Mechanisms of thrombocytopenia in platelet-type von Willebrand disease

摘要: Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused gain-of-function variants in GP1BA leading to enhanced GPIbα-von factor (vWF) interaction. GPIbα and vWF play a role megakaryocytopoiesis, thus we aimed investigate megakaryocyte differentiation proplatelet-formation platelet-type using megakaryocytes from patient carrying the Met239Val variant mice Gly233Val variant. bound at early stage generated proplatelets decreased number of enlarged tips compared control megakaryocytes. Moreover, they formed upon contact collagen, differently normal Similarly, collagen triggered showed defective activation RhoA-MLC2 axis, which prevents proplatelet formation, increased phosphorylation Lyn, acts as negative regulator GPVI signaling, preventing ectopic on collagen. Consistently, human murine bone marrow contained extravascular controls. In addition, survival mutant was shortened mice, administration desmopressin, raising circulating vWF, marked drop count. Taken together, these results show for first time that due combination different pathogenic mechanisms, i.e. formation reduced megakaryocytes, release marrow, clearance platelet/vWF complexes.