key: cord-0807480-8y66ew3t
authors: Lippi, Giuseppe; Sanchis-Gomar, Fabian; Favaloro, Emmanuel J.; Lavie, Carl J.; Henry, Brandon M.
title: Coronavirus Disease 2019 (COVID-19)-Associated Coagulopathy
date: 2020-10-31
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.10.031
sha: 57a7e3a0749ac8c14b4ec31ff10b76178d871427
doc_id: 807480
cord_uid: 8y66ew3t

Patients with the severe form of coronavirus disease 2019 (COVID-19) have been frequently found to suffer from both arterial and venous thrombotic events due to the perpetuation of a hypercoagulable state. This phenomenon, termed COVID-19-associated coagulopathy (CC), is now considered a major component of the pathophysiology of this novel infectious disease, leading to widespread thrombosis. While at first, the vascular insults may be limited to the pulmonary microvasculature, as the disease progresses, systemic involvement occurs, culminating in distant organ thrombosis and multi-organ dysfunction syndrome. In this review article, we discuss recent insights into the pathophysiologic mechanisms of CC and review the clinical, histopathologic, and laboratory evidence, which leads us to conclude that COVID-19 is both a pulmonary and vascular disorder.

Although COVID-19 was originally classified as a primary respiratory disease due to frequent lung involvement, presenting as a severe form of interstitial pneumonia and with a high risk of progression towards acute respiratory distress syndrome (ARDS), the evidence gradually accumulating over recent months has led to a clearer clinical picture.

SARS-CoV-2 infection should be defined as a multi-system disease, characterized by high mortality in specific subsets of patients, especially older males, and those with important associated comorbidities, such as hypertension, diabetes, obesity, cancer, as well as pulmonary, cardiovascular, liver, neurological and renal disorders. 3 Based on recent data, COVID-19 is characterized by dysregulation of multiple biological pathways, mirrored by an abnormal immune response and an exaggerated proinflammatory state, which finally converge to trigger the development of a profound hemostasis disturbance, 4 in the form of localized and systemic coagulopathies and thrombotic events ( Table 1) , whose presence is directly associated with poor outcomes.

This dramatic evolution has been termed "COVID-associated coagulopathy" (CC). CC J o u r n a l P r e -p r o o f appears to correlate with severity of illness, with those in the intensive care unit (ICU) suffering the most significant derangements. This narrative review aims to provide some recent updates on the clinical, histopathological, laboratory evidence demonstrating the relationship between COVID-19 and hemostasis abnormalities, as well as explore the potential pathogenic mechanisms of CC.

Data for this review were identified by electronic searches of PubMed, Scopus and Web of Science and references from relevant articles using the search terms "coronavirus disease 2019", "COVID-19", "SARS-CoV-2", "hemostasis", "coagulation", "fibrinolysis" and "thrombosis". Only articles published in English between 2019 and October 5, 2020 were included. Since systematic selection criteria cannot be applied to include articles which explored the pathogenesis of coagulopathies in COVID-19, we arbitrarily included those articles which provided the most relevant contributions to describing the clinical, histopathological, laboratory and pathogenetic evidence underlying this relationship. A narrative review was found to be better suited to discuss our results.

