Current Overview on Hypercoagulability in COVID-19

Namrata Singhania; Saurabh Bansal; Divya P. Nimmatoori; Abutaleb A. Ejaz; Peter A. McCullough; Girish Singhania


Am J Cardiovasc Drugs. 2020;20(5):393-403. 

In This Article

Clinical Features

Venous Thromboembolism

Venous thromboembolism (pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) is common in patients with COVID-19, even when prophylactic anticoagulation is used, and can be seen in up to two-thirds of patients in the intensive care unit (ICU). A search of the PubMed database using the key words 'hypercoagulability' and 'COVID-19' found 11 studies with a patient population of 10 or more. Details of the studies, including type, country, number of patients enrolled, mean age, sex, comorbidities, use of anticoagulation, incidence of thromboembolism, and other relevant laboratory findings are listed in Table 2. Two of 11 studies were autopsy studies. Older age, male sex, obesity, smoking and other chronic medical comorbidities, especially cardiovascular disease, hypertension, chronic bronchitis, active cancer, and diabetes mellitus were associated with a higher risk of thromboembolism.

In a post-mortem examination of 21 patients with COVID-19, alveolar and glomerular microthrombi were seen in 45% and 16.7% of individuals, respectively, while in another post-mortem study of 12 patients, DVT was seen in 58% of patients with 33% mortality due to a massive PE.[11,15] Extremely high values of D-dimer (> 20,000 ng/mL; normal value < 500 ng/mL) were found in 25% of patients. In a series of 184 patients (all patients receiving prophylactic anticoagulation) with severe COVID-19 and in the ICU, VTE was reported in 27%;[16] the study was associated with a 13% mortality rate. Age (adjusted hazard ratio [aHR] 1.05/year, 95% confidence interval [CI] 17–37%) and coagulopathy (prolongation of PT > 3 s or aPTT > 5 s; aHR 4.1, 95% CI 1.9–9.1) were found to be independent predictors of thrombosis. In another series of 150 ICU patients, 64 patients had clinically relevant thrombotic complications (mostly PE).[17] Clotting of the extracorporeal circuit was seen in 28 of 29 patients receiving continuous renal replacement therapy (RRT), and 2 of 12 patients undergoing extracorporeal membrane oxygenation (ECMO). All patients received anticoagulation (prophylactic dose, 70%; therapeutic dose, 30%). That study also compared patients with COVID-19-associated acute respiratory distress syndrome (ARDS) with a matched cohort of non-COVID-19 ARDS patients and found the rate of PE was higher in COVID-19 patients [11.7% vs. 2.1%; odds ratio (OR) 6.2, 95% CI 1.6–23.4; p < 0.008]. More than 95% of patients had elevated D-dimer and fibrinogen levels, with a considerable increase in vWF activity, vWF antigen, and factor VIII. The study also reported a positive lupus anticoagulant test in 87.7% of patients.

Similarly, a series of 107 ICU patients reported PE in 20.6%. By comparison, in two matched cohorts (one from the same time interval in the previous year and one from concurrent patients with influenza rather than COVID-19) 6.1% [absolute risk (AR) 14.4%, 95% CI 6.1–22.8%] and 7.5% (AR 13.1%, 95% CI 1.9–24.3%) of patients, respectively, reported PE.[18] The study also showed elevated D-dimer, plasma factor VIII and vWF antigen levels associated with higher PE risk. In one study of 74 ICU patients, VTE was associated with higher mortality (aHR 2.4, 95% CI 1.02–5.5.[19] The cumulative incidence of VTE was higher in the ICU than on the wards. Another study that performed screening leg ultrasounds in 26 patients with COVID-19 in the ICU who were all receiving either prophylactic-dose anticoagulation (31%) or therapeutic-dose anticoagulation (69%), found VTE in 18 (69%) patients, with a 12% mortality rate.[20] The majority of the above data were from ICU patients, however the data are limited in non-ICU patients. Two studies (314 and 71 non-ICU patients, respectively) found an incidence of VTE in the range of 6.4–21%, in spite of the majority of patients receiving anticoagulation.[21,22]

Arterial Thromboembolism

Although VTE is more commonly seen with COVID-19, there have been a few cases of arterial events such as ischemic stroke and acute limb ischemia. In one report, five COVID-19 patients younger than 50 years of age were identified with acute ischemic stroke due to large vessel occlusion during a 2-week period, compared with an average of 0.73 patients every 2 weeks over the previous 12 months.[23] The cumulative incidence rate of acute ischemic stroke was found to be between 2 and 3.7% in ICU patients[16,17] and approximately 2% in non-ICU patients.[21]

A report evaluated data from 20 patients (90% male; mean age 75 years) with COVID-19 who developed acute limb ischemia at a single institution over a 3-month period and found that the incidence of acute limb ischemia was significantly higher compared with the previous year (16.3% in 2020 vs. 1.8% in 2019; p < 0.001).[24] Surgical revascularization was performed in 17 patients, of whom 12 (71%) were successful. Re-intervention was not required in those who received postoperative heparin. The study was associated with a 40% mortality rate, which was significantly higher in older patients (81 ± 10 years vs. 71 ± 5 years; p = 0.008). The use of postoperative heparin infusion was significantly associated with improvement in survival (0% vs. 57.1%; p = 0.42). Another series reported on two young and healthy patients (37 and 53 years of age, respectively).[25] Both patients had very high D-dimer levels and were receiving prophylactic-dose anticoagulation at the time of the event. There are a few reports on ST elevation myocardial infarction (STEMI) and mesenteric ischemia.[17,26]