COAGULOPATHY AND THROMBOSIS IN COVID-19
Many patients with COVID-19 develop a clinically significant coagulopathy (7, 32). The coagulopathy associated with COVID-19 is characterized by thrombocytopenia, minor prolongation of prothrombin time (PT) and partial thromboplastin time (aPTT), and elevated serum D-dimer and fibrinogen, consistent with a consumptive coagulopathy (7). This profile is compatible with postmortem examinations of patients with COVID-19 describing severe endothelial injury, microangiopathy, and alveolar capillary microthrombi (2) Endotheliitis directly elicited by SARS-CoV-2 may be the pathophysiologic link to these postmortem findings (39).
In addition to laboratory and histopathological evidence of disordered coagulation and endothelial injury, several reports suggest that patients with COVID-19 are at high risk for developing clinically significant large-vessel thrombosis. Early anecdotal evidence of venous thromboembolism (VTE) in critically ill patients has been confirmed by multiple case series describing high rates of VTE in COVID-19, with incidence estimates ranging between 8% and 54% (18, 22), significantly exceeding those reported in critically ill patients with H1N1 influenza of 2% (36) and sepsis of 5% (30). Reports of large-vessel strokes in patients, including those younger than 50 yr, infected with SARS-CoV-2 also suggest hypercoagulability (28). Concordantly, a postmortem study of 12 patients positive for COVID-19 found thrombosis in 58% of cases, which was found to be responsible for 25% of deaths (45).
Taken together, it is likely that COVID-19-associated coagulopathy and thromboses contribute to the morbidity and mortality of the disease. However, it is important to recognize that other non-COVID-19 critical illnesses have demonstrated similar evidence of coagulopathy, yet failed to benefit from anticoagulation treatment in randomized controlled studies. For example, coagulopathy has been widely recognized as a contributor to organ failure in sepsis, a disease characterized by circulating D-dimer concentrations that approximate levels observed in patients with COVID-19 (Fig. 2; 10, 32, 38, 40). However, studies that have targeted this coagulopathy in sepsis with thrombomodulin (40), AT3 (42), tissue factor pathway inhibitor (1), and activated protein C (31) have all failed to improve mortality, despite improving laboratory indexes of coagulopathy. These studies suggest that coagulopathy may simply be a consequence of sepsis, as opposed to a key pathogenic driver of disease. Alternatively, as discussed below, coagulation may impart both harmful and protective effects within the injured lung, negating any clinical benefit (or harm) from anticoagulant therapy.
Fig. 2.  Coagulopathy in sepsis compared with coronavirus disease 2019 (COVID-19). Circulating levels of D-dimer, a marker of coagulopathy, have been found to be significantly and similarly elevated in sepsis and COVID-19. This panel represents medians and interquartile range. Studies: Bernard et al. (10), Vincent et al. (40), Tang et al. (38), and Richardson et al. (32). NYC, New York City; pts, patients; RCT, randomized controlled trial.