Thromboprophylaxis for COVID-19-related coagulopathy: what next?

Patients hospitalized with coronavirus disease 2019 (COVID-19) are at high risk for microand macrovascular thromboembolic events due to thromboinflammation and the coagulopathy caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).1,2 Because of its proven anticoagulation effect, coupled with possible antiviral and anti-inflammatory effects, heparin was the first candidate for prevention of adverse events in COVID-19 patients.2 Yet, a recent meta-analysis of seven clinical trials using low-molecular-weight heparin (LMWH) or unfractionated heparin suggests no difference in all-cause death between the therapeutic-, i.e. escalated, and standard-dose anticoagulation in hospitalized COVID-19 patients without a formal indication for anticoagulation therapy.3 The escalated dose significantly reduced the rates of pulmonary and other venous thromboembolism, but was associated with a higher bleeding risk.3 The findings were consistent with regard to the disease severity (critically vs. non-critically ill COVID-19 patients).3 It is important to note that the aforementioned meta-analyis3 did not include the most recent HEP-COVID trial,4 the first randomized trial using a classic antithrombotic clinical trial design. This trial, similarly to another important report by the REMAP-CAP, ACTIV4a, and ATTACC Investigators,5 suggests that therapeutic-dose LMWH reduced the risk of thromboembolism and death in non-critically ill patients. These two well-designed studies strongly suggest the use of escalated anticoagulation in this group of hospitalized patients, particularly with elevated D-dimer levels. In contrast, current data agree that escalation of heparin dose in critically ill COVID-19 patients requiring intensive care unit treatment provides no benefit,3,4,6 so the anticoagulation strategy in such patients is uncertain. In addition to coagulopathy, hyperinflammation, and endothelial disruption, mechanisms responsible for the lack of a beneficial effect in critically ill patients may include lung-related mechanisms. First, therapeutic-dose anticoagulation may exacerbate alveolar haemorrhage in patients with severe pulmonary inflammation.6 Second, the processes of intra-alveolar coagulation that through isolation of pulmonary pathogens may