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Despite the increased worldwide awareness, over the last decade, of the platelet-type von Willebrand Disease (PT-VWD), many uncertainties remain around this rare platelet bleeding disorder. This report aims to correctly identify and study the phenotype of new patients and highlights the diagnostic and therapeutic challenges this disease remains to pose. We describe four PT-VWD cases confirmed by genetic analysis in which either the diagnosis and/or the treatment posed challenge. We provide the details of the clinical presentation, laboratory analysis, and the treatment and the responses in each case. We show that in addition to type 2B VWD, PT-VWD can be misdiagnosed as idiopathic thrombocytopenic purpura, neonatal alloimmune thrombocytopenia, and unexplained gestational thrombocytopenia. The disease can be diagnosed as early as 1 year of age and with phenotypically normal parents. Bleeding in some patients can be managed successfully using Humate P and DDAVP combined with tranexamic acid with no significant thrombocytopenia. We provide for the first time an evidence of an efficient response to rFVIIa in PT-VWD. Anaphylactic reaction to VWF preparations may be related to PT-VWD and the development of HLA antibodies is not uncommon. Progressive thrombocytopenia with normal VWF levels can be seen with PT-VWD and the platelet count was normalized at 2.5 weeks postpartum in one case. We conclude that these studies represent a record of clinical observations/interventions that help improve diagnoses/management of PT-VWD, highlight the variations in age and clinical presentations, laboratory diagnostic approaches, the importance of genetic testing for accurate diagnosis and consideration of therapeutic alternatives.

: The risk of pregnancy loss in von Willebrand disease (VWD) has been inconsistently reported. Von Willebrand factor (VWF) is a known regulator of angiogenesis, so has the potential to affect placental function. We sought to determine the risk of pregnancy loss and placenta-mediated pregnancy complications in women with VWD, compared with women without VWD. Women with VWD followed in the Southern Alberta Rare Blood and Bleeding Disorders Clinic were invited to participate in a questionnaire (February-June 2014). The same questionnaire was sent to women without VWD identified in a low-risk obstetrical clinic in Calgary, Alberta, Canada. The primary outcome was the proportion of pregnancies that ended in pregnancy loss. Secondary outcomes were preeclampsia, fetal growth restriction, placental abruption, and preterm labor less than 37 weeks gestation. Of the 30 (31.6%) VWD participants that responded, 26 (86.7%) were diagnosed with Type 1 VWD, of which 11 (42.3%) had VWF antigen or activity levels less than 30%. In women with VWD, there were 20 pregnancy losses out of 80 pregnancies [25.0%, 95% confidence interval (CI), 16.81-35.48], compared with eight losses out of 50 pregnancies in the control group (16.0%, 95% CI, 8.34-28.51; P = 0.28). There was no difference in the risk of preeclampsia (1.7 versus 0%, P = 1.00) or preterm labor (16.7 versus 7.1%, P = 0.23) among VWD and control groups. There were no other placenta-mediated pregnancy complications reported. There is no significant difference in pregnancy loss between women with and without VWD; however, a large multicenter study is needed to clarify the risk of pregnancy loss in women with VWD.

Genetic variation in or near the C-type lectin domain family 4 member M (CLEC4M) has been associated with plasma levels of von Willebrand factor (VWF) in healthy individuals. CLEC4M is a lectin receptor with a polymorphic extracellular neck region possessing a variable number of tandem repeats (VNTR). A total of 491 participants (318 patients with type 1 von Willebrand disease [VWD] and 173 unaffected family members) were genotyped for the CLEC4M VNTR polymorphism. Family-based association analysis on kindreds with type 1 VWD demonstrated an excess transmission of VNTR 6 to unaffected individuals (P = .0096) and an association of this allele with increased VWF:RCo (P = .029). CLEC4M-Fc bound to VWF. Immunofluorescence and enzyme-linked immunosorbent assay demonstrated that HEK 293 cells transfected with CLEC4M bound and internalized VWF. Cells expressing 4 or 9 copies of the CLEC4M neck region VNTR showed reduced interaction with VWF relative to CLEC4M with 7 VNTR (CLEC4M 4%-60% reduction, P < .001; CLEC4M 9%-45% reduction, P = .006). Mice expressing CLEC4M after hydrodynamic liver transfer have a 46% decrease in plasma levels of VWF (P = .0094). CLEC4M binds to and internalizes VWF, and polymorphisms in the CLEC4M gene contribute to variable plasma levels of VWF.