COVID‑19 and ischemic stroke: Mechanisms of hypercoagulability (Review)

Abstract

During the coronavirus disease 2019 (COVID‑19) pandemic, some patients with severe COVID‑19 exhibited complications such as acute ischemic stroke (AIS), which was closely associated with a poor prognosis. These patients often had an abnormal coagulation, namely, elevated levels of D‑dimer and fibrinogen, and a low platelet count. Certain studies have suggested that COVID‑19 induces AIS by promoting hypercoagulability. Nevertheless, the exact mechanisms through which COVID‑19 leads to a hypercoagulable state in infected patients remain unclear. Understanding the underlying mechanisms of hypercoagulability is of utmost importance for the effective treatment of these patients. The present review aims to summarize the current status of research on COVID‑19, hypercoagulability and ischemic stroke. The present review also aimed to shed light into the underlying mechanisms through which COVID‑19 induces hypercoagulability, and to provide therapies for different mechanisms for the more effective treatment of patients with COVID‑19 with ischemic stroke and prevent AIS during the COVID‑19 pandemic.

Keywords: COVID‑19; coronavirus; acute ischemic stroke; hypercoagulability; anticoagulation.

Figure 1

HIFs, cytokines, NETs, phosphatidylserine and the complement system promote coagulation. HIF-1, cytokines, C5a, MAC and NETs increase the expression of tissue factor, which activates extrinsic blood coagulation, while HIF-1, HIF-2, cytokines and C5a promote the expression of PAI-1, which impairs fibrinolysis. Cell membrane phosphatidylserine can provide a catalytic surface for coagulation factors, promoting intrinsic and extrinsic FXa and thrombin production. NETs promote XIIa, intrinsic FXa, and thrombin production. HIF-1, hypoxia inducible factor -1; HIF-2, hypoxia inducible factor -2; PS, phosphatidylserine; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; NETs, neutrophil extracellular traps; MAC, membrane attack complex.

Figure 2

NETs contribute to SARS-CoV-2-induced acute ischemic stroke by activating endothelial cells and platelets. SARS-CoV-2 enters blood vessels through the ACE2 receptor on cerebrovascular endothelial cells. The virus activates neutrophils to release NETs through a cytokine storm derived from activated macrophages. NETs initiate thrombosis by activating endothelial cells and platelets. NETs, neutrophil extracellular traps; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3

Antithrombotic strategies for different stages of COVID-19-associated acute ischemic stroke. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NETs, neutrophil extracellular traps; MPs, microparticles; CRP, C-reactive protein; Fib, fibrinogen; ARDS, acute respiratory distress syndrome; SO2, oxygen saturation of hemoglobin; LMWH, low molecular weight heparin; tPA, tissue plasminogen activator; HrsACE2, human recombinant soluble angiotensin-converting enzyme 2.