The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management

Abstract

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

Keywords: COVID-19; SARS-CoV-2; coagulopathy; inflammation; thrombosis.

Fig. 1

Pathophysiology of the Hypercoagulable State in COVID-19. The current understanding of the pathophysiology of COVID-19 induced coagulopathy centers around the bidirectional cross-talk between inflammation (yellow arrows) and thrombosis (black arrows). COVID-19 leads to a severe inflammatory response that originates in the alveoli. Release of inflammatory cytokines leads to activation of epithelial cells, monocytes and macrophages. Direct infection of the endothelial cells through the ACE2 receptor also leads to endothelial activation and dysfunction, expression of TF, and platelet activation and increased levels of VWF and FVIII, all of which contribute to thrombin generation and fibrin clot formation. Thrombin, in turn, causes inflammation through its effect on platelets which promote NET formation in neutrophils. It also activates endothelium through the PAR receptor, which leads to release of C5A that further activates monocytes. These mechanisms are currently hypothetical based on existing findings in COVID-19 and previous understanding of the cross-talk between inflammation and thrombosis. ACE2: Angiotensin-converting enzyme 2. FVIII: Factor VIII. IL: Interleukin. NET: Neutrophil extracellular trap. TF: Tissue factor. TNF: Tumor necrosis factor. VWF: von Willebrand factor.