Thrombocytopenia in vWD type 2B

Von Willebrand factor (vWF) is a chaperone protein for coagulation factor VIII and is essential for the recruitment of platelets to the growing thrombus under conditions of high shear stress usually present in the arterial system. Deficiency (quantitative or qualitative) of vWF is associated with bleeding tendency, clinically known as von Willebrand disease (vWD).   Type 2 vWD is due to functional defect in vWF and type 2B is associated with gain-of-function mutations in the exon 28 of vWF gene resulting in an increase in the affinity of VWF for platelets. The region encoded by exon 28 binds to the platelet vWF receptor, glycoprotein Iba (GpIba). Patient with type 2B vWD present with bleeding and moderate to severe thrombocytopenia as well as a decreased in the high molecular weight vWF multimers. Thrombocytopenia is associated with the presence of giant platelets and spontaneous platelet aggregates. The molecular mechanism underlying the thrombocytopenia are unclear.

GpIba is present on the surface of megakaryocytes as well on platelets. Thus it is possible that interaction of mutated vWF from patients with type 2B vWD with megakaryocytes results in decreased platelet formation and release of giant platelets. In fact, Nurden et al showed that this may be the case. They showed that culture of megakaryocytes from controls performed with or without purified vWF had a positive influence on platelet production with specific inhibition by an antibody blocking vWF binding to GpIba . Megakaryocytes cultured with vWF from patients with type 2B vWD showed disorganized demarcation membrane system and abnormal granule distribution when examined under electron microscopy. The platelets produced from such megakaryocytes had abnormalities similar to those found in patients with vWD type 2B. This impaired megakaryocytopoiesis could not only explain the occurrence of giant platelets, but also contribute to a lower platelet count in VWD type 2B patients.

In addition to defects in platelet production, there may also be defects in platelet utilization, that is increased uptake of platelets (with attached vWF) by the monocyte-macrophage system of the body. Casari et al showed that this is also the case in a series of experiments reported here. They found that vWD type 2B platelets have a shorter circulatory half-life than wild-type (wt) platelets, which could contribute to the lower platelet counts in vWD type 2B mice. Further analysis revealed that VWF type 2B is present at the surface of platelets of thrombocytopenic
vWD type 2B mice, and that these vWF/platelet complexes were taken up efficiently by macrophages in liver and spleen. Thus, they provide direct evidence that part of the thrombocytopenia in vWD type 2B can be explained by an increased clearance of VWF/platelet
complexes.