Patients hospitalized with pneumonia often present with risk factors for venous thromboembolism (VTE), such as acute respiratory illness, active infection, proinflammatory state, diminished mobility, advanced age (>65 years), cancer, obesity, pregnancy, congestive heart failure, or history of prior VTE. 5 20 Patients with DVT were older and had lower oxygenation index, a higher rate of cardiac injury, and worse prognosis compared with patients with no DVT. 20 Nahum and colleagues performed a venous ultrasonogram of the inferior limbs in 34 severe COVID-19 patients (age 62.2±8.6 years, 78% men) with pneumonia admitted to the ICU from mid-March to the beginning of April, 2020. 21 The authors found DVT in 22 patients (65%) at admission and in 27 patients (79%) at 48 hours after ICU admission; 18 (53%) of these patients had bilateral thrombosis, while 9 (26%) had proximal thrombosis. 21 Finally, Bilaloglu and coworkers analyzed the incidence of venous and arterial thrombotic events in 3334 consecutive hospitalized COVID-19 patients at 4 hospitals in New York City. 22 Any thrombotic event were identified in 533 (16.0%) patients, of which 207 (6.2%) were venous (3.2% PE and 3.9% DVT). 22 These authors also observed that higher D-dimer levels at hospital presentation were associated with thrombotic events, as well as that all-cause mortality was higher in those COVID-19 patients with thrombotic events (43.2% vs. 21.0%, p<0.001). 22 Large-vessel stroke has also been reported in COVID-19. Five cases were described in COVID-19 patients younger than 50 years old hospitalized in New York City over a 2week period, from March 23 to April 7, 2020. 23 Yaghi and collaborators 24 conducted a retrospective cohort study of consecutive COVID-19 patients hospitalized between March 15 and April 19, 2020, within a major health system in New York. During the study period, 32 of 3556 (0.9%) had imaging-proven ischemic stroke, while cryptogenic stroke was substantially more common among COVID-19 patients. COVID-19 patients also had higher admission National Institutes of Health Stroke Scale score, higher peak D-dimer levels and higher mortality. 24 Avula et al. 25 also reported four cases of ischemic stroke in COVID-19 patients confirmed by CT. Finally, Bilaloglu et al. 22 reported that 54 (1.6%) of all thrombotic events were ischemic stroke.

In the study of Tang and colleagues on 183 COVID-19 patients, the authors reported 

ST-segment elevation due to myocardial injury has been observed among COVID-19 patients at admission and/or during hospitalization. Myocardial interstitial edema has also been reported in these patients. 27 Bangalore et al. 28 which filled the lumen of the vessels, was suggestive for in situ thrombosis rather than for embolization from peripheral vessels. With respect to other organs and tissues, intraventricular endocardial mural thrombi were found in one patient, and central liver vein thrombosis in another. In a further post-mortem investigation, Ackermann and colleagues examined the lung tissue of seven patients who died for COVID-19, and compared their findings with those obtained in the lung tissue of seven other patients who died for ARDS caused by influenza A/H1N1 and ten age-matched uninfected controls. 31 Widespread thrombosis and microangiopathy could be found in pulmonary vessels of all COVID-19 patients. The thrombi had a diameter between 1-2 mm and did not fill the lumen of the pulmonary arteries involved. Alveolar capillary thrombosis was common and was found to be 9-fold more prevalent in COVID-19 patients than in those with influenza A/H1N1. In a case series of ten autopsies of patients who died from COVID-19 published by Nunes et al., 32 the authors found cytopathic effects attributable to SARS-CoV-2 in many organs and tissues, with clear signs of thromboembolic involvement frequently observed. Microthrombi could be found in the pulmonary arteries of 8/10 (80%) autopsied patients, accompanied by the evidence of fibrin thrombi in the vessels of testis (2/2; 100%), kidney (6/8; 75%), skin (3/10; 30%), heart (2/10; 20%) and spleen (1/5; 20%). Ischemic necrosis could also be seen in the liver of 3/10 (30%) patients. Fox and co-workers performed autopsies on ten African Americans (aged 44-78 years) who died as consequence of SARS-CoV-2 infection in New

Orleans. 33 The authors found thrombosis and microangiopathy in the small vessels and In summary, the laboratory evidence to-date suggests that COVID-19 induces CC, which can be compared to a low-grade DIC, as well as microvascular immunothrombosis similar to TMA. 36, 44 While this may be localized to the pulmonary microvasculature at first, as the infection progresses, systemic vasculature involvement J o u r n a l P r e -p r o o f occurs, complicated further by inhibition of fibrinolysis, and culminating in multi-organ dysfunction syndrome.

The previously described clinical, histopathological and laboratory evidence demonstrate that COVID-19 is a pathology often complicated by thrombotic events, localized and systemic, macro-and/or micro-vascular. A clear understanding of the underlying pathogenetic mechanisms contributing to trigger and/or amplify thrombosis in COVID-19 represents a crucial aspect in the managed care of this illness, which will pave the way to establishing specific therapeutic options, tailored to target the affected hemostasis pathways.

Hemostasis can be basically divided into three major stages. Primary hemostasis, which involves blood vessels and platelets, aims to generate a temporary and somewhat unstable blood clot, which attempts to stop bleeding after an endothelial injury has occurred. Secondary hemostasis, which develops immediately afterwards, encompasses the sequential activation of many clotting factors, leading to the generation of sufficient fibrin to stabilize the initial platelet plug. Fibrinolysis involves a series of events with the purpose to dissolve the blood clot and restore normal flow within the blood vessel.

