Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19

Abstract

Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis.

Keywords: Anti-thrombotics in COVID-19; Anticoagulation in COVID-19; COVID-19; Coagulopathy; Deep vein thrombosis in COVID-19; Pulmonary embolism in COVID-19; Thrombosis.

Fig. 1

Dysregulation of Pro-thrombotic and Anti-thrombotic Factors Contributing to COVID-19 Thrombosis. Thrombosis in COVID-19 results from a complex interplay involving a functional imbalance of pro-thrombotic and anti-thrombotic factors contributing to an increase in clinical thrombotic risk. Elevations in cytokines and chemokines promote endothelial injury, increased eicosanoid expression, and enhanced platelet interactions, leading to thrombosis. Downregulation or “escape” from anti-thrombotic mechanisms through impaired fibrinolytic pathways and reduction in anti-thrombin III potentiates this pro-thrombotic state.

Fig. 2

Key therapeutic targets for anti-thrombotic therapies based on the integrated mechanisms of COVID-19 thrombosis. Strategies to treat thrombotic events in COVID-19 should be driven by the severity of thrombosis and established standards of care translated to patient specific needs. Studies are underway to determine if immunomodulation can reduce thrombosis risk. Inhibition of thromboxane A2 and prostaglandins by aspirin, inhibition of the P2Y1A receptor with clopidogrel, or inhibition of the protease activated receptor with vorapaxar may represent early preventative strategies for thrombosis in at risk COVID-19 patients. Intravenous use of argatroban or oral use of dabigatran to treat thrombosis in COVID-19 may offer significant benefit based on reduced levels of anti-thrombin III which may impair strategies centered around heparin or low molecular weight heparins. Intravenous tPA has been used successfully to treat cerebral embolism in COVID-19. Endothelitis may be potentially treated with pentoxifylline, dipyridamole, or statins.