a more severe manifestation of COVID-19 (NICE, 2020). In their case study report their findings in a man with COVID-19, ARDS and septic shock who experienced a marked response to the administration of angiotensin II. The authors discuss these findings whilst noting that a similar response has been found in non-COVID-19-related sepsis. found elevated plasma angiotensin II levels in patients with severe COVID-19 compared to a control group with COVID-19. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Garvin et al, 2020) analysed gene expression data from bronchial lavage specimens in patients with COVID-19 and used the Summit supercomputer to analyse the results. Their findings support the role of a bradykinin storm, an amplifying circuit of bradykinin production in response to the infection and mediated by RAS. They also found that the levels of hyaluronic acid were elevated and note that hyaluronic acid is associated with thrombosis. They suggest that the hyaluronic acid produces a gel in the lungs which interferes with the oxygenation of blood and thereby predisposes to hypoxaemia. (Garvin et al, 2020) looked at mRNA levels and found a reduction in ACE mRNA expression as well as an upregulation in ACE2 mRNA expression which may be expected to reduce the production of Angiotensin II. The mRNA levels do not necessarily correlate strongly with protein levels. The correlation between mRNA expression and protein levels (R 2 ) was 0.4 across species in one study (de is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Akoumianakis et al, 2020) note the relationship between obesity and dysregulation of the RAAS axis as well as myocardial and lung injury and suggest that this relationship may be relevant in COVID-19. In the Dyhor-19 Study (Villard et al, 2020 ) demonstrate a correlation between CRP and Aldosterone levels and COVID-19 severity. (Dudoignon et al, 2020) found that half of patients with COVID-19 and ARDS had acute kidney injury and this was significantly associated with activation of the RAAS with patients having high levels or renin and aldosterone on admission. In summary, SARS-COV2 gains entry to cells via the ACE-2 receptor which in turn can lead to the downregulation of ACE-2 receptors and to an increase in Angiotensin II. There is evidence of elevated Angiotensin II levels in COVID-19. Angiotensin II in turn can lead to an increased risk of thrombosis. This can be considered as a component of the blood which leads to hypercoagulability. The relationship may not be so straightforward and may be organ-specific with the results of (Garvin et al, 2020) hinting at this complexity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint C. Sepsis-Related (Valderrema et al, 2020) suggest the septic inflammatory response syndrome (SIRS) mediated by IL-6 as one of the mechanisms that predisposes to ischaemic stroke in COVID-19. (Barrios Lopez et al, 2020) cite evidence that severe inflammation occurs during the acute phase of COVID-19. The difference between sepsis and SIRS as we saw from the introduction is one of organ dysfunction and a dysregulated immune response in sepsis in contrast with SIRS. If we consider a thromboembolic event then organ dysfunction is a function of the location of the event. The key question we should consider is whether there is a dysregulated immune response and in asking this question it becomes clear that SIRS cannot lead to a clotting event as this cannot be considered a healthy response. The utility of SIRS is lost due to semantics but we can still consider the associated mechanisms and the role of IL-6. However from a clinical perspective, the new sepsis consensus definition has removed the construct of SIRS, although there is an argument for the utility of SIRS (Sprung et al, 2016 ). We will not consider this further although we will add a section for IL-6 separately below. Also we consider septic shock on the continuum with sepsis and refer back to the introduction for discussion of the procoagulant mechanisms including DIC. The suggestion of a key role for IL-6 in COVID-19 pathology is a basis for the recommenda- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. found a correlation between IL-6 levels and disease severity. found a correlation between both IL-6 levels and CD8 + T cell counts and mortality. found IL-6 to be elevated in the later stages of severe COVID-19 but found that RANTES, a chemokine, was elevated earlier in the course of illness. (Mansouri et al, 2020 ) present a case of COVID-19 in which IL-6 and other parameters normalised after treatment with Colchicine and this was accompanied by a rapid improvement in presentation. In a prospective comparative study (Giamarellos-Bourboulis et al, 2020) compared the immune responses of patients with COVID-19, influenza or bacterial sepsis. They found that in COVID-19 there was a more marked deterioration and they attributed this to immune dysregulation. This immune dysregulation was characterised by a disruption in antigenpresentation combined with lymphopenia but with monocytes producing IL-6 and TNF-α. IL-6 was elevated in patients with immune dysregulation. Immune dysregulation was characterised by a number of factors including absolute numbers of molecules of human leukocyte antigen on CD14 monocytes. (Varhana and Wolchok, 2020) review the evidence for the immune response in COVID-19 and identify an accentuated innate immune response which results in elevated IL-6 levels. They suggest that a cytokine response syndrome could mediate pathology in COVID-19. However, they advise caution with this interpretation on the basis of significant differences between the typical description of the cytokine response syndrome and the features of COVID-19. They also identify a reduced adaptive response with T-cell exhaustion. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint warranted. (Chatterjee et al, 2020) suggest that elevated IL-6 and hypoxia in COVID-19 could both lead to a reduction in Protein S and subsequent coagulopathy. In the non- and size of infarcts in ischaemic strokes. In summary, there are multiple lines of evidence to suggest that IL-6 plays a key role in COVID-19 but many details remain to be characterised and there is also evidence against IL-6 having a central role. There is a well-established evidence base for the role of IL-6 in infections independent of COVID-19 and there is also an association between IL-6 and strokes although there are questions about the direction of causality. and note that the lung injury can progress to ARDS. They also note a number of viruses associated with a cytokine storm in a number of the early descriptions (see Table 29 ). . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Table 29 Table 30 but also the earlier section on IL-6). (Coperchini et al, 2020) provide an overview of the cytokine storm in COVID-19. They suggest that ARDS in COVID-19 results from a cytokine storm. (Manjili et al, 2020 ) make a case for COVID-19 as an acute inflammatory disease and provide evidence of an association between elevated cytokine levels and more severe illness. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint In summary, there is strong evidence for the phenomenon of cytokine storms and there are clinical syndromes correlating with the relevant cytokines and evidence for a procoagulant action depending on the cytokine. There is also evidence of elevated cytokine levels in COVID-19 and a relation to the severity of illness. We have considered IL-6 separately as a special case. suggesting fibrinogen. In summary, we conclude that there is evidence of hyperviscosity but it is unlikely to result from elevated IL-6. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint syndrome in which there was a hyperinflammatory response with macrophage activation. (Cole et al, 2020) suggest that low grade inflammation with diabetes and adipose tissue dysfunction in obesity is a vulnerability in people who develop COVID-19. (Giamerellos et al, 2020) found evidence of two types of hyperinflammatory response in COVID-19 with severe respiratory failureimmune dysregulation and macrophage activation syndrome. They found that IL-6 results in immune dysregulation with monocytes producing excessive inflammatory cytokines and also resulting in CD4 lymphopenia and B-cell lymphopenia. They also found that IL-6 elevation was associated with a reduction in CD14 monocyte HLA-DR expression and that the HLA-DR expression increased in convalescence. They also found that IL-1β levels increased and resulted in macrophage activation syndrome. In summary, there is evidence of thromboinflammation in COVID-19 and independent of COVID-19, platelets have a central role in thromboinflammation. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint associated genes. (Leppkes et al, 2020) found evidence of pulmonary microvessel occlusion with NETs. (Tomar et al, 2020) suggest NETs as a source of necroinflammation leading to endothelial cell death and promoting thrombosis. found that neutrophil-to-lymphocyte ratio (NLR) was prognostic for critical illness in COVID-19 in their prospective cohort study (n=61). Using a cut-off of NLR of 3.13 they found that 50% of patients aged over 50 with an NLR > 3.13 developed critical illness. In summary, there is evidence of the involvement of neutrophils in COVID-19 and there is an evidence base for NET involvement in a number of pathologies relevant to COVID-19. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In summary there is strong evidence for myocardial pathology in COVID-19, although the papers we identified for this section did not provide evidence of direct viral invasion of the myocardium although this is revisited in a subsequent section. Therefore we can say that there is strong evidence of an association between SARS-COV2 infection and myocardial pathology. The consequences of myocardial pathology are considered separately in subsequent sections. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In the non-COVID-19 literature (El-Battrawy et al, 2020) found no difference in the rate of thromboembolic events including stroke between recurrent and non-recurrent Takotsubo Syndrome groups although finding an incidence of between 1.32 and 3.3%. In summary there is moderate evidence of an association between COVID-19 and stress cardiomyopathy but there is a well-established evidence base for the consequences of stress cardiomyopathy independent of COVID-19. The critically ill patient may provide a special case of stress cardiomyopathy representing a number of psychological and physical predisposing factors and also a substantial number of patients in terms of the scale of the pandemic. In the 56 main papers, there was evidence of cardiac thrombi with a left ventricular throm- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint In summary there is evidence of an association of SARS-COV2 infection with cardiogenic shock. Independently of COVID-19, there is an established evidence base on cardiogenic shock-related coagulopathy. Cardiovascular compromise is a broad term which encompasses many pathologies with the potential for coagulopathy including cardiogenic shock and myocardial involvement. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint antiphospholipid syndrome. There is an established literature on Chagas disease which is divided into acute and chronic phases and can lead to a coagulopathy (Woudstra et al, 2018) . In summary there is evidence of myocarditis in COVID-19. Independently of COVID-19 there is an established literature on the association of myocarditis with a coagulopathy and also with ischaemia. Thus the possibility of a myocarditis-like mechanism for COVID-19-related coagulopathy, particularly for myocardial events, is supported by some evidence but of an association rather than causality. Furthermore there is limited evidence of this relationship. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint events including small bowel necrosis. In summary, viral enteroneuropathy may be more relevant to gastric dysmotility rather than mesenteric ischaemia. This term is broad and we will refer to this as requiring further characterisation. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In summary, there is a robust evidence base for hypoxaemia/hypoxia in COVID-19, particularly as a result of ARDS. There is also a robust evidence base for a causal link with coagulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 5. Pathology of the vasculature a. Microangiopathy leading to ischaemia (Fara et al, 2020) refer to a microangiopathy that may be associated with SARS-COV2 infection in their case series of macrothrombosis and stroke. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint of anticoagulant properties of the endothelium involving the protein C pathway, Tissue Factor pathway inhibitor and heparin sulfate and other glycosaminoglycans (GAGS). An example of how endothelial cells and the glycocalyx in particular are specialised is provided by (Sol et al, 2020) . In their review they outline the contribution of the endothelium and the glycocalyx in particular to the glomerular filtration barrier (GFB) in the kidneys. Furthermore they suggest that the glycocalyx can be disrupted by processes such as inflammation and by such means can contribute to the development of focal segmental glomerulosclerosis (FSGS). Interestingly this is of particular significance in COVID-19. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Many authors in the main papers suggest endothelial dysfunction as a mediator of COVID-19-related coagulopathy. Endothelial dysfunction is well-characterised and describes a reduction in the availability of vasodilators such as nitrous oxide and an increase in endothelial-derived vasoconstrictors resulting from the action of various cardiovascular risk factors. Endothelial dysfunction is a precursor for atherosclerosis and predisposes to a number of pathologies including thrombosis (Hadi et al, 2005) . identified elevated Angiopoetin-2 and E-selectin on admission as prognostic for ICU admission in patients with COVID-19. They note that both are markers for endothelial dysfunction. Further they suggest that an intact endothelium is antithrombic and disruption of the endothelium is therefore prothrombotic and that an analogy can be drawn with pre-eclampsia. In summary, there is evidence for a role for endothelial dysfunction in increasing the risk of COVID-19-related coagulopathy although we did not identify evidence to suggest that this results from COVID-19. We therefore treat this as a risk factor but not a COVID-19-mediated mechanism for coagulopathy. The evidence base for endothelial dysfunction independent of COVID-19 is well established and so we consider this as a vulnerability factor in COVID-19-related coagulopathy although the evidence base in COVID-19 is well developed in terms of prognosis rather than coagulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Coronavirus. In SARS there was evidence of fibrinoid necrosis and inflammatory cells in the vessel walls in three cases (Ding et al, 2003) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 2020) report two cases of COVID-19 with digital gangrene mediated by small-vessel thrombosis. In summary, the association with coagulopathy is a defining feature of small vessel thrombosis and there are many lines of evidence to support the occurrence of small vessel thrombosis in COVID-19 particularly in the lungs. However we would include small vessel thrombosis under the heading of microangiopathy with thrombosis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In summary, there is evidence of antiphospholipid antibodies during the acute phase of COVID-19 but follow-up studies from those that we identified the evidence supports an association with elevated antiphospholipid antibodies but this is not persistent and appears to be distinct from antiphospholipid syndrome. Nevertheless there may be a role for these antibodies in the pathogenesis of COVID19 in a unique way. We therefore distinguish between antiphospholipid antibody syndrome-like coagulopathy for which there is evidence but not for the antiphospholipid antibody syndrome. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 2. Type-1 Interferonopathy (Bouaziz et al, 2020) noted similarities between the dermatological presentation of COVID-19 and type-1 interferonopathy. Chilblains for instance occur in Aicardi-Goutiéres syndrome (AGS) . This hypothesis is further developed by (Günther et al, 2020) and (Damsky et al, 2020) . Table 31 ) as well as the associated genotypes (see Table 32 ) and their posited role. They suggest that interferon is potent in action but also difficult to detect. In their review they state that there is insufficient evidence to support a causal is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint relationship between an upregulation of type-I interferon signalling and the associated clinical features at that time. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In summary, we interpret this as a COVID-19-induced encephalopathy that may lead to an increased risk of ischaemic stroke although the evidence is limited and one of association rather than causality. The broader concept of a critical-illness encephalopathy has been developed in the literature and is a move to organise the findings in cases which may be complex and multifaceted. In such cases, other mechanisms including those discussed in this paper may be playing a role. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint in COVID-19. (Momtazmanesh et al, 2020) in their systematic review and meta-analysis note the significance of pre-existing hypertension as a risk factor for prognosis. (Jain and Yuan, 2020) in their systematic review and meta-analysis similarly identify hypertension as a comorbidity which was predictive for severity of COVID-19. In summary we will group this with mechanical ventilation associated mechanisms and also recognise hypertension as a risk factor for COVID-19 severity and suggest that this may relate to endothelial dysfunction and is best considered under the heading of vulnerabilities. