Heparin as a therapy for COVID-19: current evidence and future possibilities

Abstract

Coronavirus disease 2019 (COVID-19), the clinical syndrome associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has impacted nearly every country in the world. Despite an unprecedented focus of scientific investigation, there is a paucity of evidence-based pharmacotherapies against this disease. Because of this lack of data-driven treatment strategies, broad variations in practice patterns have emerged. Observed hypercoagulability in patients with COVID-19 has created debate within the critical care community on the therapeutic utility of heparin. We seek to provide an overview of the data supporting the therapeutic use of heparin, both unfractionated and low molecular weight, as an anticoagulant for the treatment of SARS-CoV-2 infection. Additionally, we review preclinical evidence establishing biological plausibility for heparin and synthetic heparin-like drugs as therapies for COVID-19 through antiviral and anti-inflammatory effects. Finally, we discuss known adverse effects and theoretical off-target effects that may temper enthusiasm for the adoption of heparin as a therapy in COVID-19 without confirmatory prospective randomized controlled trials. Despite previous failures of anticoagulants in critical illness, plausibility of heparin for COVID-19 is sufficiently robust to justify urgent randomized controlled trials to determine the safety and effectiveness of this therapy.

Keywords: COVID-19; heparin; venous thromboembolism.

Fig. 1.

Structure and function of heparin. Heparins are a heterogeneous mix of heparan sulfate (HS) glycosaminoglycans. Each HS strand is composed of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) or iduronic acid (IdoA). GlcNAc can be sulfated at three distinct sites (-6S, -NS, and -3S) and IdoA at one (-2S). Unfractionated heparin is composed of HS chains that are >30 saccharides in length, whereas low-molecular weight heparin constituent HS chains are 22 saccharides or less (3). The charge distribution of heparin imparted by the presence of the precise pentasaccharide sequence shown allows for the binding of heparin to serine protease inhibitor antithrombin-III (AT3), conferring its primary anticoagulant effect. Innumerable other sulfation sequences are found in heparin preparations, which leads to binding and biologically relevant activity modulation of many other proteins.

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.

Fig. 3.

Summary of potential therapeutic effects of heparin in coronavirus disease 2019 (COVID-19). 1) Heparin’s classic function as an anticoagulant, through its interaction with antithrombin-III (AT3), may prove beneficial because of the high prevalence of coagulopathy and clinically significant thrombosis in the disease. 2) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into both endothelial and epithelial cells is believed to be dependent on its interaction with cell surface heparan sulfate; thus, heparin (or carefully designed synthetic heparin-like drugs) may inhibit this interaction and block viral entry. 3) Last, heparin has known anti-inflammatory effects that may confer benefit in COVID-19. This illustration was created with BioRender (https://biorender.com/). ACE2, angiotensin-converting enzyme 2; APC, activated protein C; HS, heparan sulfate; IL, interleukin; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TNF, tumor necrosis factor; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator, VII, factor VII.