key: cord-331481-zeaqi1uc
authors: Al-Ani, Fatimah; Chehade, Samer; Lazo-Langner, Alejandro
title: Thrombosis risk associated with COVID-19 infection. A scoping review
date: 2020-05-27
journal: Thromb Res
DOI: 10.1016/j.thromres.2020.05.039
sha: 
doc_id: 331481
cord_uid: zeaqi1uc

BACKGROUND: Infection by the 2019 novel coronavirus (COVID-19) has been reportedly associated with a high risk of thrombotic complications. So far information is scarce and rapidly emerging. METHODS: We conducted a scoping review using a single engine search for studies assessing thrombosis and coagulopathy in COVID-19 patients. Additional studies were identified by secondary review and alert services. RESULTS: Studies reported the occurrence of venous thromboembolism and stroke in approximately 20% and 3% of patients, respectively. A higher frequency seems to be present in severely ill patients, in particular those admitted to intensive care units. The thrombotic risk is elevated despite the use of anticoagulant prophylaxis but optimal doses of anticoagulation are not yet defined. Although and increase of biomarkers such as D-dimer has been consistently reported in severely ill COVID-19, the optimal cut-off level and prognostic value are not known. DISCUSSION: A number of pressing issues were identified by this review, including defining the true incidence of VTE in COVID patients, developing algorithms to identify those susceptible to develop thrombotic complications and severe disease, determining the role of biomarkers and/or scoring systems to stratify patients' risk, designing adequate and feasible diagnostic protocols for PE, establishing the optimal thromboprophylaxis strategy, and developing uniform diagnostic and reporting criteria.

The World Health Organization (WHO) declared the 2019 novel coronavirus (SARS-CoV-2) a pandemic on March 11, 2019 . The number of confirmed cases as of May 17 are over 4.5 million with over 300,000 confirmed deaths (https://www.who.int) 1 . Up to 14% of infected patients sustain interstitial pneumonia, and may evolve to acute respiratory distress syndrome requiring intensive care unit (ICU) admission, and may be accompanied by multiorgan failure 2 .

Recent findings from a pooled analysis suggested a prominent increase in D-dimer levels as a predictor of adverse outcomes was persistently seen in coronavirus disease 2019 (COVID- 19) suggesting the presence of underlying coagulopathy 3 . There is an increasing evidence that severe COVID-19 seems to be associated with pro-hemostatic state with a potential impact on thromboembolism risk, but the nature and extent of these abnormalities is not clear. Given the rapid emergence of new evidence we sought to conduct a scoping review of coagulopathy and thrombosis risk associated with COVID-19 infection with the aim of providing an overview of the current knowledge on this topic and potentially inform new areas of research.

The review is registered in Open Science Framework and the study protocol is publicly available (https://osf.io/zm2gk/). We conducted a literature search using a single search engine through J o u r n a l P r e -p r o o f 8 500 mg/L in the survivors (p<0.05) 10 . Similarly, Zhou et al. (n=191) reported a significantly higher D-dimer of around 9-fold was seen in non-survivors as compared to survivors with severe disease (81% vs. 24%; p< 0.001) 14 . Furthermore, Tang et al. reported similar findings with a higher D-dimer being seen in non survivors (n=21) (2. 12 [0.77-5.27 ]) compared to survivors (n=162) (0.61 [0. 35-1.29 ]) (p<0.001) 9 . Similarly, D-dimer was associated with disease severity in a study by Gao et al 15 . More recently, a study summarized the clinical characteristics of 25 death cases with COVID-19 in Wuhan 16 . In 9 of 12 patients where the test readings were available, the last level of D-dimer measured was higher as compared to the first test. Finally, a recent Irish prospective study that assessed coagulopathy in Caucasian patients with COVID-19 17 suggested the presence of significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the Chinese cohorts. Similarly, D-dimer levels were significantly higher in non-survivors compared to survivors during the disease.

Overall, the studies consistently reported a significant increase in D-dimer. More importantly, the D-dimer increase was dynamic, meaning it seems to continue to rise as the disease progresses and reflected a prognostic indicator of mortality. However, most of the studies were retrospective except for two prospective studies that included a small number of patients (n=41) 11, 12 .

