key: cord-1032962-tfe96ix0
authors: Angelini, Dana E.; Kaatz, Scott; Rosovsky, Rachel P.; Zon, Rebecca L.; Pillai, Shreejith; Robertson, William E.; Elavalakanar, Pavania; Patell, Rushad; Khorana, Alok
title: COVID‐19 and venous thromboembolism: A narrative review
date: 2022-02-15
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12666
sha: 05c910b163c8d955956a02d54c4bee9232f61cff
doc_id: 1032962
cord_uid: tfe96ix0

COVID‐19 (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) is associated with coagulopathy through numerous mechanisms. The reported incidence of venous thromboembolism (VTE) in hospitalized patients with COVID‐19 has varied widely, and several meta‐analyses have been performed to assess the overall prevalence of VTE. The novelty of this coronavirus strain along with its unique mechanisms for microvascular and macrovascular thrombosis has led to uncertainty as to how to diagnose, prevent, and treat thrombosis in patients affected by this virus. This review discusses the epidemiology and pathophysiology of thrombosis in the setting of SARS‐CoV‐2 infection along with an updated review on the preventative and treatment strategies for VTE associated with SARS‐CoV‐2 infection.

The novel coronavirus COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) has led to a global pandemic, with over 272 598 201 cases and 5 334 221 deaths as of December 16, 2021 (https://coron avirus.jhu.edu/map.html; accessed December 16, 2021 ). In addition to respiratory complications, early reports discussed higher rates of venous thromboembolism (VTE) in patients with severe COVID-19 disease compared to data from similar patients not affected by SARS-CoV-2. 1-3 Coagulation abnormalities are common in patients with COVID-19, and those with severe illness frequently have elevated coagulation markers, such as D-dimer and fibrinogen degradation product, with several proposed mechanisms of hypercoagulability. 4, 5 As such, preventing and treating VTE in patients with COVID-19, particularly in the inpatient setting, is of paramount importance.

The increased risk of VTE in severe SARS-CoV-2 infection was reported early in the pandemic, although there has been a high variability of reported rates. In one of the first reports, Cui et al 1 retrospectively evaluated 81 patients with severe COVID-19 hospitalized in a single institution in China and reported 25% (20/81) of intensive care unit (ICU) patients developed VTE. In this study, no preventative anticoagulant was administered. Another early report from the Netherlands described a similar VTE incidence of 27% in patients with severe COVID-19 admitted to the ICU, despite the use of pharmacologic VTE prophylaxis. 6 Other institutions have reported a smaller incidence of VTE. For example, data from the Brigham and Women's Hospital reported a 14-day cumulative incidence of symptomatic VTE of 9.3% in patients with COVID-19 who required an ICU level of care. 7 The variability in reporting is likely due to several confounders including individual institutions' VTE prophylaxis strategy, length of study, deep vein thrombosis (DVT) screening procedures, patient selection, reporting bias, and outcome definitions. Several meta-analyses and pooled aggregates have been published in an attempt to describe a more accurate depiction of the prevalence of VTE in patients with COVID-19.

A meta-analysis of 21 studies that included nearly 2000 patients with COVID-19 reported that the weighted mean prevalence (WMP) of VTE was 31.3%, with similar results seen in ICU patients (WMP, 32 .7%) and in those who received standard VTE prophylaxis (WMP, 23 .9%). The WMP of VTE was 37.1% in studies that employed routine DVT screening, whereas the WMP of VTE was 29.4% in studies that performed diagnostic imaging solely based on clinical suspicion. 8 Similarly, a meta-analysis reported by Hasan et al 9 ing versus no screening. The overall VTE prevalence was 14.1%, with higher rates found in patients with ultrasound screening versus no screening (40.3% and 9.5%, respectively). VTE prevalence was lower (7.9%) in non-ICU patients compared to those who required an ICU level of care (22.7%).

The reported rates of venous thrombosis in the published randomized control trials that aimed to assess clinical outcomes using different doses of anticoagulation (standard prophylactic dose vs higher-than-standard dose anticoagulation) are noted in Table 1 .

Aside from the HEP-COVID trial, 12 which reported thromboembolism in 29% in a standard anticoagulation dose group versus 10.9% in a therapeutic anticoagulation dose group, these trials reported much lower rates of VTE compared to rates noted in the observational studies. The difference in these rates may reflect early reporting bias in addition to current early diagnostic and treatment strategies (ie, antiviral/corticosteroids that have since become standard of care).