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Arrigo et al, 2020) in their review of Atrial Fibrillation note that this is a common condition in an ICU setting and they identify several mechanisms leading to atrial fibrillation: myocardial stretch, inappropriate oxygen delivery, electrolyte disturbances, inflammation, adrenergic overstimulation, endocrine disorders and hypothermia. They outline a number of treatment approaches depending on the underlying mechanism. albeit in a critical care setting where the prevalence of atrial fibrillation is expected to be increased due to a range of factors. Thus atrial fibrillation may be a non-specific feature of COVID-19 relating to the context of a critically unwell patient and this would not necessarily be restricted to the ICU setting given the rapid deterioration that is seen. There is a strong evidence base for atrial fibrillation as a cause of thromboembolic events which forms the basis for the practice of thromboprophylaxis. Table 33 ) and cite evidence for immobility and bed rest as risk factors for DVT. In the 56 main papers, the authors note that patients experienced thromboembolic events despite thromboprophylaxis. There is no doubt that this is an important consideration in the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint ICU setting. (McLendon et al, 2020 ) note a hierarchy of DVT risk with immobility in order from highest to lowest: Hip, knee, ankle, shoulder, elbow. The veins are valved which influences the dynamics of blood flow and periods of stasis can predispose to thrombosis. However the arterial anatomy is substantially different and in our findings the arterial ischaemic events significantly outnumbered those affecting the veins. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint mechanism may be of minor relevance in COVID-19 but in the majority of the 56 main papers describing acute limb ischaemia, deep vein thrombosis was not reported as a comborbidity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. Fever has been well characterised in COVID-19 as per the introduction and can lead to fluid loss through sweating thereby providing an additional mechanism which can lead to dehydration. In summary there is strong evidence both for fever and diarrhoea in COVID-19 and this can occur in mild as well as severe presentations of COVID-19. Fever and diarrhoea can lead to dehydration for which there is robust evidence for a causal link with coagulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint COVID-19 which was determined to be secondary to SIADH after further investigation. (Ravioli et al, 2020) report 2 cases of SIADH in COVID-19. Thus there are consistent findings with the vast majority of studies identifying hyponatraemia but when hyponatraemia or hypernatraemia occur they are both prognostic in COVID-19. A key point here is that if sodium homeostasis is working effectively then hyponatraemia or hypernatraemia would be avoided and it is likely that this is related to a disruption in the RAA system. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (n=799) and found that renal failure, hyperkalaemia and alkalosis were more common in those who died. Thus in the case of potassium, there are mixed results. With the RAA system, sodium retention is accompanied by potassium excretion whereas hypokalaemia and hyponatraemia are commonly reported in studies. Taken together with the evidence about the RAA system, the most plausible explanation is that there is a disruption of sodium and potassium regulation due to a disruption in the RAA system. found evidence of hypocalcaemia in 62.6% of 67 patients with severe COVID-19 and was inversely correlated with D-Dimer and IL-6 levels. found evidence that hypocalcaemia was prognostic in COVID-19 and associated with a higher incidence of septic shock and that calcium levels were correlated with Vitamin D levels. found that calcium levels were lower in severe COVID-19 and that calcium levels negatively correlated with CRP, D-Dimer and IL-6 levels. In a retrospective cohort is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint study (n=241), 74.7% of patients with COVID-19 were hypocalcaemic on admission . Furthermore calcium was lower in those with severe illness and those with low calcium experienced higher 28-day mortality and were more likely to develop septic shock. Another consideration for calcium homeostasis is medication. (Vila-Corcoles et al, 2020) found no significant reduction in the hazards ratio for developing COVID-19 in patients taking calcium channel blockers. There was a reduction for patients taking Angiotensin II receptor blockers but this was not statistically significant. Similarly found no significant effect of antihypertensive medication on prognosis in COVID-19 in their prospective cohort study. looked at patients taking one of five classes of antihypertensives and found no significant reduction in incidence of COVID-19 or in severity in those with COVID-19. (Solaimanzadeh, 2020) did find a significant reduction in mortality as well as a significant reduction in intervention with mechanical ventilation and intubation in older adults admitted with COVID-19 who were receiving treatment with calcium channel blockers compared to those who were not. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint They also note that thrombocytopenia occurs in up to 50% of cases of ARDS, is predictive of mortality in sepsis and septic shock, correlates with hypoxemic respiratory failure and is also seen in SARS. They suggest a range of causes may be responsible for the association of thrombocytopenia with critical illness including splenic sequestration. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint suggest that the megakaryocytes found circulating in the pulmonary microvasculature may be an important source of platelets in COVID-19. (Rapkiewicz et al, 2020) find evidence of platelet-rich thrombi in multiple organs and megakaryocytes. In summary, there is an association between thrombocytopenia and thrombosis in specific conditions. However we would argue that confounding factors are responsible for the thrombosis with thrombocytopenia. Indeed the low platelet count is likely to reflect a period of increased activation of platelets and consumption which in turn is more likely to be related to thromboembolic events. The low platelet count is similar therefore to the D-Dimers and fibrinogen in reflecting the end result of pathway activation rather than the cause. The platelet count is included in the SIC score but here we are looking specifically at biologically plausible mechanisms for thromboembolic events. HIT is appropriate to consider and this can be included with iatrogenic mechanisms. More appropriate to a COVID-19 coagulopathy is the platelet activation that is central to the modern interpretation of thromboinflammation and it is in this context that we include platelet activation in the model of COVID-19-related coagulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. Strictly speaking, septic embolisation is not coagulopathy-related and although there is strong evidence for ischaemic events resulting from septic emboli, we will not include this in the model of COVID-19-related coagulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. We have included this under the broader heading of sepsis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint have included apoptosis with the broader topic of sepsis whilst also noting that there is a strong evidence base for apoptosis in COVID-19. More recently evidence has emerged for an important role of the alternative complement pathway. The complement pathway is part of the innate immune response and is divided into three pathwaysthe classical, alternative and lectin complement pathways. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 2015). C3 glomerulopathy is another condition involving the kidneys and resulting from a dysregulated alternative complement pathway activation (Caravaca-Fontán et al, 2020). In summary, multiple lines of evidence, some indirect, suggest a role for the alternative complement pathway in COVID-19-related coagulopathy. The role of complement deficiencies in COVID-19 should also be borne in mind. Table 25 , dyslipidemia, psychosocial factors, diabetes and hypertension are not listed in Table 25 and suggest a more chronic aetiology and a role for endothelial dysfunction. This however is contrast with the acute nature of arterial thromboses in COVID-19. In the 56 main papers, there were multiple examples of medical device-related coagulopathy (including catheters). We suggest a number of mechanisms are involved. Firstly catheters may result in subtle vascular wall damage that ordinarily would not present any problems but when combined with the vasculopathy of COVID-19 acts synergistically to increase the risk of thrombosis. Secondly in the case of the ECMO centrifuge, (Helms et al, 2020) suggest that this is due to a combination of ultrafiltration and high fibrinogen levels. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint contact with artificial surfaces this can trigger the intrinsic pathway which amplifies the extrinsic pathway. There are a number of factors that act as modifiers of risk of mortality in COVID-19. Table 34 ). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In terms of genetic susceptibility (Zeberg & Pääbo, 2020) identified a haplotype that presents increased risk for severe COVID-19. In summary there are a number of vulnerabilities that include conditions that lead to endothelial dysfunction, genetic susceptibility, age, ethnicity, male gender. However these are more general susceptibilities not specifically related to COVID-19-related coagulopathy although they may be very relevant particularly endothelial dysfunction. We will include them cautiously in the model on the proviso that their relationship with the COVID-19-related coagulopathy requires further clarification. In the type III hypersensitivity reaction, antibody complexes are deposited in various tissues in the body. The complement pathway can be involved in the pathogenesis of the type III hypersensitivity reaction and so this can be considered together with the section on the al- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 There is evidence that when senescent neutrophils are not cleared through apoptosis this is associated with the development of autoimmune disease (Kawano et al, 2018) . (Tanaka et al, 2020) have demonstrated an association between apoptosis-associated release of autoantigens and SLE. note that autoantigens and damage associated molecular patterns (DAMPS) are released after apoptosis, pyroptosis, necroptosis and by NET's resulting in inflammation and with a potential for autoimmune reactions. In summary there is evidence of a type-III hypersensitivity reaction in COVID-19 with deposition of immune complexes in the skin, kidneys and vascular walls in association with vasculitis which in turn can lead to a coagulopathy. We think this is likely to occur in a minor is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint proportion of cases of coagulopathy although further data would be needed to draw even initial conclusions on this. In our paper, we draw together the findings from many studies to develop a testable model as per Table 35 and the diagrammatic mapping (see Figures 10-21) . This is a simple model with several components and is described by causal relationships but without quantitative descriptions of those same relationships. The purpose of this model is to serve as a starting point for further enquiry and to enable other researchers to refute or confirm these relationships or to quantify and expand upon them, thereby improving the understanding of the COVID-19-related coagulopathy. The revised aetiologies are shown in Table 35 . The revised aetiologies have been organised into categories following the preceding analysis. The general evidence is then considered for each potential aetiology and categorised as weak, moderate or strong. The general evidence refers to the evidence for this aetiology leading to a coagulopathy independently of COVID-19 and this is contrasted with the evidence for this aetiology leading to a coag- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . Table 35 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Host Immune Response Again since our enquiry focused on the coagulopathy, the model can be described as per the introduction section on the host response and this is reflected in the diagrammatic mapping. We have characterised the pathological response as one which may have led to the coagulopathy. We have divided up the pathological host immune response into the general mechanisms common to both innate and adaptive immune response (cytokines), innate immune response (NETs and complement pathway), adaptive immune response (antiphophospholipid antibody syndrome-like coagulopathy), immunothrombosis, type III hypersensitivity and recognised coagulopathiessepsis-induced coagulopathy and DIC although this can occur independently of the immune-response we have included it with sepsis in COVID-19. B2a1.IL-6-associated coagulopathy. In the non-COVID-19 literature, there is evidence of an association between elevated IL-6 levels and stroke as well as a suggested putative mechanism to mediate a coagulopathy. In COVID-19 there is controversy regarding elevation of IL-6 levels. B2b. Cytokine storm. There is evidence of procoagulant effects of several cytokines in the non-COVID-19 literature. In COVID-19 there is a suggestion that the cytokine storm could lead to ARDS and there is an association between cytokine levels and severity of illness although a causal direction is unclear from the literature we reviewed. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint B3a. Alternative complement pathway activation: In the non-COVID-19 literature, there is evidence of involvement of the alternative complement pathway in type III hypersensitivity. There is evidence of alternative complement pathway activation in COVID-19 and evidence for vasculitis and collapsing glomerulopathy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint thrombogenic. There is strong evidence in COVID-19 of a vasculitis and a type III hypersensitivity reaction. In the non-COVID-19-related literature there is strong evidence of a sepsis-induced coagulopathy and this is the basis for the SIC score. There is evidence of an elevated SIC score in COVID-19 although this still requires a clarification of the mechanisms unless there is overlap with other mechanisms described here. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint C4. Dehydration. There is strong evidence in the non-COVID-19-related literature between dehydration and stroke risk or a coagulopathy. There is strong evidence in COVID-19 for fever and diarrhoea although we did not find direct evidence of dehydration. Indeed the hyponatraemia and evidence for SIADH as well as disrupted RAA axis suggests this relationship may be complex. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. There is a well-established relationship between vasculitis and thrombosis and there is strong evidence of vasculitis occurring in COVID-19. D1b2. Cardioembolism secondary to cardiac injury. There are various types of cardiac injury and these can predispose directly or indirectly to thrombogenesis including through arrhythmias such as atrial fibrillation. There are a number of cases of cardiac thrombi in COVID-19 we identified but we did not identify evidence to suggest a direct link with cardiac injury. D1b3. Secondary to cardiogenic shock. There is evidence in the non-COVID-19 literature of an association between cardiogenic shock and coagulopathy. In COVID-19 there is evidence of cardogenic shock which is prognostic and associated with evidence of SARS-COV2 myocardial invasion. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 19 may be significantly different from non-COVID-19 ARDS, sufficiently so to merit a distinct construct but for the model we assume it is valid. D3a. Direct nervous system injury leading to coagulopathy. We found limited evidence for this in COVID-19 other than a case of necrotising encephalopathy and a case of encephalopathy preceding stroke. E1. Immobilisation/Bed Rest. The relationship with thromboembolism particularly DVT is well-established in the non-COVID-19-related literature although we did not find specific evidence in COVID-19. E2. Dehydration due to fever, diarrhoea. See C4. F1. Critical-illness encephalopathy. There is some evidence in the non-COVID-19-related literature with an association between critical-illness encephalopathy and coagulopathy but this is in the context of severe comorbidity and risk factors. We found limited evidence of an association in COVID-19 and there is overlap with D3a. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint We will now discuss our results, dividing this up into a general discussion of the findings, gaps in knowledge, a model of COVID-19-related coagulopathy, drawbacks of the study and then the next steps followed by a summary. In our mixed methods scoping review, we were able to identify clinical evidence of a COVID-19-related coagulopathy. We found evidence of ARDS, sepsis and disseminated intravascular coagulation in cases with thromboembolic complications. However we also found evidence of cases where ARDS, sepsis or disseminated intravascular coagulation had either not been confirmed or else had been excluded. Since ARDS, sepsis and disseminated intravascular coagulation have well-established causal links with thromboembolic events ARDS, disseminated intravascular coagulation and sepsis are likely to account for a subset of the thromboembolic events seen in COVID-19. Given the evidence for additional mechanisms associated with coagulopathy, we can demonstrate more generally that COVID-19 is a polycoagulopathy mediated by multiple coagulation mechanisms (MCM's). The mechanisms for sepsis-induced coagulopathy (SIC) were unclear although there are criteria for the identification of SIC. Nevertheless (Liao et al, 2020) found that sepsis-induced coagulopathy typically preceded DIC. The non-overt DIC criteria may similarly be useful in COVID-19. Pulmonary thromboinflammation has been suggested as one of the main mechanisms leading to respiratory failure in COVID-19 (Bhattacharyya et al, 2020) and although undoubtedly important, the relationship of the pulmonary thromboinflammation to the endothelial inflammation elsewhere is not yet clear although it most likely results from viraemia. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint We found that pulmonary arterial embolism was one of the most frequent thromboembolic events. (Benito et al, 2020) found an incidence of PE's in COVID-19 of 2.6% in a cohort of patients in Barcelona. (Mackman et al, 2020) report on the incidence of thrombosis in COVID-19 in various studies and find rates differ in ICU and non-ICU settings. In ICU settings, the rates are VTE (4.8-69%), PE (16.7-35%), DVT (0.5-69%), arterial thromboembolism (3.8%), ischaemic stroke (2.7%). In non-ICU settings the rates are VTE (0.9-6.5%), Thromboembolism is unlikely to spare any vascular territory in COVID-19 although the pulmonary vasculature is likely to be commonly affected given the transmission dynamics of SARS-COV2 together with the anatomical considerations of the pulmonary vasculature. Our findings suggest that there is evidence that the thrombi formed in COVID-19 may have unusual properties which merit further investigation. (Kalinskaya et al, 2020) investigated patients with COVID-19-related coagulopathy and compared them to a control group. They used methods including rotational thromboelastometry to characterise the clots and found that in patients with COVID-19 compared to the control group they grew more quickly, to a larger size and were lysed more quickly also which fits with a number of the themes identified in the abridged thematic analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint We suggest the construct of 'residual COVID' to describe residual irreversible ischaemic damage from thromboembolic events. Given the degree of plasticity of organs such as the brain, the necessary investigation of this construct is required but is relevant in the context of the possibility of sub-clinical thromboembolism in the acute phase of the illness. The transience of the coagulopathy in COVID-19 also requires clarification. (Garg et al, 2020) report a case of a patient who had recovered from COVID-19 but developed pulmonary emboli despite treatment with warfarin although they suggested that the PCR result may have been a false negative. The application of the model of Virchow's triad to the COVID-19-related coagulopathy highlights an important distinction between the arterial and venous system. Arterial thromboembolic events are usually a result of many decades of pathology, predominantly through the development of atherosclerotic plaques. Deep vein thromboses however can occur relatively acutely and more frequently and this reflects the importance of stasis. The veins are valved and contrast anatomically with the elastic, pulsatile arteries and the blood is more prone to coagulation in the venous system with reduced mobility. With COVID-19, we see this pattern is reversed and arterial thromboembolic events occur relatively frequently and acutely even in the absence of plaques. There are two factors that are likely to account for this. Firstly there is the marked hypercoagulability. This has been commented on by nearly all of the authors in the 56 main papers and is epitomised by the clotting that occurs in the ECMO centrifuges and dialysis machines. Although clotting is seen in the ECMO centrifuge in non-COVID-19 cases, this was noted to far exceed the degree of clotting that is expected and cannot be attributed either to stasis or to endothelial involvement except via hypercoagulability. The effect of the hypercoagulability is to accentuate the usual coagulation processes. Secondly there is also . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint involvement of the vasculature with combination of different pathologies that have been identified representing the endothelial involvement in Virchow's triad. Another finding from considering the COVID-19-related coagulopathy through the prism of Virchow's triad is that cardiac involvement may represent an important aetiology for stasis. This can be mediated via atrial fibrillation as an example and the importance of myocardial involvement in COVID-19 is becoming apparent. SARS-COV2 requires the ACE-2 receptor for entry into the cells. From our literature review, we identified evidence of a potentially significant role for the ACE-2 receptor in terms of the COVID-19-related coagulopathy. Firstly there is the location of the ACE-2 receptors which determines which tissues are directly involved. The involvement of the respiratory and cardiovascular systems are particularly important in this regards. The second point relates to the effect on Angiotensin-II which is thought to be upregulated. Angiotensin-II has many effects including vasoconstriction and is thrombogenic. Thus by gaining entry to the cells via the ACE-2 receptor, SARS-COV2 sets in process a chain of events leading to an increase in the levels of circulating Angiotensin thereby potentially contributing to hypercoagulability of the blood. The in-hospital mortality although high is in keeping with other studies . The hospital sample likely represents the most severely unwell patients. We have thus characterised a syndrome that can occurs in severe cases although this does not negate this occurring in cases that are classed as less severe and this is discussed further in the next section. Whilst we had a small sample population from the subset of 34 studies there were a number of findings that would benefit from further replication studies. We found a . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint particularly high mortality in association with acute limb ischaemia and it was not clear to us why this was. For other thromboembolic events such as strokes and STEMI's there are well-established care pathways informed by evidence-based policies. Given the high infection rate of COVID-19 even rare consequences of the infection will result in high case numbers due to the size of the infected population. The sample in the 56 main papers were all hospitalised patients and given the high mortality it is reasonable to assume that they represent the most unwell patients with COVID-19. Not all severely ill patients will be hospitalised due a variety of factors depending on the local healthcare provision which varies significantly internationally. Not all patients seen in hospital may be severely ill. Additionally thromboembolic/ischaemic events may be subclinical. The question of how relevant the syndrome is to the wider population of all patients with SARS-COV2 infection would require additional information. This information could be gained retrospectively but ideally with a prospective cohort study with a comprehensive sequential assessment for thromboembolic events through the course of the acute illness. Thematic analysis is a method used in the analysis of qualitative data which can utilise both qualitative and quantitative approaches. There are three main approaches to thematic analysis: Coding book approach, coding reliability and reflexive/organic (Braun and Clarke, 2013 ). All of these approaches have one thing in commonthe coding step which is considered central to the contemporary thematic analysis approach. Although thematic analysis has been references as far back in the 1950's in psychoanalysis (Winder and Hersko, 1958 ) and further back in other fields, the modern origins of thematic analysis are cited as 'The Thematic Origins of Scientific Thought' by Gerald Holton (Holton, 1973) . In this work, Holton examines key scientific theories to understand how they were developed. Holton's . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint sense is that there are certain aspects of theory development that occur in the minds of scientists even before they begin their work and he developed an approach to try and understand these aspects. (Merton, 1975) notes that Holton appears to have used an inductive approach to the thematic analysis. Thematic analysis is a flexible method for analysis that has been used with a variety of different approaches including philosophical underpinnings. (James, 1907) . We argue that in a pandemic, there is a strong ethical imperative to utilise and make available a methodology for rapidly analysing clinical literature to gain invaluable insights and generate understanding and testable models. Ironically it is pragmatism that led to the school of behaviourism which in turn led to response items in psychological testing which in turn can be viewed as eliciting a reactionary approach in terms of the reflexive approach that can be used in thematic analysis. The coding approach becomes impractical in the analysis of large numbers of studies and sampling is not appropriate as we had to examine all of the identified studies to extract the themes we arrived at. Thus pragmatism has provided the philosophical underpinning for the carefully considered is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint step of removing the coding step although there are further considerations in terms of ATA and Validated Abridged Thematic Analysis (VATA). ATA is justified by analysing material which is linked to an established academic field. Whereas the usual aim of thematic analysis is to describe the themes within the material, our further aim is to gain insights into COVID-19 in the midst of a pandemic. This further aim provides resource constraints including time and also the limited resources we had available to undertake the analysis. The analysis of the clinical material is most likely to be undertaken by frontline clinicians who are treating patients and who in the absence of large scale research institution support would work with limited research resources. ATA is a suitable tool in these situations, meeting the need for clinicians to rapidly develop an expert clinical knowledge base to provide care for those with COVID-19. In a more recent study (Janardhan et al, 2020) confirmed a subset of the findings from our abridged thematic analysis including COVID-19-associated clots being refractory and susceptible to rethrombosis and reocclusions and these findings provide some validation of our approach. They also suggest the primacy of the coagulopathy in COVID-19. Turning to VATA, we needed to pivot firstly from understanding the perspectives of clinical experts in various fields and then hold in mind that our aim was to understand a viral illness. We therefore needed to validate our taxonomy which is the structuring of the themes we identified and of the themes themselves against the wider perspectives of experts across diverse fields. Whilst this may seem an ambitious undertaking, there is a simple reality here which is that all frontline clinicians in a pandemic are faced with providing care for people affected by a novel infectious agent with potentially serious outcomes. In medicine this applies without exception to all medical practitioners (e.g. acute and general physicians, psychiatrists, general practitioners and surgeons). This also applies to nurses, allied health professionals and all of the other essential staff in hospital and community settings and it is . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint imperative that clear and accurate information is provided to patients and the public. COVID-19 is a multi-system disorder which crosses isolated areas of specialist practice and presents not only a significant clinical challenge but an immensely complex theoretical challenge. This is a time when silos of knowledge and training must be restructured to allow for rapid joined-up learning to enable us as a health and social care community to face a common and serious challenge and further to allow us as a global community to face this challenge with the conversations and debates that are so essential. VATA enabled us to gain insights from a diverse range of clinical experts that we ourselves would never have gained otherwise. There are many knowledge gaps identified from this scoping review and we have included a selection of specific knowledge gaps that may help to inform future studies. (Tibirica and De Lorenzo, 2020) suggest a number of approaches to investigate the microvasculature and microvascular flow in critically ill patients with COVID-19 including laser Doppler perfusion monitoring, hand-held sidestream dark field imaging and reactive hyperemia-peripheral arterial tonometry. The spleen is a secondary lymphoid tissue. From the (Williamson et al, 2020) study there was a suggestion that splenectomy is associated with a higher risk of death in COVID-19 although this did not reach significance. There is evidence that COVID-19 can result in pathological changes in the spleen. There is also evidence that post-splenectomy there is . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. an increased risk of thrombosis. This suggests that understanding the role of the spleen in COVID-19 may shed further light on aspects of the COVID-19-related coagulopathy. Does coagulopathy persist in COVID-19 after the acute illness has ended? There are different permutations such as venous-arterial and venous-venous. Do the different configurations have different risks of thrombosis given the anatomical distinction between the veins and arteries and the nature of any COVID-19-related vasculopathy. As there is a potentially significant role for Angiotensin-II in COVID-19 and in relation to hypercoagulability, is there evidence that drugs acting on the Renin-Angiotensin-Aldosterone system affect the relevant coagulation parameters? F. What is the role of Endothelial stabilising agents in COVID-19? (Weinbaum et al, 2020) review the role of glycocalyx in various vascular-related diseases and note that the glycocalyx is a target for influenza viruses as well as SARS-COV. They also review a number of therapeutic agents for stabilising the glycocalyx. note that Adrenomedullin plays an important role in stabilising the endothelium in infection and call for an investigation of the role of Adrenomedullin in COVID-19. One study found that Adrenomedullin RNA was increased in patients with severe COVID-19 compared to mild illness (Hupf et al, 2020 ). . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Kaafareni et al, 2020) have presented interesting findings in a case of mesenteric ischaemia which was accompanied by a pattern of yellow tissue overlying areas of ischaemia. This can be seen clearly in the paper by (Gartland and Velmahos, 2020) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint There were a number of drawbacks in the study. (Makin and Orban de Xivry, 2019) We used a few search terms and the search strategy was not sophisticated. We justify this by the balance of getting quick answers in a pandemic and also by our limited resources. Had we detected a larger number of papers then the analysis would have taken much longer and so this offered a pragmatic solution. Despite the simplicity of the search strategy, we did identify relevant papers which provided a range of useful results. The less rigorous approach to the search strategy was justified by our novel methodology which enabled us to extract useful information from the papers and to validate this using a further literature search and review. We used search terms which could have biased the study towards identifying throm- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint We acknowledge the limitations of the unstructured search strategy. The goal of this search was not to be definitive in answering questions but primarily to explore and test the various hypotheses that had been generated as the validation stage of the There is a widely recognised phenomenon of positive findings being published in the clinical literature which could have biased us towards overestimating the strength of evidence for a hypothesis. Whilst we acknowledge this we would point out that certain hypotheses were discounted by this process and that we propose a methodology for extending the model which would enable others to correct the errors resulting from biases with more rigorous approaches. Additionally we had also included systematic reviews and meta-analyses which typically address these issues. The omission of coding was a pragmatic decision which is based on theoretical considerations as outlined (see also the section on philosophical considerations). Whilst it may be prone to omissions and misinterpretation, the meaning we have sought is in established knowledge domains and we have triangulated this with other research publications when looking at aetiologies to determine content validity. This method of confirming content validity is not present in other approaches we have seen even is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint when they have included coding. Whilst there is a risk of omission due to oversight, we have judged the benefits to outweigh the risks in terms of rapidly summarising themes from a large number of papers where this would not have been practically possible with the usual coding process. Again we have provided a strategic methodology that enables other researchers to address any shortcomings in our work and to thereby improve the overall understanding. We acknowledge for the quantitative aspects of the study and the qualitative analysis of the clinical features of the thromboembolic events that the patient sample were people with more severe COVID-19. However a number of patients had experienced thromboembolic events after a period of being asymptomatic or having mild symptoms. Additionally the VATA and model-building drew on a wider literature base. Although not generalisable to all patients with COVID-19 we have characterised a syndrome that results from COVID-19. Here we outline hypotheses generated from the findings. The purpose of this section is to provide clinicians and scientists with hypotheses for further testing. We provide comments on the strength of the evidence informing these hypotheses. Our findings revealed a significant difference in the frequency of reported venous and arterial thromboembolic/ischaemic events in the selected papers we identified. An adult case of Kawasaki-like disease in COVID-19 has been reported (Shaigany et al, 2020) and we have is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint reviewed the evidence for endothelial dysfunction, endotheliitis and vasculitis all of which suggest the involvement of the vasculature in the pathogenesis of COVID-19. The above hypothesis does not negate the presence of venous thromboembolism but instead refers to the strong evidence for arterial thromboembolism. In so doing, we have also taken the unusual step of including the pulmonary arteries as separate from the venous circulation purely on the grounds of the anatomical structure of the arteries which shares an embryological origin with the aorta. This distinction is important in terms of the location and density of the ACE-2 receptors in smooth muscle cells in arterial walls in comparison with the veins as well as the difference in blood flow dynamics and shear stress. From the 56 main papers, we found evidence for thromboembolic events in all of these territories. This does not negate the occurrence of thromboembolic events in other arterial territories including the aorta but it emphasises clinically important locations with evidence from the literature. In most of the studies there was not a control group although there was indirect evidence of an increase in local incidence and where there were control groups this provided further supportive evidence. The occurrence in these territories would have implications for diagnostics, community and hospital surveillance and public health campaigns and it is therefore important to test this hypothesis further. Systematic reviews or meta-analyses could investigate the question of incidence, the involvement of other territories as well as the likelihood of diagnosis in different settings. Further case studies and case series would be invaluable in providing further supporting evidence, data on key variables as per the recommendations section and also providing additional clinical acumen for qualitative analyses. