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Editorials
mulation as likely cause of a (pro)platelet formation defect.8 Interestingly, the proplatelet formation defect present in mouse VWD2B MK could be rescued by treatment with LIMkinase (LIMK) or RhoA kinase (ROCK1) inhibitors.8 Moreover, the defect in platelet count and size could be res- cued in VWD2B mice that were treated with a LIMK inhibitor.8 This pathway was not studied in PT-VWD mod- els, and it would be very interesting to see if a similar approach could also rescue the thrombocytopenia in PT- VWD mice. The possibility of ectopic platelet release in
VWD2B was not studied in the mouse model, but a bone marrow aspirate in a child with VWD2B revealed the pres- ence of large platelet clumps and megakaryocyte nuclei sur- rounded by halos of clumped platelets.9 Further studies should be performed to strengthen this initial finding. Finally, enhanced clearance of VWF-platelet complexes has been suggested to occur in VWD2B.10 Studies in VWF2B mice have shown the involvement of macrophages in the removal of such VWF-platelet complexes, and significantly more platelets were found in liver and spleen of VWD2B
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 (a) granules and the glycoprotein Ib (GPIb) receptor. PT-VWD is caused by a gain-of-function (GOF) variant in GPIba 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.
haematologica | 2019; 104(7)