Notably, all these three essential hemostasis phases seem variably deranged in COVID-19, all characterized by onset of many significant pro-thrombotic abnormalities, that will be summarized in the following parts of this section, and which can be referred to as "immunothrombosis" or "thromboinflammation."

The triggering factors of COVID-19-associated immuno-thrombo-inflammation foster platelet hyper-reactivity, hypercoagulability and hypo-fibrinolysis, which seem to J o u r n a l P r e -p r o o f coexist in SARS-CoV-2 infection, thus contributing to define the portrait of a perfect storm (Figure 1) . 51 Notably, most of these causal factors of SARS-CoV-2 induced immuno-thrombo-inflammation are also hallmarks of ARDS. 52 Thus, it is no surprising that they would also be deeply involved in the pathogenesis of the "pulmonary intravascular coagulopathy" (PIC) seen in COVID- 19. 53 Understandably, as the inflammation amplifies and propagates outside the lung tissue as a consequence of SARS-CoV-2 colonization of other organs where angiotensin-converting enzyme 2 (ACE2) is strongly expressed, such as in the heart, kidneys, intestine, liver, testis, adipose tissue and central nervous system, 54 the coagulopathy also progresses systematically, with development of distant organ thrombosis, up to the development of DIC, which may occur in some patients with late-stage COVID-19. 26 

Endothelial injury, along with the ensuing disruption of blood vessel integrity, is the main trigger of primary hemostasis, encompassing a series of sequential events characterized by platelet activation, aggregation, adhesion and culminating in the generation of a primary platelet plug, as previously underlined. Several lines of evidence now concur to confirm that endothelial injury and dysfunction are commonplace in patients with COVID-19. First, the SARS-CoV-2 receptor ACE2 is physiologically expressed at the surface of arterial and venous endothelial cells and arterial smooth muscle cells, 55 and a cytopathic effect consequent to direct viral infection of these cells is likely. This has been recently confirmed in an interesting study published by Varga et al. 56 The authors clearly showed the presence of viral particles within endothelial cells, followed by onset of endotheliitis, cellular degeneration and J o u r n a l P r e -p r o o f infection, but may later spread and involve the blood vessels of many other organs and tissues.