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint From the analysis of 34 papers, we found that the arterial ischaemic pathology in the 5 main territories was 7.6-35%. The overall mortality is much higher than expected in COVID- 19 and suggests that the sample is not representative of the total population of people who develop COVID-19 (we include asymptomatic people in this generalisation). This may be due to selection bias in the cases that have been selected for publication all of whom are in a hospital setting. However the arterial ischaemic pathology may be less likely in the total population than the hospital setting alone. From the analysis of 34 papers, we found that stroke occurred in 27.7% of cases. This owed partly to the selection bias from the search strategy. Of those cases that were reported, the majority were large vessel strokes predominantly affecting the middle cerebral arteries. Additionally as this is a select population in a hospital setting with more severe COVID-19, the significance of the percentage of cases is limited to this setting and severity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint emboli, evidence of direct viral invasion of the carotid endothelium or physiological evidence of involvement of the carotid body. Additionally it has been suggested that in the case of large vessel strokes, carotid involvement is excluded in COVID-19. Competing hypotheses would include carotid artery involvement as an incidental finding or extension of vascular involvement to neighbouring arterial territories (e.g. middle cerebral artery) consistent with a vasculopathy. From the qualitative analysis of the 56 main papers, we identified multi-territory involvement in the same patient. These findings were commented on by authors. Further evidence would be needed in the form of case reports and estimation of prevalence. From the qualitative analysis of the 56 main papers, one group reported a high risk of embolisation during mechanical thrombectomy in large vessel stroke confirmed by different surgeons and using varied techniques. If the thrombi have a high risk of embolisation then in combination with a putative extension of vascular involvement along arterial walls this would increase the risk of involvement of multiple territories. Further case reports and quantification of the effect would provide further valuable evidence and the latter could be investigated using a meta-analysis or systematic review. Women are more likely than men to die from pulmonary emboli in COVID- This hypothesis is based on an analysis of 34 studies and with a relatively small number of cases. This is not an a priori hypothesis and would need to be tested in a more robust way is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; with a systematic review or meta-analysis or with original data and should be regarded with an abundance of caution until such evidence is available. Men are more likely than women to die from acute myocardial infarcts in This hypothesis is based on an analysis of 34 studies and as with hypothesis 8 is not an a priori hypothesis,and is based on small numbers and should again be viewed with an abundance of caution. Again this is based on the analysis in the 34 studies and should be considered with due caution. Again this is based on the analysis in the 34 studies and should be interpreted with the caveats for hypothesis 8. Women are more likely than men to die from acute limb ischaemia in This is based on the analysis in the 34 studies and should be considered with the caveats for hypothesis 8. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. Following on from Hypothesis 2, arterial thromboemboli in the five main territories would be expected to be associated with characteristic findings which include ischaemic events such as stroke. Whilst there is a degree of plasticity with stroke depending on a number of factors, there is also an element of irreversibility due to tissue destruction. We would term this irreversible loss of function as Residual-COVID as recovery of function would not be expected. Ischaemic lesions could be thus described on the basis of the established literature in other conditions. There may be other aspects of the pathology in COVID-19 that would fit into this category. Based on our findings, we hypothesise that a pre-existing vulnerability to coagulopathy combines synergistically with COVID-19 to increase the risk of coagulopathy further. The purpose of a scoping review is to review the subject area in preparation for further research. In this regards, we divide the proposed next steps into three. Firstly there are the immediate recommendations for reporting in papers in this area so as to move towards a standardised approach which will facilitate data aggregation. Secondly we recommend . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint specific processes that will facilitate a decentralised research program (DRP). Thirdly we make recommendations about developing a symbolic representation of causal links. This has a more general usage case than the COVID-19-related coagulopathy but this recommendation results from the problems that have been encountered both in terms of healthcare delivery in the pandemic as well as the challenges we have faced in writing this paper. This third type of recommendation requires a more profound change in practice and may not be achievable in the short-term but is particularly well-suited to meeting the challenges of a pandemic. A scoping review is limited in comparison with a systematic review or meta-analysis in the recommendations that can be made. Whilst we make no health policy recommendations, we are able to make recommendations specifically for the methodology of research publications in this area. This is justified as we have evaluated the methodology of a significant number of publications as reported here. In our paper, we have analysed the themes from the research literature including case reports and case series and have generated hypotheses for further testing on the basis of these findings. Case reports and case series are an accessible way for clinicians to communicate their findings in a timely way which is essential in the current pandemic. There has been criticism of case reports and case series as lacking the rigour of randomised controlled trials (RCT's) (Jung et al, 2020) . However as we have demonstrated, such publications can bring valuable insights that not even RCT's may offer. Indeed the problems posed by the COVID-19 pandemic have disrupted research (Kimmel et al, 2020) and caused a reappraisal of the role of different types of evidence (Greenhalgh, 2020) . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Recommendation 2: Clinical researchers reporting on clotting disorders should use a standardised approach. In our paper, we demonstrated that there was significant heterogeneity in the reporting of clinical data resulting in incomplete datasets for variables of interest. For instance, the care setting (e.g. ICU) contextualises the clinical data and findings may not generalise to other settings. Therefore the absence of such data from clinical cases can pose a challenge for including the data in a systematic review or meta-analysis. The use of a standardised dataset facilitates the extraction of further insights from analysis of the aggregated data. We provide a template for reporting. We found that case studies offered a rich albeit heterogenous source of data and with cohort studies, aggregation of data removed the possibility of secondary analyses of certain aspects of the data. We recommend reporting the gender of the patient when reporting on COVID-19-related coagulopathy. We have detected gender differences in mortality for the different types of thromboembolic/ischaemic events and we would recommend reporting on gender. We demonstrated in our findings that a diagnosis of ARDS was not always mentioned in papers either as confirmed or excluded. Since ARDS is associated with a coagulopathy and has an important association with sepsis as well as specific treatment pathways, it is essential both in the interpretation of the clinical data and for the further analysis of aggregated data. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint ARDS is an important pathology to exclude or confirm when evaluating clotting disorders in COVID-19. Whilst this is mainly seen in the ICU setting, ARDS exists along a continuum and cases may develop in the general ward setting. The potential for silent hypoxia which has been described in COVID-19 reinforces the need for an exclusion of ARDS when reporting clotting disorders in COVID-19. Since the PaO2/FiO2 interpretation involves the positive end-expiratory pressure (PEEP) or CPAP values or which are typically available only in an ICU or HDU settings an alternative is required for general settings. The Kigali modification of the Berlin definition allows the calculations to be made using the ratio SpO2/FiO2 (Riviello et al, 2016) and is a simple practical tool for clinician when reporting on an important differential in a case report or case series. where available. Disseminated intravascular coagulation is an important differential in COVID-19-related coagulopathy and a diagnosis inclusion or exclusion should be reported where available. Sepsis is an important differential in COVID-19 and particularly in terms of coagulopathy. We recommend reporting on whether mechanical ventilation was used. The association of mechanical ventilation with pulmonary coagulopathy means that this is an important differential in any consideration of COVID-19-related coagulopathy. This also . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint emphasises the importance of multidisciplinary publishing where the patient has been treated in multiple settings. We recommend reporting on the oxygen saturation at the time at which thromboembolic events are diagnosed. As hypoxia is a mediator of coagulopathy and a central feature of ARDS, the reporting of hypoxia in publications is important. The importance of cardiogenic shock and myocardial involvement in COVID-19-related coagulopathy has been discussed and would be an important differential. This is a differential that should be included for the purposes of evaluation and further analysis. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint We recommend that data on the mobility of patients are reported in publications. In this regards, general comments on whether the patient was restricted to bed without activity throughout a period of hospitalisation or in the community are helpful in identifying an important aetiology. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Reporting the prothrombin time is useful given the role of prothrombin time in the diagnosis of DIC. We recommend that alternative complement pathway biomarkers are reported where available. There is emerging evidence of a role for the alternative complement pathway in COVID-19 and so further information on this will be very useful. We recommend that Protein C levels are reported where available. but where further information will be needed. We recommend that Antithrombin III levels are reported where available. Antithrombin III is also useful for the evaluation of non-overt DIC which may be relevant in COVID-19 and further information is needed. IL-6 is key in many inflammatory processes that may be relevant to COVID-19 related-coagulopathy. Reporting of the full extent of investigations would be helpful in estimating the prevalence of venous and arterial thromboembolic events. In many of the studies, the patients are severely ill and the focus may be on managing other aspects of the presentation. Having an understanding of the extent of investigation for thromboembolic events would allow aggregated data to be analysed according to actively investigated arterial and venous territories. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. In a number of cases the location of ischaemic areas was reported rather than the arteries supplying those areas. Attempts to estimate the arterial territories are prone to errors due to anatomical considerations (e.g. circle of Willis connecting arterial territories) as well as individual anatomical variation although the latter is less likely to result in error. We recommend reporting the Dublin-Boston score if IL-6 and IL-10 levels are available. Given the controversies around the IL-6 levels, we recommend using the Dublin-Boston score given the prognostic value (McElvaney et al, 2020) . We recommend using the checklist in Table 36 when publishing original data on COVID-19-related coagulopathy and refining the checklist where necessary. The checklist is also provided in the supplementary data section. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. Clinicians are on the frontline of this pandemic and the experience of clinicians is essential both in publishing findings and also translating research findings including trial outcomes into clinical practice. Our proposal focuses on the frontline clinician who is typically not wellresourced for research unless participating in large trials and who will have varying degrees of clinical research experience. We propose a crowdsourcing approach to facilitate COVID-19 research in the pandemic. Crowdsourcing approaches have already been utilised in a number of clinical areas (Thompson and Bentzien, 2020) , , (Lacourse et al, 2020) and with a crowdsourcing approach it is possible to equal or even surpass largescale well-resourced endeavours in terms of outcomes. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. We would anticipate that after a few revisions, the clinical model may be unrecognisable from the original as the model more closely approximates reality with subsequent expert review as well as clinical and basic research findings. We outline briefly how clinicians and researchers can advance the model developed in this paper. We recognised that there are a great many talented clinicians and researchers around the world who would have insights, expertise and experience that would enable them to see flaws in our work. This is the nature of science and to expose these flaws and improve upon them is a measure of success in science for we approach ever more closely to the truth although possibly still only approximating. This matter is also complicated by the nature of systems biology. We provide the outline of a toolbox which has the following components 1. ATA. The abridged thematic analysis is a simple approach which enables the clinician/researcher to rapidly identify COVID-19-related themes in the literature. This is outlined in the methodology section and the discussion sections in more detail. This can be combined with systematic reviews and meta-analyses to produce mixedmethods approaches. These in turn can inform policy and investigate more narrow domains of enquiry than we have considered here. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 2. VATA. The validated abridged thematic analysis is an extension of ATA and involves the additional step of an exploratory literature search to validate the taxonomy generated by the ATA. The exploratory literature search can be refined and systematised as necessary and there is much scope for improving upon our approach. 