COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management

Abstract

Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.

Keywords: COVID-19; SARS-CoV-2; arterial thrombosis; coagulopathy; deep venous thrombosis; endothelial dysfunction; pulmonary arterial thrombosis; pulmonary embolism; venous thromboembolism.

Figure 1.

The schema illustrates the proposed mechanisms of SARS-Cov-2-induced coagulopathy. The virus not only enters the host lung epithelial cells but can invade endothelial cells, as well. Infection of host cells leads to the release of damage- or danger-associated molecular patterns (DAMPs) (host biomolecules that can initiate and perpetuate a noninfectious inflammatory response by activating the innate immune system), and also the release of proinflammatory cytokines and chemokines. Furthermore, leukocytes and platelets are recruited and activated that finally lead to initiation of intravascular thrombin generation which further activates endothelial cells, platelets and leukocytes in a continuous feedback loop that perpetuates thrombin generation and thrombosis. In this cascade, complement activation also plays a prothrombotic role by recruiting leukocytes and amplifying platelet activation and enhancing endothelial dysfunction and proinflammatory actions. The hypoxic milieu can further enhance these processes. This thrombotic cascade finally leads to clinical manifestations of this viral coagulopathy that include deep vein thrombosis, pulmonary embolism, arterial thrombosis, microvascular thrombosis and ischemic stroke. NETs = neutrophil extracelluar traps; PolyP = polyphosphate; TF = tissue factor; vWF = Von Willebrand factor.