The endothelial injury is then rapidly followed by a series of events leading to platelet activation, adhesion to the sub-endothelial matrix and aggregation, with the final generation of a platelet plug. 57 These events include production and acute release of VWF, inefficient cleavage of ultra-large VWF (ULVWF) catalyzed by ADAMTS13, direct contact with activating surfaces in the sub-endothelial matrix, loss of heparan sulfates at the surface of injured blood vessels, lack of generation of nitric oxide (NO), prostaglandin E2 (PGE2) and prostacyclin (PGI2), and loss of surface expression of ectonucleotidases. 58, 59 It is important to mention here that platelet activation may also occur as consequence of the generation of a considerable amount of thrombin after activation of blood coagulation, as will be discussed in detail in the following section of this article. Indirect evidence that platelet hyper-activation may play a substantial role in the pathogenesis of SARS-CoV-2 coagulopathy emerges from the study of Viecca et al., 60 who demonstrated that the administration of acetylsalicylic acid (250 mg infusion, followed by 75 mg daily for 1 month) and oral clopidogrel (300 mg initially, followed by 75 mg daily for 1 month) was effective in improving the ventilation/perfusion ratio in COVID-19 patients with severe respiratory failure. However, this investigation was performed as a retrospective case-control study, which may suffer from considerable bias, and thus the results must be interpreted with caution. However, this investigation was performed as a retrospective case-control study, which may suffer from considerable bias, and thus the results must be interpreted with caution. Roncati et al. 61 demonstrated with a postmortem biopsy report that naked megakaryocyte nuclei within lungs and bone marrow of COVID-19 patients with severe illness are increased by over 10-fold. This phenomenon has been attributed to excess IL-6 stimulation of megakaryocytopoiesis and platelet production, which would then contribute to generate a hypercoagulability state, especially within the lung tissue, thus increasing the likelihood of developing immunothrombosis. Convincing evidence of a direct interaction between platelets and SARS-CoV-2 has been provided by Zhang et al., 62 who showed that human platelets express both ACE2 and Transmembrane Serine Protease 2 (TMPRSS2) on their surface, so that the virus, through its spike protein, can directly stimulated platelets, triggering the release of clotting factors, inflammatory mediators and generation of leukocyte-platelet aggregates. Further evidence that severity of COVID-19 depends on platelet activation has been provided in the study of Hottz et al. 63 Briefly, the authors found platelet a higher degree of platelet hyperactivation in COVID-19 patients with severe illness compared to those with milder symptoms. Not only platelets were hyper-activated in severe COVID-19, but also the presence of platelet-monocyte aggregates was found to be considerably increased in COVID-19 patients compared to healthy controls, and was even higher in patients with severe illness compared to those with milder disease. Finally, monocyte expression of tissue factor, which is the initiator of the blood coagulation cascade, was found to be hyper-expressed in COVID-19 patients with severe illness. Evidence that platelets are hyper-activated in COVID-19 patients and show a considerable remarkable predisposition to generate leukocyte aggregates has been confirmed by Manne et al. 64 In this original investigation, both P-selectin expression and the number of platelet-J o u r n a l P r e -p r o o f patients with SARS-CoV-2 infection. Moreover, platelet aggregation in response to ADP, thrombin and collagen was found to be substantially higher in COVID-19 patients compared to controls. Overlapping evidence has been reported by Zaid et al., 65 showing that SARS-CoV-2 was able to bind to platelet surface, that the platelet content of platelet factor 4 (PF4) and serotonin were significantly reduced in COVID-19 patients, especially in those with severe illness, and that the relative concentration of these two molecules was consequently higher in these patients' plasma. Importantly, platelet aggregation and adhesion were also enhanced in patients with COVID-19, especially in those with severe illness, thus confirming that platelets are much more predisposed to clotting in this condition. It has been finally shown that agonist-stimulated expression of active fibrinogen receptor on platelet surface was reduced by over 50% in patients with SARS-CoV-2 infection, whilst a vast array of cytokines, chemokines, growth factors and even procoagulant factors (especially fibrinogen and VWF) are released in large amounts after stimulating platelets collected from COVID-19 patients. 66 Platelet activation with ensuing generation and release into the bloodstream of a vast array of cytokines and inflammatory mediators would hence further contribute to worsening the endothelial injury, both directly (e.g., further decreasing NO availability and releasing reactive oxygen species) and/or indirectly (e.g., enhancing leukocyteendothelial interaction, promoting the migration of inflammatory cells). 67 

The activation of blood coagulation is a second essential aspect for effective prevention of bleeding following vessel injury. Unlike older theories, it has now been clearly elucidated that physiological hemostasis originates mainly with the exposure of tissue J o u r n a l P r e -p r o o f a series of sequential catalytic reactions finalized to generate a sufficient amount of fibrin for strengthening and stabilizing platelet plugs. 68, 69 Notably, the role of the socalled intrinsic pathway in activation of secondary hemostasis has been considerably resized during the past decades, whereby the presence of factor (F) XII appears unnecessary for physiologic activation of blood coagulation. However, its capacity to activate FXI is retained in some pro-thrombotic conditions, such as atherosclerosis and severe infections. 70 Endothelial injury and/or dysfunction appears to be the main driver in the COVID-19-dependent activation of blood coagulation. The widespread damage of endothelia, as previously described, is likely associated with consistent release of TF, both in the pulmonary circuit, as well as in the blood vessels of other organs and tissues, which would hence contribute to activating secondary hemostasis. Substantial exposure and release of TF can also occur from cells of the macrophage/monocyte lineage and in microvesicles directly shed by these cells, 71 which may be highly activated in COVID-19, as noted by the occurrence of macrophage activation syndrome (MAS) that is frequently observed in patients with severe or critical forms of COVID-19, 72 as well as in other life-threatening viral diseases such as Ebola. 73 Macrophage activation can occur because of direct interaction with SARS-CoV-2. Viral particles have been detected within these cells, either penetrating the cell directly or being opsonized through the Fc receptor, where they likely exert both an activating and cytotoxic effect. 74 On the other hand, extensive macrophage/monocyte activation can also occur as a consequence of an exaggerated pro-inflammatory reaction (also known as "cytokine storm"), which is J o u r n a l P r e -p r o o f common in the severe/critical forms of COVID-19 and is characterized by extremely high values of IL-6, IL-8, IL-12, transforming growth factor-β (TGFβ), interferon-γ (IFNγ), CCL2, C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10). 75 Neutrophil activation is another essential mechanism underlying the common observation of a pro-thrombotic state in patients with COVID-19. Neutrophils can be colonized by SARS-CoV-2 by internalization through the Fc receptor or can be activated by endothelial cells, platelets and monocytes/macrophages, and are then capable of producing neutrophil extracellular traps (NETs), which can directly activate FXII and thereby the intrinsic pathway of blood coagulation. 76 In addition, complement may also interact with the platelet/ NETs/thrombin axis. 77 In effect, increased plasma levels of NETs, TF activity and sC5b-9 has been detected in COVID-19 patients, while thrombin or NETosis inhibition or C5aR1 blockade attenuated thrombogenicity. 77 Importantly, the severe pro-inflammatory condition is then associated with a remarkable associated increase in the circulating levels of many acute-phase proteins, including fibrinogen, VWF and FVIII, 78, 79 and which may hence contribute to amplify the thrombotic process. Evidence has also been provided that the ongoing thrombotic process would contribute to sustain or even amplify the pro-thrombotic state, as mirrored by a progressive decline in the activity of the major endogenous anticoagulants such as antithrombin, tissue factor pathway inhibitor (TFPI) and anticoagulation proteins C and S. 75 In fact, Lippi et al. recently found in a meta-analysis that low antithrombin levels were significantly associated with COVID-19 severity. 80 Prolonged immobilization and venous stasis, as consequence of the long stay in subintensive and intensive care units of COVID-19 patients with respiratory failure and/or J o u r n a l P r e -p r o o f multiple organ dysfunction, is likely another contributing factor of thrombosis in COVID-19. 81 