Furthermore, many of those papers were conducted at a single center. Limitations of evidence include: 1) all studies were limited to a single ethnic population, and extrapolation of this data to other populations might not be accurate, and 2) except for the study by Tang With regards to association with mortality, Zhou and colleagues reported a significantly higher prothrombin time (>16 seconds) in non-survivors (n=54) compared to survivors (n=137) (13% vs. 3%; p=0·0004) 14 . Another study echoed that association in which significantly longer prothrombin time found in non-survivors (n=21) compared to survivors (n=162) on admission (p < 0.001) 9 .

Moreover, Fogarty and colleagues found no significant difference in PT between survivors and no-survivors on admission 17 . Unlike Chinese studies, no progressive increase in PT was observed in the adverse prognostic group.

Several studies reported no difference in platelets count between ICU and non-ICU patients 8, 10, 11 . In the study by Guan al. around half (46.6%) of patients with one or more composite outcomes (ICU admission, the use of mechanical ventilation, or death) had a platelet count less than 150 8 . With regards to mortality, Zhou et al. reported that a platelet count of less than 100 was more frequently seen in non-survivors than survivors (20% vs 1%) 14 22 . Interestingly, researchers also J o u r n a l P r e -p r o o f 11 noted an initial increase in fibrinogen with advanced COVID-19; however, the level tended to be significantly lower in non-survivors and was associated with a decrease in antithrombin levels.

This observation might indicate that a hypercoagulable status associated with the course of severe COVID-19 infection could be related to prognosis. A second study reported a significantly higher incidence of DIC reported among non survivors compared to survivors (6.4% vs. 0, p = 0.006), however, the study did not provide a DIC definition 24 . Moreover, in the study by Fogarty et al., despite the increased D-dimer level, DIC was not evident 17 . Another study reported DIC in 2.1% of 388 patients, with no bleeding complications but a high mortality (88%) 25 . Other 2 studies have reported an association of DIC with disease severity but they have serious methodological limitations 7, 8 .

Overall, studies have reported marked derangement in hemostasis in non survivors with markedly elevated D-dimers, prolonged prothrombin time, and increase in fibrin degradation products. However, modest degree of thrombocytopenia and high fibrinogen levels were observed with advanced COVID-19 disease as opposed to significant reduction in those levels with DIC seen with sepsis 6 . This finding was echoed in a recent Italian study in which the pattern of prothrombotic coagulopathy and DIC was different from that in sepsis, where platelets count is usually decreased, and the prothrombin time is prolonged with associated hemorrhagic tendency 12 . Therefore, DIC associated with severe COVID-19 infection could represent a distinct entity of coagulopathy. In case reports of COVID-19 patients, PE was identified in patients with no VTE risk factors 28 .

A case series of post-mortem autopsy found that venous thromboembolism was present in 7 of 12 (58%) patients with COVID-19, with PE being the direct cause of death in 4 (33%) 29 .

Similarly, alveolar damage on autopsy was reported in 2 more studies 30 J o u r n a l P r e -p r o o f 13 was diagnosed in 4 patients (2.9%). Of these, 3 were critically ill. Critically ill patients were defined as being admitted to the ICU and requiring mechanical ventilation or requiring at least 60% FiO2 to maintain oxygen saturation at an acceptable level. In total, 15 patients were defined as critically ill, which meant that in this small sample size, VTE was present in 20% of critically ill patients. All 4 patients who developed DVTs did so despite use of routine thromboprophylaxis with either low molecular weight heparin (LMWH) or unfractionated heparin (UFH) 32 . A more recent and larger study reviewed COVID-19 patients admitted to the ICU at three centres in the Netherlands (n=184) 34 . In this study, patients were enrolled from the time they were admitted to ICU. Patients were followed until they were discharged from ICU, died, or until the study period ended. All patients received standardized doses of subcutaneous nadroparin although the exact dose regimen varied by centre. One centre used 2,850 international units (IU) per day, or 5,700 IU per day if body weight was greater than 100 kg. The second centre used Crude cumulative composite outcome of venous and arterial events was 57%, or 49% when adjusting for competing risk of death. Authors did note that 17 patients entered the study already on long-term therapeutic anticoagulation (although the exact drug was not specified), and of these, 3 patients developed PE. They also noted that diagnoses were made using CT and ultrasound on basis of suspicion, with no screening. However, CT pulmonary angiogram was used more liberally to investigate patients who were not weaning off the ventilator, especially after the results of the initial study were published 35 .

