Pathophysiological mechanisms of thrombosis in acute and long COVID-19

Abstract

COVID-19 patients have a high incidence of thrombosis, and thromboembolic complications are associated with severe COVID-19 and high mortality. COVID-19 disease is associated with a hyper-inflammatory response (cytokine storm) mediated by the immune system. However, the role of the inflammatory response in thrombosis remains incompletely understood. In this review, we investigate the crosstalk between inflammation and thrombosis in the context of COVID-19, focusing on the contributions of inflammation to the pathogenesis of thrombosis, and propose combined use of anti-inflammatory and anticoagulant therapeutics. Under inflammatory conditions, the interactions between neutrophils and platelets, platelet activation, monocyte tissue factor expression, microparticle release, and phosphatidylserine (PS) externalization as well as complement activation are collectively involved in immune-thrombosis. Inflammation results in the activation and apoptosis of blood cells, leading to microparticle release and PS externalization on blood cells and microparticles, which significantly enhances the catalytic efficiency of the tenase and prothrombinase complexes, and promotes thrombin-mediated fibrin generation and local blood clot formation. Given the risk of thrombosis in the COVID-19, the importance of antithrombotic therapies has been generally recognized, but certain deficiencies and treatment gaps in remain. Antiplatelet drugs are not in combination with anticoagulant treatments, thus fail to dampen platelet procoagulant activity. Current treatments also do not propose an optimal time for anticoagulation. The efficacy of anticoagulant treatments depends on the time of therapy initiation. The best time for antithrombotic therapy is as early as possible after diagnosis, ideally in the early stage of the disease. We also elaborate on the possible mechanisms of long COVID thromboembolic complications, including persistent inflammation, endothelial injury and dysfunction, and coagulation abnormalities. The above-mentioned contents provide therapeutic strategies for COVID-19 patients and further improve patient outcomes.

Immune and metabolic perturbations in COVID‐19‐associated pulmonary mucormycosis: A transcriptome analysis of innate immune cells

“…Interestingly, the complement inhibitors, clusterin and CD59 were upregulated in the monocytes and neutrophils from the CAPM cohort. Thus, it is possible that viruses and fungi can downplay complement activation by inhibiting MAC assembly 50,51 . Coagulation is an early protective response and can be detrimental if it leads to thrombotic or haemorrhagic coagulopathy 52–54 .…”

Increased Levels of Inflammatory and Endothelial Biomarkers in Blood of Long COVID Patients Point to Thrombotic Endothelialitis

“…It has already been demonstrated that Long COVID patients have endothelialitis, together with an increased risk of thrombosis. 11 12 13 As mentioned previously, there may be various mechanisms involved in the genesis of the thrombotic endothelialitis and the formation of microlots, including viral persistence and immune dysregulation. 14 15 16 17…”

Intrinsic factors behind long‐COVID: I. Prevalence of the extracellular vesicles

“…The ECVs play multiple roles in pathophysiology associated with the long-COVID patients, as in addition to their viral genomic/proteomic cargo, the ECVs contain several coagulopathy markers, such as tissue factor and phosphatidylserine (PS), which may aggravate thrombosis. 126,127 Exosomes recovered from mild/moderate patients showed enrichment in proteins associated with immune stimulation, effector involvement, and migration/chemotaxis, which is likely to reflect a more effective functioning of the immune system. However, exosomes in severe patients harbored proteins related to metabolism, inflammation, and stress responses.…”

“…This suggests the possibility that the presence of other receptors collaborates in the SARS‐CoV‐2 entry or the ability of exosomes to transmit ACE2 to deficient cells. The ECVs play multiple roles in pathophysiology associated with the long‐COVID patients, as in addition to their viral genomic/proteomic cargo, the ECVs contain several coagulopathy markers, such as tissue factor and phosphatidylserine (PS), which may aggravate thrombosis 126,127 …”