As discussed earlier, significant evidence has emerged as of late to support a major derangement of fibrinolysis in COVID-19. PAI-1, the major inhibitor of the fibrinolytic pathway, is largely contained in endothelial cells, megakaryocytes, and circulating platelets. 82 It is thus reasonable to suspect that the endothelial injury and dysfunction that develops in the advanced stages of COVID-19 would be associated with enhanced endothelial release of PAI-1, as well as release from platelets following activation. 83 This concept is supported by evidence of increased PAI-1 activity that is common in patients with ARDS, and which cumulatively contributes to a declining clinical status by inhibiting fibrinolysis, thus worsening the thrombotic burden. 84, 85 As noted above, PAI-1 levels have been reported to be elevated in patients with severe COVID-19. 50 On the contrary, elevated levels of bradykinin likely occur due to the inflammatory response to the virus, which may in turn induce the release of tPA from endothelium. 44 However, this release appears insignificant in comparison to the elevation of PAI-1 and consumption by endogenous fibrinolysis, as noted by the significantly lower levels of tPA were observed in patient developing severe Based on the data reported to-date, we proffer that elevated D-dimer early in the COVID-19 disease course are reflective of pulmonary inflammation with local activation of platelets and blood coagulation. 44 

As in other infections, the emergence of antiphospholipid antibodies has been reported in patients with COVID-19, [86] [87] [88] which may then contribute to trigger and/or amplify the coagulopathy. However, it should be noted a persistent presence of these antibodies has not been observed, and many severe infections are noted to be associated with a temporary appearance and disappearance of such antibodies. 44 Although the exact pathogenetic mechanisms remain uncertain, it has been demonstrated that these antibodies may activate endothelial cells, monocytes and platelets, as well as directly interfere with some proteins of the coagulation pathways. 89 More specifically, antiphospholipid antibodies may directly trigger endothelial cell activation 90 and the further development of a pro-inflammatory and pro-coagulant endothelial phenotype, 91 as well as upregulation and enhanced expression of TF in monocytes. 92 These specific antibodies bind to the platelets and contribute to triggering platelet hyper-reactivity. 93 The effects of antiphospholipid antibodies on blood coagulation include inhibition of natural inhibitors, such as antithrombin and activated protein C 94 and hyper-activation of some clotting factors, such as thrombin and FXa. 95, 96 It should be noted that elevated C-reactive protein (CRP) values may interfere in J o u r n a l P r e -p r o o f Therefore, LAC results should be carefully interpreted in patients with high CRP levels.

