The VWD2B saga continues to Montreal

In this issue of Blood, Jackson and colleagues report that members of a large family with severe thrombocytopenia, spontaneous platelet aggregation, and giant platelets (which was previously published as MPS) possess the V1316M VWD2B mutation. This observation, which is important for patient care, highlights the link between VWF and platelet production.

Von Willebrand disease type 2B (VWD2B), a disease with an autosomal dominant inheritance, is characterized by an abnormal VWF structure resulting in enhanced affinity to platelet glycoprotein (GP)Ibα. The mutations that account for this modified function occur in exon 28 of the VWF gene and give rise to heterozygous amino acid substitutions in the VWF A1 domain. These result in gain-of-function binding to GPIbα.¹  Clinically, this inherited disease is responsible for a bleeding syndrome that can be severe. Biologically, it is characterized by positive ristocetin-induced platelet agglutination (RIPA), a defect in the largest multimers of VWF, and variable degrees of thrombocytopenia. Circulating platelet agglutinates have also been described in rare VWD2B families. All of these findings are present in the family described by Jackson et al.²  Classically, the thrombocytopenia in VWD2B has been attributed to enhanced elimination of platelets coated with VWF bound to platelet GPIbα. This new report suggests that altered platelet production may contribute to the VWD2B phenotype in some families. In this regard, we have recently shown defective megakaryocytopoiesis in a VWD2B family with a R1308P mutation,³  confirmed recently in a second family with the same mutation.⁴  In VWD2B, severity of thrombocytopenia is variable, but always more pronounced during surgery, pregnancy, and stress periods, when VWF synthesis is increased. Using a nanobody, Federici et al showed that VWF circulates in increased amounts in a GPIbα-binding conformation in VWD2B patients, at levels inversely correlated with the degree of thrombocytopenia.⁵ 

When Montreal platelet syndrome (MPS) patients were first described, the VWD2B saga was just beginning.⁶  It is in light of the current knowledge of VWD2B that Jackson et al have reconsidered the diagnosis of the giant platelet syndrome in this family. It is very important to recognize the involvement of VWF in this disease for the prevention and treatment of bleeding episodes. It is of interest that, while the patients responded well to VWF concentrates, the best results were when platelet transfusions were given simultaneously. This story illustrates the link between giant platelet syndromes and VWD2B, a link which is progressively being established but is not yet really understood. The binding of abnormal VWF to the platelet surface is an important factor in explaining the disappearance of platelets and the loss of large VWF multimers through facilitated cleavage by ADAMTS13.⁷  But this phenomenon cannot directly explain the presence of giant platelets in the circulation.

Another lesson from the report by Jackson et al is the absolute need to investigate RIPA and VWF in patients with unexplained congenital macrothrombocytopenia, with or without spontaneous agglutination. The analysis of exon 28 of the VWF gene should also be considered because, in some cases, the affinity of the remaining mutated VWF for GPIbα is so high that the observed ratio between VWF:Ag and VWF:RCo can be normal.³  The second very important point for the saga of VWF and thrombocytopenia is to focus on the origin of the abnormal platelets; the authors raise questions about the implication of a specific mutation for the observed phenotype. The figure shows an identical phenotype for a French patient with the same mutation, showing that MPS indeed occurs elsewhere. The search for modifier genes explaining the heterogeneity in VWD2B is for the future. Another key question concerns the role of VWF during megakaryocytopoiesis. How does the abnormal VWF in the bone marrow affect platelet production? Are joined platelets really agglutinated after they have been produced or are they incompletely separated during megakaryocytopoiesis? The saga of VWD2B is not closed and new episodes are required.