COVID-19 and thrombosis: The role of hemodynamics

Abstract

Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, a leading cause for adverse outcomes in patients afflicted by the more serious manifestation of the disease. These thromboembolic complications expressed as sepsis-induced coagulopathy, disseminated intravascular coagulation, venous and arterial thromboembolism, pulmonary embolism, microthrombosis, and thrombotic microangiopathy have been observed to affect different organs such as the lungs, heart, kidneys, and brain. Endothelial injury and dysfunction have been identified as the critical pathway towards thrombogenesis, and contributions of other mechanisms such as hypercoagulability, cytokine storm, neutrophils have been studied. However, the contribution of hemodynamic pathways towards thrombosis in severe COVID-19 cases has not been investigated. From the classical theory of Virchow's triad to the contemporary studies on the effect of shear enhanced platelet activation, it is well established that hemodynamics plays a role in the initiation and growth of thrombosis. This article reviews recent studies on COVID-19 related thrombotic events and offers hypotheses on how hemodynamics may be responsible for some of the adverse outcomes observed in severe COVID-19 cases. While thrombogenesis through endothelial injury and the effects of hypercoagulability on thrombosis are briefly addressed, the crux of the discussion is focused on hemodynamic factors such as stasis, turbulent flow, and non-physiological shear stress and their effects on thrombosis. In addition, hemodynamics-dependent venous, arterial, and microvascular thrombosis in COVID-19 cases is discussed. We also propose further investigation of diagnostic and therapeutic options that address the hemodynamics aspects of COVID-19 thrombus formation to assess their potential in patient care.

Keywords: COVID-19; Endothelial injury; Hemodynamics; Hypercoagulability; Shear stress; Thrombosis.

Fig. 1

Virchow's triad and a few interconnected pathways contributing to thrombosis in severe COVID-19 cases. Per Virchow's triad, hypercoagulability, endothelial injury, and hemodynamics are the factors that contribute to thrombosis. While many biological pathways result in thrombosis, shown here are subfactors that either directly (e.g., prolonged patient immobilization, which leads to stasis induced thrombosis) or indirectly influence the hemodynamics (e.g., increased fibrinogen levels contribute to greater resistance to flow by increasing blood viscosity). The production of antithrombotic elements (e.g., NO and prostacyclin) initiated by endothelial injury is also disrupted through non-physiological shear stress. Some factors have a cascading effect, such as the release of vWF post endothelial injury leading platelet dysfunction, which could cause hyperviscosity leading to stasis and non-physiological shear stress.

Fig. 2

Schematics of hemodynamics parameters in a blood vessel for possible thrombus formation in COVID-19 patients. A) SARS-CoV-2 binds to ACE2 receptors causing endothelial cell injury which initiates various thrombotic pathways to form a blood clot under different environments. Endothelial cell injury exposes tissue factor, vWF, collagen, and other thrombotic factors into the bloodstream which initiate both the intrinsic and extrinsic pathways of the coagulation cascade. Furthermore, the vessel lumen reduces due to injury-induced vasoconstriction. In small vessels and capillaries, such as alveolar capillaries, vasoconstriction may have a significant impact, leading to massive capillary congestion, diffuse microthrombi, and organ damage. B) In smaller arteries, there is a reduction of the vessel lumen due to blood clot formation and vasoconstriction, leading to higher velocity and higher shear rate. Increased shear rate induces morphological changes of vWF, activating platelets and increasing thrombus formation. Downstream the thrombus, recirculation/stagnation zones are likely to present themselves, and these areas are associated with platelets deposition. C) Increase in plasma viscosity is observed in COVID-19 patients, which in smaller veins and capillaries leads to lower velocities and lower shear rates. Non-physiological low values of shear influence platelets agglutination.