It is important to note, however, that these trials were not powered for venous thrombosis as a primary end point. However, the true incidence of VTE may be even higher than reported in these studies, as pulmonary embolism (PE) may be the cause of sudden respiratory decompensation in severely ill patients with COVID-19. A German autopsy study of patients who died of COVID-19 revealed venous thrombosis in 58% of patients, in whom VTE was not suspected before death. In this study, PE was the cause of death in 4 of 12 autopsy specimens. 13 Another autopsy study described thrombosis of small and midsized pulmonary arteries in all 11 patients examined. 14 

The RIETE registry is an ongoing, international, multicenter prospective registry of patients with acute VTE. This group analyzed clinical features and outcomes of 455 patients with COVID-19 who had a VTE during their hospital admission. In this registry, men comprised 71% of the population, and the median age was | 3 of 15

had isolated DVT. At the time of VTE diagnosis, 88% were receiving pharmacologic VTE prophylaxis. The mortality rate was 12% within 10 days, and 2.9% of patients had a major bleeding event. 15 Hematologic and inflammatory laboratory abnormalities have been found to correlate with disease severity in patients with COVID-19. Specifically, elevations in fibrinogen, fibrinogen degradation product, C-reactive protein (CRP), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), and D-dimer have been found to be associated with increased severity of disease. [16] [17] [18] Severe thrombocytopenia and lymphopenia have also been associated with poorer outcomes, both independently and in the setting of disseminated intravascular coagulation (DIC). 19, 20 Obtaining these clinical parameters may provide further information for the prediction of VTE (as discussed below) as well as overall prognosis.

Hospitalized patients with COVID-19 share many risk factors for VTE as traditional inpatients including older age, obesity, ICU level of care, and immobility. However, in addition to these well-established VTE risk factors, severe SARS-CoV-2 infection is associated with coagulopathy and an inherent increased risk of thromboembolic complications. 21 Early reports from China described the risk of mortality from severe SARS-CoV-2 infection was associated with older age in addition to an abnormal coagulation profile similar to DIC. 22 In this study, 71% of nonsurviving patients with COVID-19 meet criteria for DIC using the ISTH criteria. 23 There are, however, some differences between traditional DIC seen in sepsis and the coagulopathy seen in patients with severe COVID-19. For example, DIC due to sepsis usually results in a more profound consumptive coagulopathy and thrombocytopenia compared to the coagulopathy seen in patients with COVID-19. 24 It is proposed that the relative lack of consumptive coagulopathy may be why patients with COVID-19 are more prothrombotic rather than disease evolution into a bleeding propensity due to hyperfibrinolysis. Also in SARS-CoV-2 infection, there is a predilection for thrombotic microangiopathy to affect the lung vasculature, rather than widespread systemic organ damage from microthrombosis. 25 Several studies have reported widespread microangiopathy and thrombosis within the pulmonary vasculature of patients with COVID-19. 14, 26, 27 Localized pulmonary thrombi may be one mechanism for the predilection of PE over DVT in patients with COVID-19. It has been postulated that localized pulmonary thrombi (as opposed to PE) may develop as a consequence of pulmonary vascular damage and severe localized inflammation. 27 COVID-19 is thought to promote coagulation by several mechanisms. The virus interacts with the angiotensin-converting enzyme 2 receptor on endothelial cells, which can cause severe endothelial inflammation with a resultant shift toward a procoagulant state with microvascular coagulopathy. 28 The robust inflammatory response is thought to play a primary role in COVID-19-induced coagulopathy by several mechanisms. Microorganisms accumulate polyphosphates, which activate the contact pathway of coagulation. 29 Complement activation, endothelial injury, platelet activation, and cytokines such as IL-6 also play notable roles in thrombogenesis. 30, 31 There have also been several reports of positive antiphospholipid antibodies in critically ill patients with COVID-19. [32] [33] [34] [35] However, it is not clear whether these antibodies are reactive (as often seen in critical illness), or whether they contribute to a direct causative role of developing thrombosis. Stringent design of data collection and interpretation is needed to understand the role of antiphospholipid antibodies in COVID-19 coagulopathy. Overall, the coagulopathy of COVID-19 likely results from a mixture of inflammation with endothelial dysfunction, low grade DIC, and microvascular thrombosis ( Figure 1 ).

With the known risks of micro-and macrovascular thromboses, there have been numerous attempts to identify predictive biomarkers for VTE in patients with COVID-19. The previously mentioned early report from Cui et al 1 reported that VTE was associated with a lower lymphocyte count, longer activated partial thromboplastin time (aPTT), and higher D-dimer quantification. Quantitative D-dimer was one of the first biomarkers studied in patients with COVID-19. A multicenter retrospective study reported by Al-Samkari et al 36 quantified that D-dimer >2500 had an adjusted OR of 6.79 for developing thrombosis. Additional biomarkers predictive of VTE in this study included platelet count >450 × 10 9 /L (adjusted OR, 3.56), CRP > 100 mg/L (adjusted OR, 2.71), and ESR >40 mm/h (adjusted OR, 2.64). However, this study also reported that D-dimer was associated with increased bleeding (adjusted OR, 3.56). Another study found that male sex, elevated admission CRP, and elevated admission platelet count were associated with VTE risk in a univariate analysis, although only male sex continued to show predictions in the multivariate analysis. 7 It is known that men are at increased risk for recurrent VTE compared to women, but the risk of a first VTE is similar among both sexes. It is postulated that men are more at risk than women when hospitalized for COVID-19 because those hospitalized in the initial waves of the pandemic were typically older adults, which removes the traditional VTE risk factors in women such as oral contraception and pregnancy. One study demonstrated that an elevated prothrombin fragment 

