HEPARIN AS AN ANTICOAGULANT IN COVID-19
Previous failures of anticoagulants in critical illness notwithstanding, compelling observations of coagulopathy and high rates of VTE in COVID-19 raise the possibility that heparin may benefit patient outcomes. The utility of heparin as an anticoagulant in COVID-19 was first posited by a retrospective report of 449 patients with COVID-19 from Wuhan, China, where prophylaxis in medical patients is relatively uncommon due to a low incidence of VTE (48). In this cohort, 350 patients received no heparin therapy (neither low-dose prophylactic nor high-dose therapeutic), whereas 99 had received low-dose prophylactic doses of heparin. Patients with an elevated D-dimer (>6-fold higher than the upper limit of normal) or elevated sepsis-induced coagulopathy scores that received prophylactic heparin had ~20% lower mortality than patients who had not (38). It has also been reported that intravenous tissue plasminogen activator, a potent thrombolytic, can transiently improve oxygenation in COVID-19-related acute respiratory distress syndrome, supporting clinical relevance of thrombosis in severe disease (41).
Since these initial reports, there has been one study published and two studies available in preprint format that have investigated the effects of therapeutic heparin in COVID-19. The largest available study evaluating anticoagulation was an analysis of 2,773 patients with COVID-19 in the Mount Sinai Health System (29). In patients requiring invasive mechanical ventilation included in this cohort, anticoagulation was associated with an in-hospital mortality of 29.1% compared with 62.7% for patients who did not receive anticoagulation. In contrast, this study found that patients who received anticoagulation were significantly more likely to require invasive mechanical ventilation. This report was retrospective, and the rationale for anticoagulation was not directly investigated, thus making these observations difficult to interpret. In a smaller retrospective cohort study evaluating 44 patients, those who received heparin had improved coagulation parameters and normalized immunity as evidenced by increased lymphocyte counts and decreased interleukin (IL)-6 levels compared with control subjects (35). Another group observed that initiation of heparin for 27 patients infected with COVID-19 improved oxygenation; this study did not include a control group (26). Based on these limited data, clinical treatment guidelines for COVID-19 have not yet recommended the use of therapeutic heparin or other forms of therapeutic anticoagulation (25). To address this question, a total of 18 clinical trials, 9 of which are recruiting, have been registered with the National Institutes of Health (https://www.clinicaltrials.gov/; as of June 2, 2020) to investigate the utility of therapeutic anticoagulation in COVID-19.