The RAAS has been a focus of pathophysiologic interest since ACE2 has been identified as the host receptor for SARS-CoV-2. ACE2 metabolizes angiotensin II (Ang II) into angiotensin 1,7 (Ang 1,7), which opposes the vasoconstrictive and proinflammatory properties of Ang II. 99 It has been hypothesized that the binding of the virus to ACE2 attenuates the activity of the enzyme, resulting in a state of high Ang II and low Ang 1,7. 99 Such a derangement, in theory, would lead to alterations fostering a hypercoagulable state. High Ang II would lead to increased PAI-1 and TF expression, further promoting hypercoagulability and impairing fibrinolysis, as well as further inflammation and vasoconstriction, thus exacerbating an underlying endothelial dysfunction. 44 Moreover, Ang II receptors present on platelets potentiates platelet aggregation and activation. 100 However, variability has been reported with respect to Ang II levels in patients with COVID-19. While Liu et al. reported in a small cohort of 12 COVID-19 patients from China drastically elevated Ang II levels, 101 Henry et al. in a cohort of 30 patients not taking a direct RAAS modifying drug, reported normal physiologic levels of Ang II and aldosterone in patients with COVID-19, that did not increase with disease severity, nor was different from levels measured in healthy controls. 102 On the contrary, Henry et al. 103 observed significantly low levels of Ang 1,7 as compared to healthy controls. Moreover, Ang 1,7 was found to be significantly lower in those who progressed to severe disease. 103 J o u r n a l P r e -p r o o f Physiologically, Ang 1,7 possesses multiple properties that may be important to the maintenance of normal hemostasis. 44, 104 Within microcirculation, Ang 1,7 exerts a vasoprotective effect through via NO-mediated vasodilation by endothelial cells and anti-thrombotic effects via NO-mediated release from platelets, which inhibits platelet aggregation and activation. [104] [105] [106] Thus, low Ang 1,7 in patients with COVID-19 may likely contribute to trigger a coagulopathy. Multiple clinical trials with angiotensin II receptor blockers in COVID-19 are ongoing, and trials using Ang 1,7 peptide have recently began.

Finally, obese patients have worse outcomes with COVID-19, including respiratory failure, need for mechanical ventilation, and higher mortality. [107] [108] [109] Obesity and overweight are associated with an increased risk of developing VTE. [110] [111] [112] Hypercoagulability has been reported in overweight patients, increasing with the severity of obesity, 113 mainly due to mechanisms such as: action of adipocytokines, coagulation factors hyperactivity, hypofunctional fibrinolysis, increased inflammation, Ang II/Ang 1,7 imbalance, increased oxidative stress and endothelial dysfunction, lipids and glucose tolerance disorders together with metabolic syndrome, and venous stasis and impaired venous return. [114] [115] [116] Thus, obesity may have additive effects in the hypercoagulability status and thrombosis observed in certain COVID-19 patients.

It is now clear that the outcome of COVID-19 depends on the severity of both pulmonary and circulatory involvement, thus encompassing alveolar damage and local (i.e., lung) and systemic thrombosis. The evidence to date supports the development of a thrombotic process in COVID-19, which can be defined immuno-thrombo-J o u r n a l P r e -p r o o f inflammation. This is likely the consequence of derangement of multiple biological pathways, including endothelial injury, macrophages/monocytes and neutrophils activation, exacerbated by prolonged immobilization and development of antiphospholipid antibodies.

Vast questions remain on COVID-associated coagulopathy. First and foremost, we need to investigate what mechanisms are driving this pro-thrombotic phenomenon.

Importantly, we must evaluate whether the coagulopathy is driving the underlying pathophysiology of SARS-CoV-2 or if this coagulopathy is a result of secondary factors during the infection. Second, we need to identify targets for pharmacologic therapy, determine appropriate anti-coagulation, anti-platelet and anti-fibrinolytic regimens, and discern the ideal timing for initiation of such therapies. Finally, we must work to risk stratify patients at initial presentation for individual risk for development of severe COVID-19 and thromboembolism, to enable early intervention and careful monitoring.

To likely achieve improved outcomes in COVID-19, a personalized therapeutic approach is likely needed for each individual patient, based on one's personal risk of progressing towards severe illness and their current biological and metabolic derangements. It is also noteworthy that pooling data obtained from studies that used different methods and measurement units is an objective challenge. Better harmonization of both analytical and post-analytical (e.g., measurement units) variables shall be considered a research priority.

