Coagulation markers are independent predictors of increased oxygen requirements and thrombosis in COVID‐19: Response from Original Authors Susen, et al.

We thank Bhogal and colleagues for their positive comments on our manuscript and their perspective on von Willebrand factor (VWF) being a potential driver of coronavirus disease 2019 (COVID‐19) microvascular thrombosis rather than a mere biomarker of endotheliopathy. It is well‐known that VWF promotes neutrophil recruitment to endothelial surfaces under low‐shear conditions and supports neutrophil extravasation toward inflamed tissues.¹ This pro‐inflammatory role of VWF involves two distinct pathways: (a) a direct interaction of neutrophil receptors (PSGL1 and β2‐integrins) with VWF and (b) an indirect interaction in which neutrophils adhere to VWF‐bound platelets.¹ It should also be mentioned that NETosis² and complement activation³ have been recently involved in severe acute respiratory syndrome coronavirus 2 pathogenesis and may contribute to prothrombotic clinical presentations in severe COVID‐19 patients.

Interestingly, VWF could also be directly involved in immunothrombosis and complement activation through several mechanisms. In a mouse model of transfusion‐related acute lung injury induced by anti‐HNA‐3a alloantibodies, interaction of neutrophils with VWF via the choline transporter‐like protein‐2 receptor leads to neutrophil agglutination and activation.⁴ VWF is also a binding partner of neutrophil extracellular traps (NETs) through its A1 domain⁵ and VWF fibers included in NETs promote microvascular thrombosis. Indeed, peptidylarginine deiminase type IV, an enzyme essential for NET formation, was reported to promote thrombus formation after endothelial injury through ADAMTS13 inhibition.⁶ Activated neutrophils can also release small antimicrobial peptides, known as α‐defensins, which are potent inhibitors of ADAMTS13 activity, likely by binding to VWF A2 domain.⁷ Recent evidence suggests that VWF may also promote the activation of alternative complement pathway. Importantly, this role of VWF in in complement regulation is dependent on VWF multimer size. Normal plasma VWF multimers act as cofactors in the factor I–mediated cleavage of C3b to iC3b and inhibit complement activation, whereas this regulatory role is absent with ultra‐large VWF multimers.⁸

Although being an attractive hypothesis, whether early administration of drugs disrupting VWF‐platelet GPIbα interaction could translate into improved outcomes in COVID‐19 patients remains totally unknown. An alternative approach could be to reduce VWF multimers size, and two potential options could be considered. First, the use of a recombinant ADAMTS13 concentrate.⁹ However, this molecule is still under evaluation and not yet approved for clinical application. Second, N‐acetylcysteine could be applied. This molecule has a long history of medical use, and has been shown to dissolve ultra‐large VWF multimers under different conditions in both animal models and humans.¹⁰

CONFLICT OF INTEREST

The authors declare no disclosures relevant to the manuscript.

AUTHOR CONTRIBUTIONS

Sophie Susen, Antoine Rauch, and Peter J. Lenting wrote the manuscript.