3. Taxonomy. Our taxonomy for COVID-19-related coagulopathy is outlined in Table 35 . This can be used in a number of ways. Thus a publication could be based solely on updating the whole or part of the Table on is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 8. Keys and locks Model. All of items 1-7 can be included in papers but particularly 3-7. In this manner a series of research papers can become interlocked with each other, one publication responding to another and a further publication responding to that one. A chain is thus formed and can be tracked through the references and be linked to successive revisions of the taxonomy or other aspects of the toolbox. 10. Tracking publications that use the toolbox. Papers could be shared using headings which identify the toolbox so that they are more easily found e.g. hashtags on social media platforms. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 clinical signs as in the case of chilblains relating to the interferon response. By this means it is possible to represent the process from increased levels of circulating molecules through to the clinical features including signs and symptoms. We note that symptoms are a response of the mind to pathophysiological events and thus for any inclusion of symptoms or indeed psychological stressors or other factors the model would rightly be considered psychopathophysiological. We have developed a simple set of rules for describing the relationships. Thus a simple line denotes an 'example of' rather than a causal relationship. We have also included causal relationships and colour coded them into weak, moderate and strong evidence both for COVID-19 specifically and separately for the more general non-COVID-19-related cases. By this simple set of rules, we are able to take our earlier analysis and translate it into simple diagrams which illustrate relationships between concepts. Whilst this may appear straightforward enough, there is a further point to this in that the diagrams are not an end to themselves but rather as symbolic representations open up further possibilities related to a decentralised research program. As a scoping review, we consider this as a starting point. In future iterations the rule set can be modified thus offering various possibilitiesthey may be maintained, expanded or replaced but with the intention that they become generally more useful or else more useful for certain applications of the model. For example, the rule set can be expanded to include associations and thereby incorporate the findings from additional research studies or else allocate associations to existing causal relationships where they are considered more appropriate (e.g. elevated IL-6 and stroke). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint In the diagram mapping, we have utilised non-COVID-19-related research to demonstrate relationships between concepts. In the COVID-19 pandemic, the medical community has been required to respond to a novel pathogen which can lead to severe illness without the advantage of years or decades of research into the treatment approaches. In this context it is possible to start with some assumptions about the virus and the subsequent illness is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org /10.1101 The purpose of the inductive model is to provide an underlying framework for understanding the COVID-19-related pathology and to generate hypotheses for testing in COVID-19. To give an example, there is evidence that Angiotensin II leads to thromboinflammation in non-COVID-19-related research although we did not find this evidence in the literature we examined for COVID-19 although it is entirely plausible and can be extrapolated through induction. However if this were to form the basis for a therapeutic trial we may consider it too early to jump to such conclusions and this is the purpose of the diagram mapping. Instead the next step would be to formulate the hypothesis that Angiotensin II leads to thromboinflammation in COVID-19 and investigate this in the usual way through case studies, case series, meta-analyses, systematic reviews, narrative reviews and various types of trials or cohort studies. In so doing, we are able to utilise the vast amount of literature on the related areas to generate further hypotheses specific to COVID-19 rather than discounting this literature as irrelevant. By using induction we may also generate a number of possible mechanisms as we examine each causal link. In this manner we may end up with a lot of ultimately irrelevant causal links. The diagrammatic mapping does not remove the irrelevancies but serves as a framework for communicating the reality of research findings which can be controversial, contradicted, irrelevant or turn up unexpected links to other areas of theory. Thus the mapping exercise simply gives us a way to visualise the complexity that alright exists but otherwise may not be so obvious. The question instead is how do we use the mapping to manage this complexity. The generation of symbolic diagrams may seem somewhat limited in application but it provides the clinician with the beginnings of an invaluable tool for clinical analysis. In clinical analysis, we are used to dealing with the analysis of laboratory results, imaging findings, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint symptoms and signs, other aspects of the clinical history as well as relating this to our readings of the clinical literature. The analysis involves direct clinical data or else a discussion of that data in text and diagrams. By developing this symbolic system we are able to perform a level of analysis which is two steps removed from the direct data. Whilst this can also be accomplished through spoken language, language is not designed specifically for this purpose but is instead a tool for generic application. In other words, the symbolic system is a specialised symbolic language designed with the intention of communicating clinical concepts and facilitating abstract analysis. A new level of analysis is possible which involves the manipulation of abstract symbols which signify clinical meaning. This opens up new avenues including the ability of the clinician to rapidly develop pattern recognition depending on the dataset and for the possibility of symbolic computation. As our scoping review was broad in nature, the diagrammatic mapping covers many subjects but to a limited depth. By inspection of the diagrams, the clinician or research is able at a glance to see areas that require improvement or with which they disagree. During the writing of this paper, we made a number of observations about the process of characterising the COVID-19-related coagulopathy. 3. The explanatory mechanisms were described in language/text in the papers we examined. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint 4. Diagrams were used in many of the papers to support the text-based description of the mechanisms. The diagrams differed in their construction, the components which were illustrated and the relationships and this included descriptions of the same concepts. 5 . In the process of diagram construction, there were a number of valid approaches that we could use to illustrate key concepts including relationships and this required investment of resources such as time. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint oversight of knowledge is required. Having an oversight of knowledge can be likened to having a map of knowledge which enables orientation. 12. COVID-19 is a complex, multi-system disorder which involves changes in the host immune and haemostatic responses. The immune and haemostatic systems communicate with each other and can themselves be associated with multi-system disorders. Additionally there is evidence of direct viral injury to multiple systems. In summary, our observations led us to conclude that there is a need for standardisation of the descriptive notation for clinically relevant pathological processes. The descriptive notation would need to describe relevant biopsychosocial domains and would need to be language independent. In short, this would need to be a clinical symbolic notation with each symbol capturing clinically relevant logical relationships or constructs. This would solve a number of the problems identified including the ability for the international clinical community to rapidly communicate important concepts (e.g. during public health emergencies) as well as facilitating cross-speciality communications. The symbolic notation would also facilitate education and training. In the final part of the next steps, we look not to the immediate future but to the intermediate and even long term future and consider the benefits of a languageless clinical symbolic notation and how this may be reached. This follows on from the diagram mapping that has been of practical benefit in communicating our results. In the pandemic, diagnostic overshadowing is possible given the multi-system nature of COVID-19. Diagnostic overshadowing as a term was originally used in the field of Learning Disability and in other areas of mental health to describe the attribution of physical illness to mental illness (Shefer et al, 2014) . We use the term diagnostic overshadowing in a more is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint general sense to describe the attribution of one illness to another regardless of whether this is a physical or mental illness and as a result of factors including symptom overlap, incapacity (e.g. to provide a history) and urgency of treatment for main differential (e.g. in the resuscitation setting). The occurrence of diagnostic overshadowing in the original context is likely to represent the challenges of hierarchical as opposed to multiaxial diagnostic systems and an analogy can be drawn with polycoagulopathy. The consideration of a polycoagulopathy as opposed to a unitary coagulopathy presents the same challenges both clinically and in the research setting. In both the research setting this also raises the question of how we should compare the pairing of inductive with deductive reasoning versus inductive with abductive reasoning. In clinical medicine we are dealing with the whole, also referred to as holistic or integrated. In effect we are dealing with systems biology and this is done routinely in clinical practice. When dealing with this in clinical practice, the clinician will readily understand what we mean by clinical intuition and that clinical medicine is an art as well as a science and a technology (application of clinical knowledge). The clinician must quickly deal with clinical matters by means of the clinical assessment which involves the history, examination and an analysis of the results of the various investigations. The clinician thereby builds up an intuitive understanding of the whole picture, with an often understated but necessary reference to the systems biology of the patient. Consider a case in which there is an acute deterioration in renal function. How will this impact on the clearance of medication? How will this impact on the history and in what way will that impact on the interpretation of other aspects of the history? How will this in turn impact on the evaluation of cognition as a marker of mind and brain function? These few questions hint at the many layers of complexity that the clinician must routinely evaluate. There is a hidden layer in communication whereby the many links that the clinician makes in an instant are hidden from view. The clinician may be unaware of these tiny steps as they is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint arrive quickly at the correct diagnosis. The question of how the mind runs through many tens or even hundreds of steps to arrive at an apparently simple answer to a question is addressed elegantly by (Hofstadter, 1979 ). On encountering a clinical problem, the clinician's mind races intuitively through many steps. The years and decades of meticulous study, training and experience will lead the mind's direction of inquiry almost imperceptibly but if that is unpacked we may expect to see a depth of understanding and consideration of systems biology. We may draw an analogy to the classic studies of psychology Professor Van der Groot who investigated the abilities of chess players. His subjects ranged from novices to former world champions such as Alexander Alekhine and Dr Max Euwe. Van der Groot found that the expert player was able to recall substantially more of chess positions than novices even after a short glance at the board (de Groot, 1965). Subsequent work by (Chase and Simon, 1973) determined that brain divided the chess positions into chunks and that stronger players utilised 'larger' chunks. As per (Hofstadter, 1979) , (de Groot, 1965) and (Chase and Simon, 1973) , Dr Sigmund Freud and Dr Carl Jung both understood the importance of symbols in the unconscious mind (Freud, 1913) (Jung, 1964) . We hereby propose that a clinical symbolic notation would provide clinicians with a medium for expressing the hitherto unconscious aspects of their clinical reasoning and enable an improved ability to train and develop this intuition. We have in the current system a move from the analysis of the data to the diagnosis with intermediate written accounts predominantly in the form of a generalised written language albeit with specialist terminology. Spoken and written language is general in function and although a specialised clinical terminology exists, this causes the clinician to depend on verbal intelligence to communicate with writing as a correlate. The brain is capable of a range of modes of thinking which includes verbal and non-verbal. The generation of a . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. With clinical symbols having meaning and attached to a set of logical rules including their interrelationship with other symbols, they have computable properties. Provided there is a sufficient set of symbols and that they become routinely used in clinical practice, then the computable properties of these symbols offers up completely new approaches in clinical medicine. The clinician may without recourse to spoken or written language, assess their clinical intuition according to their interaction with an abstract symbolic set. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Precision medicine is the application of "individual variability in genes, environment, and lifestyle" into the treatment of cancer and then into other areas of medicine (Collins et al, 2016) . With the expansion of knowledge resulting from other branches of science, precision medicine can be interpreted more broadly as the application of an ever increasing body of scientific knowledge to medicine. This knowledge occupies the space between the clinical data and the diagnosis, this intermediate zone that the clinician may also deal with intuitively. With the abundant scientific data available, it is possible to answer questions about the data computationally and there is no shortage of questions that can be asked. However it is this intermediate zone between clinical data and diagnosis and the intersection with the vast amount of scientific data that provides the most clinically relevant area. A clinical symbolic notation allows this area to be mapped out continuously. If this were mapped out on a venn diagram with the intermediate zone and the total body of biological science data, then the intersection would be an area of particular interest. This intersection would be an area where symbolic computation solutions would be expected to develop more rapidly given the potential for clinical application. Additionally areas of basic science which were able to demonstrate links to this intersection would potentially be more able to secure research funding. A directory linked to this intersection would enable clinical groups to more easily establish connections with relevant researchers and vice versa. The symbolic notation would enable many of the missing steps in clinical thinking to be captured as a practical symbolic language would exist to capture this with the aid of simple software tools such as autocompletion, frequently used structures, keyboard shortcuts and menus. Decision-support tools would reach a more sophisticated level as the computation reaches closer to biological reality and thereby becomes more ecologically valid. Education would be transformed. (Sadler and Regan, 2019 ) have written about the success of AlphaZero, an artificial intelligence chess program that was programmed to teach itself to . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint play chess and which has achieved a considerable degree of success in this endeavour playing with human-like strategic manoeuvres which at times are incomprehensible, long before reaching positions reminiscent of some of the greatest strategic chess players such as Anatoly Karpov. (Sadler and Regan, 2019) have demonstrated in their work that valuable insights can be obtained for human chess players to learn from and improve their play based upon an analysis of the games of AlphaZero. Chess is a useful analogy for medicine as both involve considerable cognitive demands and where methodical study can improve performance. To draw an analogy, if similar achievements were possible for programs that were applied to clinical symbolic notation datasets then medical students of the future could receive training from software programs with deep insights into clinical medicine. By assessing clinical intuition using symbolic structures, algorithms could be developed which are able to ever more effectively train the doctors of the future to improve their clinical intuition in ways which could potentially be incomprehensible to humans or even tailored so that they are understandable. This would enable the possibility of accelerated programs which is of direct relevance to the early graduation of medical students that we have witnessed in this pandemic. Lastly it is important to note that first and foremost this notation is for the frontline clinician and the primary driver should be that the notation in the most basic format should be intuitive enough for the clinician to be able to use including students. While silos may develop, they would be distinct from the basic notational system which would be universally available. The road to a languageless clinical symbolic notation faces many challenges but also partially mapped routes. The field of semiotics which is closely related to the philosophy of pragmatism is the study of symbols (Chandler, 2017) . With the development of Emojis is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint (Danesi, 2016) , while practically useful and bringing benefits to mass communication, demonstrates the success of such an endeavour. The use of Emoji's has been closely aligned with the use of mobile devices and social media. Standardisation of clinical practice has precedents. Thus Karl Jaspers transformed the practice of psychiatry by developing the field of psychopathology after he observed different approaches to psychiatric history taking (Jaspers, 1997) . The International Statistical Institute was responsible for the development of the International Classification of Diseases (WHO, 2020) demonstrating that other disciplines can have a profound influence on the course of medicine. There are also profound barriers to the development of a standardised symbolic clinical notation SSCN. The most important principle is that any symbolic clinical notation system becomes a de facto language and that in turn is dependent on a social contract. Thus the SSCN cannot develop simply on the basis of a range of potential benefits but occurs secondary to a cultural change. In modern healthcare practice, such changes in culture require funding as IT changes to support sustainable infrastructure requires investment. This is usually tied up with performance data and so realistically these changes are likely to happen when the utilisation of a standardised symbolic clinical notation becomes a billable activity. This in turn requires considerable planning. Any alternatives would require creative funding or open-source approaches. A different route is for the SSCN to be developed by related groups such as in research settings. (Kuhn, 1962) comments that individual scientific communities develop their own specialised languages and so if this is developed by smaller communities, the notation may be quite specialised and perhaps not useful to clinicians. Indeed such notations exist within chemistry for instance. This is distinct from the notation that is required in clinical medicine which covers multiple ontological levels and requires different logical rule sets. The solution may to better define the transitional zone and for the research communities to work towards . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint a portion of their symbolic notation which can be understood and used by clinicians. This would provide a potential route to research funding. If sufficient research groups adopted this approach, the transitional zone would slowly emerge and the foundation would be cemented by congresses which bring together the different groups to bring about standardisation. From this point it may then be possible to build a case for billable activities and subsequent mainstreaming. There are other routes also. The use of social media may enable the development of apps to experiment with this approach for clinicians using social media. Additional the use of GitHub could draw upon the international developer community to create open source solutions that address many of the challenges of an SSCN. The challenges include the construction of a symbolic system which may eventually need to describe thousands of concepts and which therefore may require large numbers of pixels and standardised approaches for graphical design (e.g. rules for utilisation of a grid-like framework). We conclude with a summary of the main findings in this paper and determine from our evidence that SARS-COV2 infection leads to a viral clotting fever syndrome with high mortality. COVID-19 is a polycoagulopathy with multiple clotting mechanisms (MCM's) causing serious clinical thromboembolic sequalae. Our findings are based on a population that was hospitalised and where there was evidence of more advanced age. Fever occurred in most but not all of the patients with this presentation and therefore the clotting fever syndrome is an indication that if both fever and clotting events occur that COVID-19 should be considered as a differential. The absence of fever or thromboembolic events should not discount COVID-19 as a differential and the respiratory as well as other manifestations contribute to a variable presentation. The D-dimer is a key prognostic indicator in COVID-19 and bears special significance as a marker of underlying thromboembolic events as per our results. In is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint the most severe cases, the D-Dimers were elevated up to some 200-fold over the upper limit of the reference range and had significant clinical correlates. Overall we found an average of 1.3 thromboembolic events per patient but these were predominantly arterial rather than venous in nature albeit where we had classified pulmonary emboli as arterial rather than venous on the basis of the vessel anatomy rather than the consideration of the flow of blood towards or away from the heart. This is particularly relevant in COVID-19 given the distribution of ACE-2 receptors in the smooth muscle cells which in turn are more densely arranged in the arterial vasculature. Of note is that we found not a single case of pulmonary vein thrombosis in the 56 main papers whilst pulmonary arterial emboli were found in abundance. We found that there were five main groups of arterial thromboembolic events according to arterial territoriessplanchnic arteries, coronary arteries, pulmonary arteries, the femoral and other arteries of the lower limbs as well as the cortical and subcortical arterial supply but particularly the middle cerebral arteries. The involvement of these territories leads to characteristic signs and symptoms which are well-established in the literature and where further work can lead to clinical algorithms and the development of public health messages with sufficient evidence. We also identified carotid artery thromboemboli in association with strokes and many authors drew attention to this important finding. Thrombi were also found in the aorta and the heart. We found sporadic reports of the involvement of the veins with the exception of the deep veins in the lower limbs which were more frequently identified. Of special note is the occurrence of thromboembolic/clotting events in association with medical devices which we use broadly to include catheters, ECMO centrifuges and dialysis machines. The occurrence of upper limb DVT's was predominantly associated with catheters. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint A combination of more general factors in the setting of either mild or severe illness may also contribute. The insensible fluid loss from diarrhoea and vomiting may lead to dehydration and electrolyte disturbances. Periods of immobility may increase the risk of a lower limb DVT. Hypokalaemia and hyponatraemia may both predispose to atrial fibrillation which in turn results in cardiac muscle stasis and generation of thrombi and subsequent thromboembolic events. The disruption of the RAA system may impact on the correction of these disturbances. On analysis of a subset of papers, we were able to quantify other findings albeit on the basis of a small sample size which limits our ability to generalise these findings and suggests that these findings need to be further validated. We found sex differences amongst the occurrence of arterial thromboembolic events as well as differences in mortality. We draw special attention to the occurrence of acute limb ischaemia in COVID-19 which is associated with a particularly high mortality albeit with evidence of selection bias in the data we analysed and which merits further attention. The qualitative analysis identified the general clinical findings with an experiential (clinical) account. Thus clots were described in unusual locations, occurring in multiple territories and with unusual findings such as desert foot. During interventions, the thromboemboli were found to be friable, breaking away and further embolising into new territories. Repeated occlusion of arteries was identified after recanalisation and in one case the clot was altogether undetachable from the arterial wall necessitating an alternative surgical procedure. Thromboemboli occurred despite prophylactic anticoagulation. Patients would present with serious clinical thromboembolic events after being either asymptomatic or else with an apparently mild course of the illness. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint In terms of the validated abridged thematic analysis, we were able to assess the content validity of the proposed aetiological mechanisms by means of an examination of the literature. This was not limited to the papers screened in an exploratory literature search but also with reference to the other papers we had examined for the purposes of this scoping review. By means of an iterative process utilised in thematic analysis we were then able to assemble the selected mechanisms into a taxonomy. Furthermore we were able to translate the taxonomy into a rudimentary symbolic representation, a process which may be of use to other clinicians and researchers investigating this field of enquiry as the model can be extended and refined. In theoretical terms, we utilised Virchow's triad as a means of structuring the taxonomy. We were able to confirm overarching themes of hypercoagulability, vascular wall involvement and to a lesser degree stasis. The primary pathology would appear to be the viral invasion of the endothelium which is mediated via the ACE-2 receptors which together with heparin sulfate affords the virus a route for entry into the cells. Once inside the cells, the virus appropriates the cellular machinery and escapes RNA intracellular sensing mechanisms by means of the construction of replication organelles including double membrane vesicles. The RNA sensing mechanisms typically trigger an interferon response upon successful detection and it should be noted that the interferon response or lack thereof appears critical in determining the subsequent course of the illness. An exaggerated interferon response may result in a mild illness and possibly chilblains as a dermatological finding. A delayed interferon response may result in a more severe course and this may be of more relevance to the risk of coagulopathy and the concept of immunosenescence may also be relevant. Following the invasion of the endothelium, there is found to be endotheliitis and also various degrees of thrombosis in the small blood vessels. From our examination of the literature there appear to be many details requiring clarification but there are a few events which . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint appear to be more robustly supported in the literature. Firstly the endothelium is specialised according to the organ in which it is located. In the lungs, the blood vessels have a physiological function of ventilation-perfusion matching whilst in the kidneys this forms part of the filtration mechanism. The viral invasion appears to degrade the function of the endothelium and it would appear that together with a disruption of the RAA axis likely resulting from the utilisation of the ACE-2 receptors, there is a subsequent degradation of ventilation-perfu- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint importance and in particular endothelial dysfunction is related to the metabolic syndrome. This likely contributes to a low grade inflammatory, prothrombotic potential and a possible vulnerability to viral invasion. Another important aspect of the pathology is the role of the neutrophils. One clear finding is the presence of NETs and when taken together with the evidence of apoptosis and related mechanisms, a key feature of COVID-19 is exposure of intracellular material to the extracellular environment. Thus while the virus has carefully avoided detection in the intracellular space through the replication organelles, the intracellular material of the host cells is exposed. There is thus the potential for the host immune system to generate an autoimmune response. Furthermore if the tissue destruction is overwhelming and the clearance insufficient then there may be a large amount of circulating antibody complexes leading to a type-III hypersensitivity response in a minority of cases. This in turn can lead to deposition of immune complexes in the skin, kidneys and vasculature with the latter resulting in a vasculitis which can predispose to further thromboembolic events. Finally returning to the original question in this paper, we found evidence of thromboembolic events with and without each of sepsis, DIC and ARDS. We conclude with Tables 37 and 38 which summarise the main results of the qualitative and quantitative analysis and these should be used in conjunction with Table 35 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Breakdown of thrombembolic events in Table 8 Thromboembolism is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint B 57: 289-300. . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint a. Viral enteroneuropathy . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20228809 doi: medRxiv preprint Outbreak of a new coronavirus: what anaesthetists should know A Novel Coronavirus from Patients with Pneumonia in China Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United States Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions Korean Society of Epidemiology 2019-nCoV Task Force Team. An interim review of the epidemiological characteristics of 2019 novel coronavirus. Epidemiol Health Clustering and superspreading potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Hong Kong Erratum in: Lancet Infect Dis Semple MG; ISARIC4C investigators. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study Obesity aggravates COVID-19: a systematic review and metaanalysis SARS-CoV-2 transmission dynamics should inform policy A tale of two cities: A comparison of Hong Kong and Singapore's early strategies for the Coronavirus Disease 2019 (COVID-19) Impact of Population Mask Wearing on Covid-19 Post Lockdown. Infectious Microbes & Diseases Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical features of patients infected with 2019 novel coronavirus in Wuhan Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China Sheikh Mohammed Shariful Islam. Risk Factors Prediction, Clinical Outcomes, and Mortality of COVID-19 Patients Covid-19: What do we know about "long covid"? Extrapulmonary manifestations of COVID-19 Digestive Manifestations in Patients Hospitalized with Extrapulmonary Features of COVID-19: A Concise Review Silent hypoxia: A harbinger of clinical deterioration in patients with COVID-19 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease COVID-19 and its implications for thrombosis and anticoagulation Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd Middle East Respiratory Syndrome (MERS), and SARS-CoV-2. Reference Module in Biomedical Sciences COVID-19 and coagulative axis: review of emerging aspects in a novel disease Coronavirus biology and replication: implications for SARS-CoV-2 Virus Life Cycle. Molecular Virology of Human Pathogenic Viruses Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell Gene of the month: TMPRSS2 (transmembrane serine protease 2) The protein expression profile of ACE2 in human tissues Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation Pericyte alteration sheds light on micro-vasculopathy in COVID-19 infection Six characters in search of an author: the history of the nomenclature of coagulation factors Overview of the coagulation system How it all starts: Initiation of the clotting cascade Hippocrates of Kos, the father of clinical medicine, and Asclepiades of Bithynia, the father of molecular medicine Cardiovascular and pulmonary interactions: why Galen's misconceptions proved clinically useful for 1,300 years Historical Review. The Spleen The history and historical treatments of deep vein thrombosis Virchow and his triad: a question of attribution Virchow's triad revisited: abnormal flow The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine Acute ophthalmic artery occlusion in a COVID-19 patient on apixaban New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey Handbook of Sepsis. European Sepsis Academy Acute respiratory distress in adults Acute Respiratory Distress Syndrome. Second Edition. Informa Healthcare Sepsis in the Acute Respiratory Distress Syndrome: Treatment implications Acute Respiratory Distress Syndrome. Second Edition. Informa Healthcare Thromboinflammation in COVID-19 acute lung injury Microparticles and acute lung injury Epidemiology of Acute Lung Injury: A Public Health Perspective Acute respiratory distress syndrome: new definition, current and future therapeutic options Acute Respiratory Distress Syndrome. Second Edition. Informa Healthcare Mechanical ventilation in the Acute Respiratory Distress Syndrome Fluid therapy and hemodynamic monitoring in Acute Lung Injury Cell-based therapy for acute lung injury and Acute Respiratory Distress Syndrome Does making a diagnosis of ARDS in COVID-19 patients matter? Chest Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation on behalf of the ScientificSubcommittee on Disseminated Intravascular Coagulation of theInternational Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation Disseminated intravascular coagulation: Present and future perspective Disseminated intravascular coagulation Sepsis and disseminated intravascular coagulation Sepsis-associated disseminated intravascular coagulation and thromboembolic disease Complement, thrombotic microangiopathy and disseminated intravascular coagulation Japanese Surviving Sepsis Campaign Guideline Working Group for disseminated intravascular coagulation, and Wada H. Sepsis-associated disseminated intravascular coagulation and its differential diagnoses Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET) COVID-19 coagulopathy vs disseminated intravascular coagulation Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia COVID-19 can present with a rash and be mistaken for dengue PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation GPMB statement on the outbreak of 2019-novel Coronavirus (2019-nCoV). 