Another retrospective study from the Netherlands included 198 patients (74 in ICU, 124 on a medical ward) admitted to the Amsterdam University Medical Centres 36, 37 . Patients were classified as ward patients if they remained stable enough to be on the medical ward, or ICU patients if they went to ICU at any point during their clinical course. All ICU patients required J o u r n a l P r e -p r o o f 15 mechanical ventilation in this study. All ICU patients were given thrombosis prophylaxis. at standard or double doses. The primary outcome, which included distal or proximal DVT, PE, or venous thrombus in another site, occurred in 33 patients (17%) with an additional patient developing an extensive thrombophlebitis requiring therapeutic anticoagulation. Cumulative incidence calculated using a competing risk model was 15% at 7 days and 34% at 14 days. When considering only symptomatic VTE, the cumulative incidence was 11% at 7 days and 23% at 14 days. The incidence of VTE was drastically different when comparing ICU vs ward patients (39% versus 3.2%). In this study, patients were investigated for thrombotic events based on clinical suspicion, but also were screened at regular intervals.

A third study included COVID-19 patients admitted for ARDS in France included 150 patients admitted to four ICUs at two centres of a tertiary care hospital and compared them to a historical database of patients admitted for ARDS from bacterial and other viral sources using propensity score matching 38 . Primary endpoint was any venous or arterial thrombotic event, and secondary endpoint was to compare the primary endpoints, but also to assess thrombosis of renal replacement therapy (RRT) machines and median lifespan of the machines, ECMO oxygenator coagulation, along with assessing for hemorrhagic complications and coagulation parameters.

Out of the 150 patients initially enrolled, there were 25 (16.7%) documented PE and 3 (2%)

DVT. After matching, COVID-19 ARDS patients had statistically significant higher rates of PE (11.7% versus 2.1%). There were also higher rates of RRT related thrombotic events. However, other venous and arterial thrombotic events, as well as bleeding, were not significantly different. The results of this study showed an elevated risk of pulmonary embolism in patients with COVID-19 induced ARDS compared to a population of patients with ARDS from other causes.

This study may have underestimated the rate of VTE, given many of the enrolled patients were still intubated at the time the data was reported. This study also demonstrates that the risk of VTE is higher despite the use of guideline-recommended thromboprophylaxis. Furthermore, the coagulopathy seen in COVID-19 was not related to a true DIC, nor was there a high rate of SIC.

It could mean that the coagulopathy, and coagulation, is due to a different mechanism. The role of antiphospholipid antibodies also remains unclear.

A fourth study including 26 COVID-19 patients admitted to the ICU reported the occurrence of VTE in 69% of patients, using routine ultrasound screening despite the use of prophylactic or therapeutic anticoagulation 40 . Two additional studies from the United Kingdom and China reported in 9% and 25% of patients, respectively. 41, 42 .

The largest study included 388 patients (362 closed cases) 61 of whom were admitted to the ICU in Milan, Italy 25 . The median duration of hospitalization was 10 days This study reported thromboembolic events in 7.7% of closed cases with a cumulative rate of 21%. The incidence was higher for patients admitted to the ICU (proportion 16.7% versus 6.4%; cumulative rate 27.6% versus 6.6%). The authors did note that half of the thromboembolic events were diagnosed within 24 hours of hospital admission, raising speculation that thrombosis may be either an early complication of COVID-19 or a determinant of further deterioration.

A study from a tertiary care hospital in France evaluated 106 confirmed COVID-19 patients for presence of PE using CTPA. Of the 106 patients, 32 (30%) were found to have PE present on J o u r n a l P r e -p r o o f 17 CTPA and 5 of which were in subsegmental arteries only. Patients with PE tended to have higher D-dimer than those who were negative 43 .

