Reply

To the Editor:

We appreciate Dr. Palmer‐Toy et al's interest in our article. We agree that vWF is an important mediator of thromboinflammation. After activation of endothelial cells and platelets, vWF is released from Weibel‐Palade bodies and platelet alpha granules, respectively, leading to a cascade of heterotypic cellular interactions that support a procoagulant and proinflammatory milieu (1). Correlations between increases in the circulating pool of vWF and severity of COVID‐19 or death resulting from complications of COVID‐19 have been reported by many investigators (2, 3, 4, 5, 6, 7), including Palmer‐Toy and colleagues.

Because polyclonal COVID‐19 antibody fractions have been shown to activate neutrophils and platelets, as well as to suppress physiologic antiviral responses, we focused on autoantibodies in our study's exploration of endothelial dysfunction in COVID‐19. Of note, we reported that purified IgG fractions from patient COVID‐19 serum samples, especially from patients with elevated circulating antiphospholipid antibodies, recapitulated activation of endothelial cells by intact COVID‐19 serum, suggesting that the circulating antibody milieu in COVID‐19 bears a foudroyant capacity to transform the endothelial surface and facilitate leukocyte adhesion. The specific targets of these antibodies and whether they ligate receptors or recognize antigens at the endothelial surface remain unknown and are worthy of investigation. Additional mechanisms of endothelial activation in COVID‐19 include denudation of the protective glycocalyx, mobilization of Weibel‐Palade bodies, and sex‐specific steroid effects. In our opinion, defining these upstream stimuli that trigger the shift away from a quiescent state likely supersedes understanding the kinetics by which the endothelium acquires a thromboinflammatory phenotype.

Although we did not examine platelet–endothelial interactions in our study, these have been described in COVID‐19 and have been shown to be, at least in part, attributable to the actions of vWF (8). Polyclonal COVID‐19 IgG pools enriched in antiphospholipid antibodies may facilitate platelet–endothelial interactions through vWF string formation, as previously reported in antiphospholipid syndrome (9, 10). We certainly support the intent of Palmer‐Toy and colleagues to promote the exploration of endothelial and hematopoietic cell interactions in pursuit of understanding the mechanisms that differentiate normal physiologic responses from their maladaptive counterparts that result in tissue injury.