30 th Chapter 5. Finding relevant studies. In An Introduction to Systematic Reviews Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases Using thematic analysis in psychology, Qualitative Research in Systematic Reviews in the Social Sciences. A Practical Guide Literature search for research planning and identification of research problem Handbook of Biological Statistics Controlling the false discovery rate: a practical and powerful approach to multiple testing Treatment of Acute Ischemic Stroke due to Large Vessel Occlusion With COVID-19: Experience From Paris Macrothrombosis and stroke in patients with mild Covid-19 infection Acute cerebral stroke with multiple infarctions and COVID-19 Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia Stroke in a young COVID -19 patient Acute Stroke Care Is at Risk in the Era of COVID-19: Experience at a Comprehensive Stroke Center in Barcelona Ictus isquémico e infección por SARS-CoV-2, ¿asociación casual o causal? Intravenous Thrombolysis for Stroke in a COVID-19 Positive Filipino Patient, a Case Report Coexistence of COVID-19 and acute ischemic stroke report of four cases Acute ischemic stroke complicating common carotid artery thrombosis during a severe COVID-19 infection Emergency room neurology in times of COVID-19: malignant ischaemic stroke and SARS-CoV-2 infection Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Acute limb ischemia in patients with COVID-19 pneumonia Acute Thrombosis of an Aortic Prosthetic Graft in a Patient with Severe COVID-19-Related Pneumonia COVID-19 With Limb Ischemic Necrosis Severe Acute Respiratory Syndrome Coronavirus 2 Infection and the Upper Limb Deep Vein Thrombosis Risk Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Vascular skin symptoms in COVID-19: a french observational study Acute intestinal ischemia in a patient with COVID-19 COVID-19-RELATED AORTIC THROMBOSIS: A REPORT OF FOUR CASES. Annals of vascular surgery Coronavirus disease 2019 (COVID-19) and ischemic colitis: An under-recognized complication. The American journal of emergency medicine Thrombophilic State 1 Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis Prevalence and Impact of Coagulation Dysfunction in COVID-19 in China: A Meta-Analysis Hemostatic Changes in Patients with COVID-19: A Meta-Analysis with Meta-Regressions Coagulation dysfunction is associated with severity of COVID-19: a meta-analysis High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there? Receptor Mediated ACE-2 mediated pathways via lung and heart binding 1. Miesbach W. Pathological Role of Angiotensin II in severe COVID-19. TH Open Hypertension-related coronary thrombosis: prothrombic role of angiotensin II COVID-19 rapid evidence summary: angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in people with or at risk of COVID-19 COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Women and Children. Front Pediatr The deleterious role of the prostaglandin E2 EP3 receptor in angiotensin II hypertension Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease Eicosanoids: the Overlooked Storm in COVID-19? Angiotensin II suppression in SARS-CoV-2 infection: a therapeutic approach Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Elife Global signatures of protein and mRNA expression levels Activation of the renin-angiotensin-aldosterone system is associated with Acute Kidney Injury in COVID-19 COVID-19: a hypothesis regarding the ventilation-perfusion mismatch Little BP. Pulmonary Vascular Manifestations of COVID-19 Pneumonia. Radiol Cardiothorac Imaging The renin-angiotensin-aldosterone system as a link between obesity and coronavirus disease 2019 severity COVID's Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19 COVID-19 Usurps Host Regulatory Networks. Front Pharmacol Angiotensin II, NADPH oxidase, and redox signaling in the vasculature A Pathophysiological Perspective on the SARS-CoV-2 Coagulopathy COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight? Med Hypotheses Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems The intracellular renin-angiotensin system: Friend or foe. Some light from the dopaminergic neurons The Plasmatic Aldosterone and C-Reactive Protein Levels, and the Severity of Covid-19: The Dyhor-19 Study Hyperinflammatory State Hemophagocytic syndrome and COVID-19 The new sepsis consensus definitions: the good, the bad and the ugly A glimpse into the eye of the COVID-19 cytokine storm Insights from immuno-oncology: the Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19 Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes Is a "Cytokine Storm" Relevant to COVID-19? Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19 IL-6 and CD8+ T cell counts combined are an early predictor of in-hospital mortality of patients with COVID-19 Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe The many faces of the anti-COVID immune response IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature Sepsis-associated Disseminated Intravascular Coagulopathy Cytokine storm/cytokine Clinical and immunological features of severe and moderate coronavirus disease 2019 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system COVID-19 as an Acute Inflammatory Disease Targeting potential drivers of covid-19: neutrophil extracellular traps Into the eye of the cytokine storm Clinical Features of Cytokine Storm Syndrome in Cytokines as Regulators of Coagulation Clinical and immunological features of severe and moderate coronavirus disease 2019 Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management The IL6(-174G/C) polymorphism is a prognostic factor for survival after treatment initiation in Waldenstrom macroglobulinemia patients aged 65 years or less COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Lancet Thromboinflammation/thrombogenesis Thromboinflammation and the hypercoagulability of COVID-19 von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke. Front Immunol Editorial: Platelets and Immune Responses During Thromboinflammation. Front Immunol Microvascular thrombosis: experimental and clinical implications Platelets as Modulators of Cerebral Ischemia/Reperfusion Injury. Front Immunol The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases. Front Immunol Inflammation Induced by Platelet-Activating Viperid Snake Venoms: Perspectives on Thromboinflammation. Front Immunol The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System. Front Immunol Platelets as Mediators of Thromboinflammation in Chronic Myeloproliferative Neoplasms. Front Immunol Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction Ischaemic stroke: a thrombo-inflammatory disease? The dual role of platelet-innate immune cell interactions in thrombo-inflammation. Res Pract Thromb Haemost Behçet's syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects The Role of Thromboinflammation in Delayed Cerebral Ischemia after Subarachnoid Hemorrhage. Front Neurol The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study COVID-19-Associated Coagulopathy: An Exacerbated Immunothrombosis Response The COVID-19 Pandemic during the Time of the Diabetes Pandemic: Likely Fraternal Twins? Pathogens Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe Neutrophil extracellular traps in COVID-19 Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19. The Journal of Experimental Medicine Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19. Front Immunol Vascular occlusion by neutrophil extracellular traps in COVID-19. EBio-Medicine Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19 Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage High neutrophil-to-lymphocyte ratio associated with progression to critical illness in older patients with COVID-19: a multicenter retrospective study Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids Regulation of cell death during infection by the severe acute respiratory syndrome coronavirus and other coronaviruses Risk of ruling out severe acute respiratory syndrome by ruling in another diagnosis: variable incidence of atypical bacteria coinfection based on diagnostic assays Haematological parameters in severe acute respiratory syndrome Pathology and pathogenesis of severe acute respiratory syndrome Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis Pathogenesis of severe acute respiratory syndrome Pathology of the thyroid in severe acute respiratory syndrome Clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome Lung pathology of fatal severe acute respiratory syndrome The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon Interferon and cytokine responses to SARS-coronavirus infection Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation Malakan Rad E. Cardiovascular disease in COVID-19: a systematic review and meta-analysis of 10,898 patients and proposal of a triage risk stratification tool Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome Biventricular thrombi associated with myocardial infarction in a patient with COVID-19: a case report Right Ventricular Clot in Transit in COVID-19: Implications for the Pulmonary Embolism Response Team Epub ahead of print Clot in Acute Respiratory Distress Syndrome. CASE (Phila) Acute pulmonary embolism in conjunction with intramural right ventricular thrombus in a SARS-CoV-2-positive patient Cardiac manifestations in COVID-19 patients-A systematic review Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is 'shock liver' the unrecognized provocateur of ischemic limb necrosis Admission levels of C-reactive protein and plasminogen activator inhibitor-1 in patients with acute myocardial infarction with and without cardiogenic shock or heart failure on admission Mechanical circulatory support and heart transplantation. Pre-operative status and outcome 10-epoxy-12-octadecenoate: a possible responsible factor in circulatory shock and disseminated intravascular coagulation The proteinase inhibitor complexes (antithrombin III-thrombin, alpha 2antiplasmin-plasmin and alpha 1antitrypsin-elastase) in septicemia, fulminant hepatic failure and cardiac shock: value for diagnosis and therapy control in DIC/F syndrome Stress Cardiomyopathy Update of takotsubo syndrome in the era of COVID-19 Eitel I, Akin I. Incidence and Clinical Impact of Recurrent Takotsubo Syndrome: Results From the GEIST Registry Cardiovascular disease and COVID-19 Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) Viral myocarditis and coagulopathy: increased tissue factor expression and plasma thrombogenicity Disseminated intravascular coagulation and myocarditis associated with Mycoplasma pneumoniae infection Infarct-like myocarditis with coronary vasculitis and aneurysm formation caused by Epstein-Barr virus infection Myocarditis suggesting acute myocardial ischemia, without occlusion of the coronary artery, in a patient with antiphospholipid syndrome and systemic vasculitis in the course of cold agglutinin disease Infectious myocarditis: the role of the cardiac vasculature Acute colonic pseudo-obstruction: A systematic review of aetiology and mechanisms Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2 Disentangling the Hypothesis of Host Dysosmia and SARS-CoV-2: The Bait Symptom That Hides Neglected Neurophysiological Routes Fuel availability and fate in cardiac metabolism: A tale of two substrates Mechanism of death: there's more to it than sudden cardiac arrest Cardiac Injury Patterns and Inpatient Outcomes Among Patients Admitted with COVID-19 Epub ahead of print Atrial fibrillation in acute ST-elevation myocardial infarction: clinical and prognostic features Hypoxia with vasoconstriction The endothelium in hypoxic pulmonary vasoconstriction COVID-19-Related Aortic Thrombosis: A Report of Four Cases Hypoxic pulmonary vasoconstriction Hypoxia and HIF activation as a possible link between sepsis and thrombosis A relative ADAMTS13 deficiency supports the presence of a secondary microangiopathy in COVID 19 Are chilblains a skin expression of COVID-19 microangiopathy? Thrombotic microangiopathy, DIC-syndrome and COVID-19: link with pregnancy prothrombotic state Thrombotic microangiopathy in a patient with COVID-19 COVID-19, microangiopathy, hemostatic activation, and complement Pulmonary Vascular Endothelilitis, Thrombosis, and Angiogenesis in Covid-19 Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily Is COVID-19 an endothelial disease? Clinical and basic evidence The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch Endothelial Cell Perturbation and Disseminated Intravascular Coagulation Landes Bioscience Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases. Front Pharmacol Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19 Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation Preliminary Post-Mortem COVID-19 Evidence of Endothelial Injury and Factor VIII Hyperexpression. Diagnostics (Basel) How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms Endothelial Dysfunction Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients Vasculitis or vasculitis-like mechanism The clinical pathology of severe acute respiratory syndrome (SARS): a report from China Thrombosis in vasculitis: from pathogenesis to treatment COVID-19-associated vasculitis and vasculopathy The coagulopathy, endotheliopathy, and vasculitis of COVID-19 Widespread cutaneous small vessel vasculitis secondary to COVID-19 infection Vasculitis Presented as Pulmonary Hemorrhage in a Positive COVID-19 Patient: A Case Report Pulmonary and Cardiac Pathology in Covid-19 The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19 Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a Prospective, Single-Center Digital Gangrene as a Sign of Catastrophic Coronavirus Disease Drug-Induced Thrombophilic or Prothrombotic States: An Underestimated Clinical Problem That Involves Both Legal and Illegal Compounds M Col-hounAssociations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study Caution against corticosteroid-based COVID-19 treatment Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis Pathogenic role of antiphospholipid antibodies Antiphospholipid antibodies in patients with COVID-19: a relevant observation? Brief Report: Anti-phospholipid antibodies in critically ill patients with Coronavirus Disease 2019 (COVID-19) Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review) Prevalence, specificity, and clinical association of anti-phospholipid antibodies in COVID-19 patients: are the antibodies really guilty Prothrombotic antiphospholipid antibodies in COVID-19 Autoinflammatory and autoimmune conditions at the crossroad of COVID-19 Clinically significant anticardiolipin antibodies associated with COVID-19 COVID-19) Infection Associated With Antiphospholipid Antibodies and Four-Extremity Deep Vein thrombosis in a Previously Healthy Female Viral infections and their relationship with catastrophic antiphospholipid syndrome: a possible pathogenic mechanism of severe COVID-19 thrombotic complications Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism The coagulopathy, endotheliopathy, and vasculitis of COVID-19 Flare of Antiphospholipid Syndrome in the Course of COVID-19. TH Open Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review) Cutaneous autoimmune diseases during COVID-19 pandemic When interferon tiptoes through COVID-19: Perniolike lesions and their prognostic implications during SARS-CoV-2 infection Coronavirus (COVID-19) infection-induced chilblains: A case report with histopathologic findings. JAAD Case Rep Type I interferon in rheumatic diseases Type III Interferons in Antiviral Defenses at Barrier Surfaces The probacterial effect of type I interferon signaling requires its own negative regulator USP18 Immune Profiling and Precision Medicine in Systemic Type-I interferons in atherosclerosis Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions. Cell Rep Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview The molecular basis for differential type I interferon signaling Evaluation of safety, efficacy, tolerability, and treatment-related outcomes of type I interferons for human coronaviruses (HCoVs) infection in clinical practice: An updated critical systematic review and meta-analysis Evasion of Type I Interferon by SARS-CoV-2. Cell Rep Are type 1 interferons treatment in Multiple Sclerosis as a potential therapy against COVID-19? Mult Scler Relat Disord Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature Neurologic Features in Severe SARS-CoV-2 Infection Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies Norepinephrine vs Vasopressin: Which Vasopressor Should Be Discontinued First in Septic Shock? A Meta-Analysis Incidence of Hypotension after Discontinuation of Norepinephrine or Arginine Vasopressin in Patients with Septic Shock: a Systematic Review and Meta-Analysis Diagnosis and management of sepsis Induced hypotension and brain ischaemia Predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission: a systematic review and meta-analysis Lymphocyte-to-Monocyte Ratio: A Novel Predictor of the Prognosis of Acute Ischemic Stroke Neuroanatomical correlates of stroke-associated infection and stroke-induced immunodepression Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases Stroke-induced immunodepression and poststroke infections: lessons from the preventive antibacterial therapy in stroke trial Immediate and long-term consequences of COVID-19 infections for the development of neurological disease Prognostic Value of Leukocytosis and Lymphopenia for Coronavirus Disease Severity. Emerg Infect Dis Atrial Fibrillation Management of atrial fibrillation in critically ill patients