Another French study analyzed data of 280 COVID-19 patients admitted between March 15 to April 14 44 . Ultimately, 100 of these patients had contrast CT pulmonary angiography to investigate for presence of PE. Of the 100 patients scanned, 23 (23%) were positive for PE.

Authors noted patients with PE were more likely to be mechanically ventilated and tended to have their CT scan performed with a longer delay after initial symptom onset. Although not a direct comparison, this finding may contradict the findings from Lodigiani et al. 25 While all the previous studies included a significant proportion of patients admitted to an intensive care unit, a recent study conducted in Northern Italy evaluated a group of 388 patients admitted to a non-ICU ward. In this study no patient was found to have a DVT, including 64 patients who had routine lower extremity ultrasound screening. The authors did not comment on whether any of these patients developed PE 45 .

Overall, these studies including 1765 patients reported the occurrence of VTE in approximately 20% of patients but with cumulative incidences up to 49% during hospitalization. There were significant differences in screening strategies and definition of outcomes ( Table 2) . Given the discrepant findings in the reported studies, a post-hoc meta-analysis was conducted (Table 3) and the results suggested that, a) the proportion of VTE is much higher in studies including mostly patients admitted to an intensive care unit and, b) the estimates have a high statistical heterogeneity and there may be a risk for publication bias as suggested by a funnel plot analysis.

Regarding cerebrovascular disease a case series from New York described 5 patients with SARS-CoV-2, all less than 50 years old, who presented with acute ischemic stroke. Only one had a history of prior stroke 46 Table 4 . A retrospective study of 214 COVID-19 patients admitted to hospital was conducted in Wuhan. Six (2.8%) patients had acute stroke, 5 of them classified as having "severe" disease. Although no definition was provided, patients with "severe" disease had higher frequency of co-morbidities including hypertension and were older on average 47 . Reports from other groups are very similar with a reported occurrence of stroke between 2.7% and 3.8% of patients 25, 34, 35, 38, 42 . Overall, all studies included 973 patients with a pooled proportion (random effects model) of 3.5% (95% CI 2.4 to 4.8) with no statistical heterogeneity.

A case report highlighted the possibility of cardiovascular arterial thrombosis in a patient presenting with ST segment myocardial infarction in whom coronary angiography and optical coherence tomography revealed the presence of thrombus without atheroma, and therefore, it was hypothesized that in-situ thrombosis was responsible for their formationCOVID-19 48 .

Findings of cardiovascular thrombosis have been seen in other studies as well 25 .

Diagnosis of thromboembolic disease can be difficult in patients with SARS-CoV 2 infection. Patients with severe disease requiring hospitalization often have elevated D-Dimer levels since it is considered as an acute phase reactant, thus limiting its utility as a screen for venous thromboembolism 9 because, although it has a very high sensitivity for thrombotic disease, its specificity is poor 49 

Effect of Heparin on Mortality. Given the potential severity of the disease in hospitalized patients, as well as the risk of thrombosis, current guidelines recommend using pharmacological DVT prophylaxis in all patients. However, these recommendations are based on general thromboprophylaxis, and are not specific to COVID-19 5, 6 . There is no general agreement on the optimal dosing in this setting, and various papers have suggested heterogeneous protocols. was defined as meeting one of the following criteria: respiratory rate  30, arterial oxygen saturation  93% at rest, or a P/F ratio  300 mmHg. A total of 449 severe COVID-19 patients were evaluated in the study. All COVID-19 patients received antivirals and supportive care. 99 (22%) of these patients received either UFH (10,000-15,000 units/day) or LMWH (Enoxaparin 40-60 mg/day). There was no difference in mortality in heparin users vs non-users. However, in a subset of COVID-19 patients who had D-Dimer levels > 3.0 g/mL (six-fold the upper limit of normal), there was a statistically significant decrease in mortality in heparin users vs non-users 

