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


The management of hypercoagulability in COVID-19 can be challenging due to limited data. Although all hospitalized patients are at higher risk for thrombosis, ICU patients are at the highest risk (incidence 1.1% in non-ICU patients vs. 79% in ICU patients).[3] It is recommended to start prophylactic-dose anticoagulation with low molecular weight heparin (LMWH) in all acutely ill hospitalized patients unless contraindicated.[30] Many experts suggest initiating intermediate-dose (LMWH 30–40 mg subcutaneously twice daily) or full-dose anticoagulation in critically ill individuals with COVID-19 due to the high percentage of patients with VTE despite receiving prophylactic anticoagulation.[16,31–33] Due to the lack of high-quality studies favoring such interventions, and the risks of bleeding associated with antithrombotic therapies, some medical societies have deferred from adopting these recommendations in universal guidelines.[30] In addition, data are lacking comparing different doses of anticoagulation (prophylactic or therapeutic) in patients with COVID-19. Most institutions have made their own criteria to manage coagulopathy in these patients. It is advised to balance the risks of thrombosis with bleeding while making decisions regarding antithrombotic therapy. The ISTH has also issued interim guidelines to manage coagulopathy in COVID-19.[34]

In a pre-proof retrospective study of 2773 patients hospitalized with COVID-19, patients who received anticoagulation (786 patients, 21%) had an in-hospital mortality rate of 22.5% and a median survival of 21 days, compared with 22.8% and a median survival of 14 days in those who did not receive anticoagulation.[35] A significantly higher number of patients required mechanical ventilation in those who did not receive anticoagulation compared with those who did (29.8% vs. 8.1%, p < 0.001). The in-hospital mortality rate was 29.1% and a median survival of 21 days in a subgroup of intubated patients who received anticoagulation compared with a mortality rate of 62.7% and a median survival of 9 days in those who were intubated but did not receive anticoagulation. In a multivariate proportional hazard model, a longer duration of anticoagulation was associated with a reduced risk of mortality (aHR 0.86/day, 95% CI 0.82–0.89; p < 0.001). Of a total of 62 patients who received anticoagulation, 24 had bleeding events (not statistically significant); of those 24 patients, 15 had bleeding events after starting anticoagulation. The above study had multiple limitations, such as its retrospective observational nature, unknown reasons for not starting prophylactic anticoagulation in 79% of patients, unobserved confounding factors, and a lack of metrics to classify patients based on severity. Another retrospective study of 449 patients (99 patients received anticoagulation for > 7 days) with severe COVID-19 (defined as a respiratory rate of ≥ 30 breaths/min, arterial oxygen saturation ≤ 93% at rest, and PaO2/FiO2 ≤ 300 mmHg), 28-day mortality benefit was found in patients who received heparin and had either a high sepsis-induced coagulopathy score (40% with heparin vs. 64.2% without; p = 0.029) or a high D-dimer of more than sixfold the upper limit of normal (32.8% vs. 52.4%; p = 0.017).[9] This mortality benefit was not significant in the cohort as a whole.

The recommended prophylactic dose of LMWH for patients with creatinine clearance (CrCl) > 30 mL/min is 40 mg once daily, and 30 mg once daily for CrCl 15–30 mL/min. For patients with a body mass index > 40 kg/m2, it is recommended to increase the dose by 30%. Unfractionated heparin should be considered in patients with CrCl < 15 mL/min or receiving RRT, or in those where an invasive procedure is anticipated, such as a cesarean section. Other medications, such as dalteparin (5000 units once daily), nadroparin (3800–5700 units once daily), and tinzaparin (4500 units once daily), are alternatives in other parts of the world. Therapeutic-dose (full-dose) anticoagulation (e.g. LMWH 1 mg/kg every 12 h) is appropriate in patients with documented VTE, similar to those individuals without COVID-19, and in a few cases of suspected VTE where confirmatory testing is not feasible and the patient developed unexplained respiratory failure with stable chest radiograph, along with elevated D-dimer and/or fibrinogen levels. More than 70% of the studies summarized in Table 2 showed D-dimer levels being positively correlated with risk for VTE or illness severity. D-dimer levels were in the range of 1600–40,000 ng/mL (normal range < 500 ng/mL).[21] Full-dose anticoagulation is appropriate for individuals with recurrent clotting of intravascular access devices (arterial lines, central venous catheters) or extracorporeal circuits, such as continuous RRT or ECMO, despite prophylactic-dose anticoagulation. Alternative therapy should be considered in patients with contraindications for heparin, such as heparin-induced thrombocytopenia or active or recent bleeding. Tissue plasminogen activator can be used in cases of arterial thrombosis, such as acute limb ischemia, acute STEMI, acute ischemic stroke, and massive bilateral PE associated with hemodynamic instability. Surgical consultation is recommended in patients with acute mesenteric ischemia. In patients with severe acute kidney injury, initiating RRT is recommended. Patients with COVID-19 and documented VTE need at least 3 months of anticoagulation post-discharge from the hospital, with appropriate follow-up. A few patients who are at high risk, such as those with immobilization due to recent surgery and trauma, may need post-discharge prophylaxis even without documented VTE. Rivaroxaban 10 mg daily for 31–39 days is considered a reasonable alternative as outpatient prophylaxis in such high-risk patients.[36]