The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

Abstract

Montreal platelet syndrome (MPS), hitherto described in only one kindred, is a hereditary thrombocytopenia associated with mucocutaneous bleeding, giant platelets, and spontaneous platelet aggregation in vitro. These are features shared with some forms of type 2B von Willebrand disease (VWD); however, the MPS kindred had not been investigated for VWD. We found that all affected MPS family members had borderline to normal von Willebrand factor antigen (VWF:Ag; 0.43-0.75 U/mL), discrepantly low ristocetin cofactor activity (VWF:RCo; 0.16-0.29 U/mL), and normal factor VIII coagulant activity (FVIII:C; 0.57-1.04 U/mL). Unaffected family members all had normal VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, persons with MPS, but not unaffected family members, had loss of plasma (but not platelet) high molecular weight VWF multimers, and were heterozygous for the previously reported V1316M type 2B VWD mutation. Thus, in reevaluating this kindred, we determined that patients with MPS have type 2B VWD with the V1316M VWF mutation. (Blood. 2009;113:3348-3351)

Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B

“…Giant platelets have also been reported in the Montreal platelet syndrome first considered to be a platelet disease, 30 but now shown to be VWD2B-associated with the presence of platelet agglutinates. 15 Giant granules are rare but well described in the ParisTrousseau syndrome 31 given by mutations of the Fli gene, but the mechanism responsible for their formation is unknown. Our results implied that enhanced binding of endogenous VWF to GPIb␣ observed in patients with VWD2B can interfere with the fine regulation of megakaryocytopoiesis.…”

“…37 Circulating platelet agglutinates were also a feature of VWD2B Tampa, 12 and they are also present in the Montreal platelet syndrome recently ascribed to a V1316M mutation as discussed in the "Introduction." 15 BSS and VWD2B are 2 syndromes with giant platelets and thrombocytopenia. The platelet morphology differs, however: BSS has round giant platelets deficient in internal membranes.…”

“…More recently, the very rare Montreal platelet syndrome, an autosomal-dominant form of inherited thrombocytopenia associated with lifelong mucocutaneous bleeding, giant platelets, and spontaneous platelet agglutination, has been recognized to be associated with the V1316M VWF mutation typical of VWD2B. 15 Given this complex background, we tested here the hypothesis of a role for VWF in human megakaryocytopoiesis. Studies were performed to evaluate the role on platelet morphology and production of the enhanced VWF-GPIb interaction using the human model of patients with VWD2B who are characterized by a gain of function of VWF.…”

Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions

“…27 The phenotype of Montreal platelet syndrome was reproduced in the mice expressing the V1316M mutation, with the presence of both macrothrombocytopenia and platelet clumping on peripheral blood smears.…”

Platelet morphological changes in 2 patients with von Willebrand disease type 3 caused by large homozygous deletions of the von Willebrand factor gene

“…However, gadolinium should be used with caution in patients with hemoglobinopathies who have severe renal dysfunction. Antonella Meloni, 1 Brunella Favilli, 1 Vincenzo Positano, 5 Platelet morphological defects have previously been described in von Willebrand disease type 2B (VWD2B), we now describe that they may also occur in patients with VWD3 lacking both platelet and plasma von Willebrand factor (VWF). Electron microscopy (EM) and immunofluorescence labeling (IF) were used to examine platelets from two VWD3 patients with a homozygous deletion involving VWF and TMEM16B genes.…”