Hyperthrombotic Milieu in COVID-19 Patients

Abstract

COVID-19 infection has protean systemic manifestations. Experience from previous coronavirus outbreaks, including the current SARS-CoV-2, has shown an augmented risk of thrombosis of both macrovasculature and microvasculature. The former involves both arterial and venous beds manifesting as stroke, acute coronary syndrome and venous thromboembolic events. The microvascular thrombosis is an underappreciated complication of SARS-CoV-2 infection with profound implications on the development of multisystem organ failure. The telltale signs of perpetual on-going coagulation and fibrinolytic cascades underscore the presence of diffuse endothelial damage in the patients with COVID-19. These parameters serve as strong predictors of mortality. While summarizing the alterations of various components of thrombosis in patients with COVID-19, this review points to the emerging evidence that implicates the prominent role of the extrinsic coagulation cascade in COVID-19-related coagulopathy. These mechanisms are triggered by widespread endothelial cell damage (endotheliopathy), the dominant driver of macro- and micro-vascular thrombosis in these patients. We also summarize other mediators of thrombosis, clinically relevant nuances such as the occurrence of thromboembolic events despite thromboprophylaxis (breakthrough thrombosis), current understanding of systemic anticoagulation therapy and its risk-benefit ratio. We conclude by emphasizing a need to probe COVID-19-specific mechanisms of thrombosis to develop better risk markers and safer therapeutic targets.

Keywords: COVID-19; Coronavirus; SARS-CoV2; VTE; embolism; endotheliopathy; kidney failure; microvascular thrombosis; myocardial infarction; respiratory failure; strokes; thrombosis.

Figure 1

Extrinsic coagulation cascade is characterized by sequential activation and amplification of downstream components that finally culminate into the generation of the fibrin clot. Tissue factor (TF) is the primary trigger of the coagulation cascade. It is activated in the damaged endothelial cells. Platelets, polymorphonuclear cells and red blood cells (RBCs) entangled in the fibrin mesh result in clot expansion. Several components of the extrinsic coagulation cascade activate the complement system, as shown in the box.

Figure 2

The prothrombotic milieu in COVID-19 patients is generated by several factors of which stimulation of extrinsic coagulation assumes a central stage. Damage to the endothelial cells activates TF which serves as the primary trigger for the extrinsic coagulation cascade. Several components of cytokine storm such as tumor necrosis factor alpha (TNF-α), interleukin-1 β (IL-1β) and interleukin-6 (IL-6) (through their cognate receptors and hypoxia associated with shock) upregulate TF mRNA in the endothelial cells. Other cells involved in the thrombotic process such as platelets and polymorphonuclear cells (PMNs) are activated in the milieu of cytokine storm and secrete TF-laden microparticles that augment thrombogenesis. SARS-CoV-2 RNA in the blood can serve as an activator of extrinsic coagulation cascade. (Insert) IL-6 augments thrombosis by several mechanisms. IL-6 increases the secretion of prothrombotic von Willerbrand facror (VWF) and factor VIII from liver and induces thrombocytosis in bone marrow. It also downregulates protein S in blood, a known inhibitor of thrombogenesis.