In addition to differing protocols for obtaining imaging studies (symptomatic versus screening), another contributing factor for the disparate rates of VTE reported across institutions may be due to the varying practices surrounding the use of prophylactic anticoagulation. Because COVID-19 has been associated with thrombotic complications, there has been an intense debate surrounding the optimal prophylactic anticoagulation management for these patients. Several

studies early in the pandemic demonstrated improved survival and lower VTE rates with the use of pharmacologic VTE prophylaxis. [40] [41] [42] [43] However, there is an ongoing debate about using higher-thanstandard prophylactic anticoagulation (intermediate or therapeutic

doses of anticoagulation) in inpatients with COVID-19. A recent review comparing and contrasting major societal guidelines found that the most common theme was to take an individualized approach to patient management and that randomized controlled trials (RCTs) to address these important anticoagulation issues are much needed. 44 Given the observation of increased thrombotic events, especially in patients with more severe disease, higher-than-prophylactic doses of anticoagulation were used during the early phase of the pandemic.

However, the retrospective observational data for such intermediate or therapeutic dosing has been mixed; some studies showed a potential improvement in outcomes with higher doses of anticoagulation in some, but no difference or worse outcomes in others. [45] [46] [47] There are now emerging data from prospective randomized trials to address the question of optimal thromboembolism prophylaxis.

Of note, these trial outcomes were composite outcomes of thrombo- Table 1 Additional bleeding rates from published trials are listed in Table 1 .

Bleeding in this population may be related to thrombocytopenia, hyperfibrinolysis, and coagulation abnormalities along with therapeu-

itself. These data highlight the importance of balancing the risk of bleeding when considering thromboprophylaxis in this population. The initial choice between UFH and LMWH should be determined on the basis of the patient's clinical parameters like hemodynamic stability, renal function, and the potential need for invasive procedures.

In non-critically ill inpatients, LMWH is the preferred first-line agent for treatment of VTE because it does not require laboratory monitoring and minimizes exposure and personal protective equipment use.

For patients with contraindications to LMWH, UFH should be used and provides the advantage of prompt reversal of the anticoagulant effect with discontinuation of the infusion and protamine sulfate.

Monitoring UFH using aPTT can be unreliable in the setting of baseline abnormalities in coagulation tests, 64 and patients with COVID-19

have been reported to have a prolonged aPTT. 22, 72 Therefore, it is important to obtain baseline aPTT before starting heparin infusion. In patients with a prolonged aPTT at baseline, anti-Xa assays should be preferred for monitoring the therapeutic range of UFH. 64 Another potential issue with the use of UFH reported in some patients with COVID-19 is heparin resistance, which is defined as the levels. The C-trough levels for DOACs were more than six times higher during hospitalization compared to prehospitalization levels. 

Wang et al 77 been an intense interest and explosion of randomized trials to answer some of these important and still unanswered clinical questions. Table 2 includes several randomized studies near recruiting or actively recruiting patients with COVID-19 to study the optimal approach for VTE prevention. Figure 2 highlights some emerging data that will help answer these important clinical questions.

The COVID-19 pandemic has affected hundreds of millions of people worldwide, and it is known that SARS-CoV-2 infection is associated with coagulopathy and an increased risk of VTE. The pathophysiology of thrombosis in severely ill patients with COVID-19 is likely multifactorial due to an intense immune-inflammatory response, endothelial injury, and microvascular thrombosis. Worldwide, the medical community has worked tirelessly to improve prediction, diagnostic approach, prevention, and treatment of VTE in these patients. Despite these efforts, the optimal VTE prediction tools, thromboprophylaxis, and treatment strategies are still not clear. Many well-designed prospective studies are under way to optimize our clinical approach to these patients. Given the recent resurgence of COVID-19 cases, the medical community will continue to press forward in effort to provide highquality data to help answer these important questions. 

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All authors contributed to the organization of the work and contributed to writing and revising the manuscript critically for accuracy and completeness.

Rachel P. Rosovsky @RosovskyRachel

William E. Robertson @medikprof