Role of von Willebrand Factor and ADAMTS-13 in the Pathogenesis of Thrombi in SARS-CoV-2 Infection: Time to Rethink
Nuccia Morici, Maurizio Bottiroli, Roberto Fumagalli, Claudia Marini, Marco Cattaneo
Abstract
There is growing evidence supporting the idea that vascular occlusions in pulmonary and systemic circulation are among the most severe and common causes of poor outcome in COVID-19 patients.[1] [2] [3] [4] [5] [6] [7] These vascular events appear to be mostly caused by local formation of thrombi, rather than by venous thromboembolism, which likely form as a consequence of a thromboinflammatory process, triggered by viral infection-induced endothelial damage and cytokine storm, with consequent activation of hemostasis leading to thrombus formation and boosting inflammation further.[8] Among the several hemostasis players that are implicated in thromboinflammation, von Willebrand factor (VWF) has a leading role.[9] [10] [11] VWF plays two important roles in normal hemostasis: it carries factor VIII and mediates platelet-vessel wall and platelet-to-platelet interaction, especially at high shear, through its binding to the platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa.[12] VWF is a multimeric protein that is released into the circulation from endothelial stores in a highly thrombogenic form, characterized by the presence of ultralarge multimers. Under normal circumstances, these ultralarge multimers are cleaved by the protease ADAMTS-13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and, consequently, the high thrombogenicity of released VWF is reduced.[12] [13] [14] Conditions that are associated with congenital or autoantibody-induced ADAMTS-13 deficiency are characterized by increased incidence of thrombotic complications, which may be very severe and potentially fatal, as in thrombotic thrombocytopenic purpura (TTP).[15] [16] Acquired deficiency of ADAMTS-13 is associated also with systemic disorders, including severe inflammatory diseases and sepsis.[9] [10] [17] Considering that COVID-19 is a severe inflammatory disease, it is plausible that it is associated with acquired ADAMTS-13 deficiency and, hence, increased thrombogenicity of VWF.