J o u r n a l P r e -p r o o f 

The novel coronavirus (2019-nCoV) outbreak: think the unthinkable and be prepared to face the challenge

Covid-19: WHO declares pandemic because of "alarming levels" of spread, severity, and inaction

Assessment and treatment of older individuals with COVID 19 multi-system disease: Clinical and ethical implications

COVID-19 and its implications for thrombosis and anticoagulation

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy

Acute pulmonary embolism and COVID-19 pneumonia: a random association?

Pulmonary embolism in patients with Covid-19 pneumonia

Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-Dimer Levels

Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence

Acute Pulmonary Embolism and COVID-19

Thrombotic risk in COVID-19: a case series and case-control study

Deep Vein Thrombosis in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: Prevalence, Risk Factors, and Outcome

Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19)

Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

SARS2-CoV-2 and Stroke in a New York Healthcare System

COVID-19 presenting as stroke

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)

ST-Segment Elevation in Patients with Covid-19 -A Case Series

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study

With Fatal Outcome: Results From a Prospective, Single-Center

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Pulmonary and systemic involvement of COVID-19 assessed by ultrasound-guided minimally invasive autopsy

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis

Coagulation abnormalities and thrombosis in patients with COVID-19

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis

D-dimer is Associated with Severity of Coronavirus Disease 2019: A Pooled Analysis

Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis

Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19

Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2

Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Endothelial cell infection and endotheliitis in COVID-19

Arterial thrombus formation in cardiovascular disease

Endothelium--role in regulation of coagulation and inflammation

Endothelial cell control of thrombosis

Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study

A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients

SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19

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

Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19

Platelets promote thrombo-inflammation in SARS-CoV-2 pneumonia

Platelet-mediated vascular dysfunction during acute lung injury

Laboratory hemostasis: from biology to the bench

Understanding the "philosophy" of laboratory hemostasis

Factor XII in Hemostasis and Thrombosis: Active Player or (Innocent) Bystander?

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

The role of mononuclear phagocytes in Ebola virus infection

Macrophages: a Trojan horse in COVID-19?

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms

Complement and tissue factorenriched neutrophil extracellular traps are key drivers in COVID-19

The significance of evaluating conventional inflammatory markers in Von Willebrand factor measurement

Fibrinogen gene regulation

Plasma Antithrombin Values Are Significantly Decreased in Coronavirus Disease 2019 (COVID-19) Patients with Severe Illness

COVID-19: ICU delirium management during SARS-CoV-2 pandemic

Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions

Functional plasminogen activator inhibitor 1 is retained on the activated platelet membrane following platelet activation

Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study

Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Lupus anticoagulant is frequent in patients with Covid-19

Characteristics of ischaemic stroke associated with COVID-19

The antiphospholipid syndrome: from pathophysiology to treatment

Association of anticardiolipin antibodies with vascular injury: possible mechanisms

Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms

The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome

Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin

Pathophysiology of the antiphospholipid antibody syndrome

Autoimmune antiphospholipid antibodies impair the inhibition of activated factor X by protein Z/protein Z-dependent protease inhibitor

Identification of anti-prothrombin antibodies in the anti-phospholipid syndrome that display the prothrombinase activity

Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?

Interference of Creactive protein with clotting times

Clinical Characteristics of Covid-19 in China

Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Circulating plasma levels of angiotensin II and aldosterone in patients with coronavirus disease 2019 (COVID-19): A preliminary report

Coronavirus disease 2019 is associated with low circulating plasma levels of angiotensin 1 and angiotensin 1,7

Vascular Actions of Angiotensin 1-7 in the Human Microcirculation: Novel Role for Telomerase

The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets

Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/-mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation

Obesity and Outcomes in COVID-19: When an Epidemic and Pandemic Collide

Obesity is Associated with More Critical Illness in COVID-19

COVID-19 and obesity: links and risks

Obesity and thrombosis

Thrombosis and obesity: cellular bases

Association between obesity and a prothrombotic state: the Framingham Offspring Study

Hypercoagulability in overweight and obese subjects who are asymptomatic for thrombotic events

Hemostatic abnormalities associated with obesity and the metabolic syndrome

Obesity, haemostasis and the fibrinolytic system

Inflammation, obesity, and thrombosis