Cardiac Involvment in COVID-19-Related Acute Respiratory Distress Syndrome New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people Atrial fibrillation: a risk factor for unfavourable outcome in COVID-19? A case report Immobilisation/Bed rest Deep Venous Thrombosis (DVT) Risk Factors Risk factors for venous and arterial thrombosis Phlegmasia cerulean dolens: complication of femoral vein catheterization. CEN Case Rep Compression stockings for preventing deep vein thrombosis in airline passengers Health risks to air travelers A retrospective study of the initial 25 COVID-19 patients in Luoyang, China Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis Gastrointestinal involvement in COVID-19: a systematic review and metaanalysis. Ann Gastroenterol SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: A systematic review and meta-analysis Epidemiological and Clinical Characteristics of 6635 COVID-19 Patients: a Pooled Analysis Traveler's Diarrhea Contribution of dehydration to END in acute ischemic stroke not mediated via coagulation activation. Brain Behav Hemostatic responses to exercise, dehydration, and simulated bleeding in heat-stressed humans Dehydration is a strong predictor of long-term prognosis of thrombolysed patients with acute ischemic stroke. Brain Behav Metabolic/electrolyte disturbance 1 Chapter 250. Disorders of Sodium in the critically ill IL-6, and SARS-CoV-2 (COVID-19) infection: may all fit together? Sodium status and kidney involvement during COVID-19 infection Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19) Hyponatremia in Infectious Diseases-A Literature Review Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis Hyponatremia in stroke Disorders of Potassium in the critically ill Assessment of Hypokalemia and Clinical Characteristics in Patients With Coronavirus Disease Clinical characteristics, management and in-hospital mortality of patients with COVID-19 The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis Disorders of magnesium in the critically ill. In Oxford Textbook of Critical Care Disorders of calcium in the critically ill Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study, 1987-1996 Immunologic Effects of Vitamin D on Human Health and Disease Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic Severe hypocalcemia in a thyroidectomized Prevalence and predictive value of hypocalcemia in severe COVID-19 patients Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease Use of distinct anti-hypertensive drugs and risk for COVID-19 among hypertensive people: a population-based cohort study in Southern Catalonia Could Anti-Hypertensive Drug Therapy Affect the Clinical Prognosis of Hypertensive Patients With COVID-19 Infection? Data From Centers of Southern Italy Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19 Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19 Hypernatremia-A Manifestation of COVID-19: A Case Series. A A Pract Hypokalemia as a sensitive biomarker of disease severity and the requirement for invasive mechanical ventilation requirement in COVID-19 pneumonia: A case series of 306 Mediterranean patients Epub ahead of print Possibility of magnesium supplementation for supportive treatment in patients with COVID-19 A Novel Case of Hypoparathyroidism Secondary to SARS-CoV-2 Infection. Cureus Concomitant calciphylaxis and COVID-19 associated thrombotic retiform purpura Prevalence and Impact of Hyponatremia in Patients With Coronavirus Disease IgA Vasculitis with Nephritis (Henoch-Schönlein purpura) in a COVID-19 patient Epub ahead of print Kidney disease and electrolytes in COVID-19: more than meets the eye Acute kidney injury is associated with severe infection and fatality in patients with COVID-19: A systematic review and meta-analysis of 40 studies and 24,527 patients Fluid Replacement Versus Fluid Restriction in COVID-19 Associated Hyponatremia. Cureus Prevalence and predictive value of hy-Sep COVID-19 presenting with diarrhoea and hyponatraemia A case of adrenal infarction in a patient with COVID 19 infection. BJR Case Rep Acute symptomatic hyponatremia in setting of SI-ADH as an isolated presentation of COVID-19. IDCases The syndrome of inappropriate antidiuresis in COVID-19 pneumonia: report of two cases. Clin Kidney J Clinical characteristics of hospitalized patients with 2019 novel coronavirus disease indicate potential proximal tubular dysfunction Acute Hyperglycemic Crises with Coronavirus Disease-19: Case Reports Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study Fahr's syndrome presenting with seizures in SARS-CoV-2 (COVID-19) pneumonia-a case report The spectrum of biochemical alterations associated with organ dysfunction and inflammatory status and their association with disease outcomes in severe COVID-19: A longitudinal cohort and time-series design study. EClinicalMedicine Acute pancreatic injury induced by COVID-19. IDCases Coronavirus disease-19 (COVID-19) associated with acute necrotising pancreatitis (ANP) COVID-19 associated atrial fibrillation: Incidence, putative mechanisms and potential clinical implications Baseline electrolyte abnormalities would be related to poor prognosis in hospitalized coronavirus disease 2019 patients. New Microbes New Infect Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19 Kidney Infarction in Patients With COVID-19. Am J Kidney Dis Laboratory findings and a combined multifactorial approach to predict death in critically ill patients with COVID-19: a retrospective study Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease Neurological manifestations of the coronavirus (SARS-CoV-2) pandemic 2019-2020 A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Coagulation abnormalities in critically ill patients Heparin-induced thrombocytopenia Neutrophil accumulation and NET release contribute to thrombosis in HIT Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia Momjian-Mayor I. Cerebral venous thrombosis due to cryptogenic organising pneumopathy with antiphospholipid syndrome worsened by heparin-induced thrombocytopenia Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p Multivessel coronary thrombosis in a patient with idiopathic thrombocytopenic purpura Clinical implications of elevated antiphospholipid antibodies in adult patients with primary immune thrombocytopenia Beyond thrombosis: the versatile platelet in critical illness Impact of splenectomy on thrombocytopenia, chemotherapy, and survival in patients with unresectable pancreatic cancer Laparoscopic splenectomy reverses thrombocytopenia in patients with hepatitis C cirrhosis and portal hypertension A case of deep vein thrombosis and pulmonary thromboembolism after intravenous immunoglobulin therapy Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19 Platelet gene expression and function in patients with COVID-19 COVID-19 update: Covid-19-associated coagulopathy Revisiting Platelets and Toll-Like Receptors (TLRs): At the Interface of Vascular Immunity and Thrombosis Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series Pathological findings of COVID-19 associated with acute respiratory distress syndrome Pneumonia as a cardiovascular disease Secondary Infection Analysis of cardiopulmonary findings in COVID-19 fatalities: High incidence of pulmonary artery thrombi and acute suppurative bronchopneumonia A Case Series of Patients Coinfected With Influenza and COVID-19. J Investig Med High Impact Case Rep Diabetic Ketoacidosis Precipitated by COVID-19 in Patients Without Respiratory Symptoms: Case Reports Molecular pathogenesis of secondary bacterial infection associated to viral infections including SARS-CoV-2 Epub ahead of print Nicolás D; Hospital Clínic 4H Team. Pneumococcal superinfection in COVID-19 patients: A series of 5 cases The Coincidence of 2 Epidemics, Coccidioidomycosis and SARS-CoV-2: A Case Report Metagenomic Analysis Reveals Clinical SARS-CoV-2 Infection and Bacterial or Viral Superinfection and Colonization COVID-19 complicated by parainfluenza co-infection in a patient with chronic lymphocytic leukemia Epub ahead of print Co-infections in COVID-19 critically ill and antibiotic management: a prospective cohort analysis Crit Care Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens Fatal Superimposed Bacterial Sepsis in a Healthy Coronavirus (COVID-19) Patient. Cureus A Case of COVID-19 and Pneumocystis jirovecii Coinfection Community Acquired Co-infection in COVID-19: A Retrospective Observational Experience Epub ahead of print Fatal Invasive Aspergillosis and Coronavirus Disease in an Immunocompetent Patient. Emerg Infect Dis Invasive pulmonary fusariosis in an immunocompetent critically ill patient with severe COVID-19 Epub ahead of print SURGICAL RESECTIONS OF SUPERINFECTED PNEUMATOCELES IN A COVID-19 PATIENT COVID-19 Associated Pulmonary Aspergillosis (CAPA)-From Immunology to Treatment. J Fungi (Basel) Recovery from COVID-19 following hepatitis C, human immunodeficiency virus infection, and liver transplantation The Metabolic Changes and Immune Profiles in Patients With COVID-19. Front Immunol Acute ischaemic stroke and infection: recent and emerging concepts Infection and Stroke: an Update on Recent Progress Infectious burden and risk of stroke: the northern Manhattan study HIV infection and stroke: current perspectives and future directions Hepatitis C virus infection and risk of stroke: a systematic review and meta-analysis. PLoS One Lakshminarayan K. Hospitalized Infection as a Trigger for Acute Ischemic Stroke: The Atherosclerosis Risk in Communities Study A systematic review and meta-analysis on herpes zoster and the risk of cardiac and cerebrovascular events. PLoS One The activation of IL-17 signaling pathway promotes pyroptosis in pneumonia-induced sepsis The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China Insights into the apoptotic death of immune cells in sepsis European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management Collapsing Glomerulopathy in a Patient With Coronavirus Disease 2019 (COVID-19) Tubuloreticular inclusions in COVID-19-related collapsing glomerulopathy Acute Kidney Injury Due to Collapsing Glomerulopathy Following COVID-19 Infection COVID-19-Associated Collapsing Glomerulopathy: An Emerging Entity COVID-19-Related Glomerulopathy: A Report of 2 Cases of Collapsing Focal Segmental Glomerulosclerosis Thrombotic microangiopathy in a patient with COVID-19 Collapsing Glomerulopathy Associated with COVID-19 Infection in a Heart Transplant Recipient Could severe COVID-19 be considered a complementopathy? Update on C3 Glomerulopathy: A Complement-Mediated Disease Collapsing glomerulopathy is common in the setting of thrombotic microangiopathy of the native kidney Complement Activation in Patients with Focal Segmental Glomerulosclerosis Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab Epub ahead of print General Factors Relating to Arterial Thrombosis Arterial Thrombosis in Practical Hemostasis and Thrombosis Complications in the adult asplenic patient: A review for the emergency clinician Factors associated with COVID-19-related death using OpenSAFELY Endocrine and metabolic aspects of the COVID-19 pandemic COVID-19, Renin-Angiotensin System and Endothelial Dysfunction. Cells Metabolic Syndrome and COVID 19: Endocrine-Immune-Vascular Interactions Shapes Clinical Course Endothelial activation and dysfunction in metabolic syndrome, type 2 diabetes and coronavirus disease 2019 COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review Thrombectomy within 8 hours after symptom onset in ischemic stroke The Role of Microvasculature in COVID19 Importance of the evaluation of systemic microvascular flow and reactivity in critically ill patients with coronavirus disease Type 3 hypersensitivity in COVID-19 vasculitis COVID-19 type III hypersensitivity reaction COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmun Rev Collapsing glomerulopathy in a patient of Indian descent in the setting of COVID-19. Ren Fail Collapsing glomerulopathy: a 30-year perspective and single, large center experience Lupus-like autoimmune disease caused by a lack of Xkr8, a caspase-dependent phospholipid scramblase LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients. Sci Rep Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus Spectrum of podocytopathies in new-onset nephrotic syndrome following COVID-19 disease: a report of 2 cases COVID-19 The major genetic risk factor for severe COVID-19 is inherited from Neanderthals Obesity in patients with COVID-19: a systematic review and meta-analysis. Metabolism Post-Mortem Findings in Italian Patients with COVID-19 -a Descriptive Full Autopsy Study of cases with and without co-morbidities Acute Splenic Artery Thrombosis and Infarction Associated with COVID-19 Disease. Case Rep Crit Care Atraumatic splenic rupture due to covid-19 infection Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study The Interplay Between Coagulation and Inflammation Pathways in COVID-19-Associated Respiratory Failure: A Narrative Review. Pulm Ther Pulmonary Thrombosis or Embolism in a Large Cohort of Hospitalized Patients With Covid-19. Front Med (Lausanne) Coagulation Abnormalities and Thrombosis in Patients Infected With SARS-CoV-2 and Other Pandemic Viruses Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement. Microvasc Res COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City Venous Thromboembolism among Hospitalized Patients with COVID-19 Undergoing Thromboprophylaxis: A Systematic Review and Meta-Analysis Dynamics of coagulopathy in patients with different COVID-19 severity A Case of COVID-19 Infection With Delayed Thromboembolic Complication on Warfarin Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations Successful Qualitative Research. A Practical Guide for Beginners A thematic analysis of an outpatient psychotherapy group Thematic Origins of Scientific Thought: Kepler to Einstein Thematic analysis in science: Notes on Holton's concept Dilemmas in qualitative research Edited with an introduction and notes by Giles Gunn. Penguin Books COVID-19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy Clinical characteristics, management and in-hospital mortality of patients with COVID-19 in Genoa, Italy. Clinical Microbiology and Infection Adrenomedullin in COVID-19 induced endotheliitis. Crit Care RNA-expression of adrenomedullin is increased in patients with severe COVID-19 Bowel Necrosis in the Setting of COVID-19 A Peculiar Case of Small Bowel Stricture in a Coronavirus Disease 2019 Patient with Congenital Adhesion Band and Superior Mesenteric Vein Thrombosis Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans Epub ahead of print Surgical Recurrence The Mesenteric Fat and Intestinal Muscle Interface: Creeping Fat Influencing Stricture Formation in Crohn's Disease. Inflamm Bowel Dis The Role of Adipose Tissue in the Pathogenesis and Therapeutic Outcomes of Inflammatory Bowel Disease. Cells The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases Critical Role of Type III Interferon in Controlling SARS-CoV-2 Infection in Human Intestinal Epithelial Cells Ten common statistical mistakes to watch out for when writing or reviewing a manuscript. Elife Tissue-specific tolerance in fatal Covid-19 doi COVID-19 Presenting as Takotsubo Cardiomyopathy Complicated with Atrial Fibrillation Atrial fibrillation: a risk factor for unfavourable outcome in COVID-19? A case report An adult with Kawasaki-like multisystem inflammatory syndrome associated with COVID-19. The Lancet Methodological Rigor in COVID-19 Clinical Research: A Systematic Review and Case-Control Analysis Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition International survey on D-dimer test reporting: a call for standardization Epub ahead of print Impact of the COVID-19 Pandemic on Biomedical and Clinical Research The Impact of COVID-19 on the Conduct of Clinical Trials for Medical Products in Korea Impact of the coronavirus disease 2019 pandemic on surgical research and lessons for the future. Surgery Impact of the COVID-19 pandemic on orthopaedic and trauma surgery training in Europe Redeployment of Surgical Trainees to Intensive Care During the COVID-19 Pandemic: Evaluation of the Impact on Training and Wellbeing Redeployment of ophthalmologists in the United Kingdom during the Coronavirus Disease Pandemic Epub ahead of print COVID-19: lessons for junior doctors redeployed to critical care. Postgrad Med J UK medical students graduating early to work during the COVID-19 pandemic How to investigate multisystem disease SAT-219 Allgrove Syndrome: How to Suspect a Problem? Crowdsourcing and open innovation in drug discovery: recent contributions and future directions Factors Influencing Doctors' Participation in the Provision of Medical Services Through Crowdsourced Health Care Information Websites: Elaboration-Likelihood Perspective Study Massive online data annotation, crowdsourcing to generate high quality sleep spindle annotations from EEG data. Sci Data ANMCO POSITION PAPER: Considerations on in-hospital cardiological consultations and cardiology outpatient clinics during the COVID-19 pandemic Welcome to the 21st Edition The Structure of Scientific Revolutions Diagnostic overshadowing and other challenges involved in the diagnostic process of patients with mental illness who present in emergency departments with physical symptoms--a qualitative study Bach: An Eternal Golden Braid Thought and choice in chess Perception in chess Man and his symbols. Doubleday The Interpretation of Dreams. Third Edition Information Needs in the Precision Medicine Era: How Genetics Home Reference Can Help AlphaZero's Groundbreaking Chess Strategies and the Promise of AI Semiotics: The Basics The Semiotics of Emoji: The Rise of Visual Language in the Age of the Internet. Bloomsbury Advances in Semiotics General Psychopathology -Volumes 1 & 2. translated by WHO. History of the development of the ICD We would like to extend our immense gratitude to family, friends and colleagues whose support has been essential in managing the many challenges we have faced in this pandemic.