Immunothrombosis in the Pathogenesis of COVID-19 Coagulopathy

SARS-CoV-2 virus causes severe multisystem disease beyond acute respiratory distress syndrome. The mechanism of nonpulmonary involvement seems to involve a coagulopathy driven by a dysregulated immune response.

Nicolai and colleagues describe the lung histopathology from a fatal case of severe COVID-19. They found microvascular thrombosis in the presence of antemortem respiratory and renal failure, myocardial injury, and dysregulated coagulation, as evidenced by elevated D-dimer. The microvascular thrombi contained platelets, fibrin, and large numbers of neutrophils. Neutrophils were also evident in microthrombi from an additional four fatal cases — also in lung, cardiac, and renal tissue.

The investigators then compared the neutrophil activation state from severe COVID-19 cases (requiring mechanical ventilation) and from patients with less severe disease (requiring only supplemental oxygen). They determined that neutrophil activation marker CD177 was highly upregulated in severe cases compared with less severe infections.

The authors next examined platelet dynamics and found a small but highly activated platelet subpopulation in severe cases. Hemostatic measurements under high shear conditions showed increased plug formation in response to collagen-epinephrine, suggestive of platelet hyperactivity in severe cases. Severe cases also showed shorter clot formation times, increased maximal clot firmness, and reduced maximal clot lysis, which correlated with neutrophil counts and illness severity. Finally, neutrophils from healthy donors were combined with platelet-rich plasma from severe cases or controls. The platelets from severe cases showed enhanced neutrophil adhesion and enhanced neutrophil extracellular trap (NET) formation. NET-like structures were subsequently identified in pulmonary, kidney, and heart specimens.