Figure 1.

Model for platelet-type von Willebrand disease (PT-VWD)-associated thrombocytopenia explains a defect in platelet formation and clearance. Megakaryocytes (MK) mature in the bone marrow and express von Willebrand factor (VWF) that is typically stored in their alpha (α) granules and the glycoprotein Ib (GPIb) receptor. PT-VWD is caused by a gain-of-function (GOF) variant in GPIbα that results in spontaneous binding to VWF. Thrombocytopenia present in PT-VWD seems to result from diverse mechanisms. 1) Ectopic platelets are released in the bone marrow due to enhanced Lyn phosphorylation (Lyn-P) as a result of the GPIb-VWF interaction and Lyn-P blocks the normal RhoA-dependent inhibition of proplatelet formation in the presence of collagen. 2) PT-VWD MK release larger but less (pro)platelets. 3) GPIb-VWF positive platelets are more rapidly released from the blood circulation. WT: wild type.