Although data is sparse, a study from Italy Data regarding when patients are most at risk of thrombosis are lacking. While some studies seem to suggest thrombosis may be an early finding 25 , others have found thrombotic events occurring even after patients are discharged from hospital 48 . This highlights a need for more research, and whether these events can be more accurately predicted by biomarkers, such as Ddimer. Several studies suggest substantial coagulation activation with severe COVID-19 infection likely related to sustained inflammatory response due to cytokines release induced by virus invasion. Pulmonary vasculature thrombosis is likely to be at least in part a result of the severe hypoxia for hypoxia is a profound stimulant of coagulation 56 . The most prominent coagulation marker is the marked and dynamic elevation of D-dimer levels that has been consistently reported in those studies, potentially representing a prognostic indicator for severity and mortality. The high D-dimer probably indicates a severe inflammatory response accompanied by a secondary hypercoagulable state. In fact, D-dimer is also a marker also of J o u r n a l P r e -p r o o f 24 pulmonary fibrin deposition typical of several lung diseases, notably ARDS 57 , commonly seen in severe COVID-19. This is supported by data showing that the time course of D-dimer elevation mirrors that of other inflammatory markers including ferritin, interleukin 6, troponin I and lactate dehydrogenase 14 . Moreover, DIC as defined by the ISTH score demonstrated to be a significant finding among non-survivors indicating that it is an adverse prognostic marker 9 . Of note, platelet count seems to be only mildly reduced in general, and prothrombin time showed persistent elevation as opposed to the expected reduced fibrinogen levels seen in DIC with sepsis.

However, those studies have methodological limitations mainly related to sample size and short incomplete follow up. Additionally, it has been demonstrated that D-dimer reagents are not interchangeable when assessing their use for clinical diagnosis of VTE 58, 59 . Currently, it is not known whether this would be a limitation for their use in prognostic models in COVID-19 patients. Properly conducted prospective studies are needed in this area.

The significant and overwhelming inflammatory response in patients with severe COVID-19 infection may increase the likelihood of thromboembolic disease and in turn explain the high frequency of VTE, particularly in patients admitted to the ICU. However, it is unclear if COVID-19 is more likely to cause venous or arterial thrombosis than other conditions. It has been previously reported that patients with severe sepsis (non-COVID-19) or septic shock have a very high incidence of VTE of up to 37% despite the use of guideline-recommended thromboprophylaxis 60 , and it is known that general ICU patients frequently fail VTE prophylaxis (4.45%, 7.14%, 7.53% at 7, 14 and 21 days, respectively) 61 . Inferences on the risk of VTE in patients with COVID-19 need to be interpreted in this context, keeping in mind that severe sepsis causes a similar picture with higher rates of VTE despite adequate VTE prophylaxis although some evidence suggests that indeed COVID-19 has a higher thrombotic risk compared to J o u r n a l P r e -p r o o f 25 patients admitted to the ICU for other causes 38 . An important point is the fact that there is no information regarding the risk of thrombosis after hospital discharge. This topic needs to be urgently addressed.

An emerging hypothesis worth considering is the possibility that the pathophysiology of the pulmonary thrombotic events in COVID-19 may not be embolic at all which could have major implications for treatment. Support for this hypothesis comes from both pathology and clinical data. A review of 10 autopsies of COVID-19 patients (5 men, 5 women) found evidence of microthrombi in lung tissue, raising the speculation that in-situ pulmonary thrombosis may be the culprit pathophysiological mechanism 62 . From a clinical perspective, several studies have found that a disproportionate high number of venous clotting events are pulmonary thrombi [34] [35] [36] 38 without an associated increase in deep vein thrombosis 45 . Given this data, we and other authors question whether the high number of PE are due to embolic events, or rather, in-situ pulmonary thrombosis 45 and pose the question of whether focusing on anticoagulation is the right approach to decrease the thrombotic risk in COVID-19 patients as treating all patients with higher doses of anticoagulants without a clear indication may be more harmful.. It seems that thrombosis, be it macro or microvascular, is the result of the severe inflammatory response induced bu SARS-CoV-2 with its subsequent endothelial dysfunction and procoagulant environment and thus targeting inflammation in conjunction with rational anticoagulant management might be a preferable approach.

For this reason, some groups have proposed a staging classification that considers both clinical and laboratory criteria and suggests potential treatments for each stage 63 

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Research (CanVECTOR) Network; the CanVECTOR Network. The CanVECTOR Network receives grant funding from the Canadian Institutes of Health Research (Funding Reference:CDT-142654).