Editorial Focus Platelet-Type von Willebrand Disease: Toward an Improved Understanding of the “Sticky Situation” Maha Othman, MD, MSc, PhD 1,2 Jonas Emsley, PhD 3 1 Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada 2 Health Sciences, St Lawrence College, Kingston, Ontario, Canada 3 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom Semin Thromb Hemost Address for correspondence Maha Othman, MD, MSc, PhD, Department of Biomedical and Molecular Sciences, Queen’s University, Boterell Hall Room 513, Kingston, ON K7L 3N6, Canada (e-mail: Othman@queensu.ca). We are pleased to highlight in this issue of Seminars in Thrombosis & Hemostasis, the study by Wood et al, 1 wherein the authors describe a novel mutation in the platelet GP1BA gene creating a hyperresponsive GPIbα protein—a receptor for von Willebrand factor (VWF)—and causing platelet-type von Willebrand disease (PT-VWD). This is a new naturally occurring mutation in a 23-year-old male patient and is considered the sixth reported mutation thus far in patients described with this disease worldwide. Despite being a rare bleeding disorder, PT-VWD represents a significant challenging clinical problem as it may cause life-threatening bleeding, if not appropriately treated, particularly in situations related to surgeries and childbirth. The clinical diagnosis challenge stems from the close similar- ity of PT-VWD to the more common bleeding disorder, type 2B VWD. 2,3 The discrimination and correct diagnosis can only be made after carefully assessing less commonly performed laboratory tests, 3–8 and confirmed only after DNA analysis of the binding regions in the two genes VWF and GP1BA 9 has been performed. The report by Woods et al 1 highlights some important issues that add to our understanding of this rare but poten- tially life-threatening bleeding disorder. First, the patient presented with severe bleeding symptoms (rather than mild/moderate bleeding symptoms, and unlike previously reported cases) while also showing other typical laboratory phenotypic data known in this disease such as macrothrom- bocytopenia, mild spontaneous platelet aggregation, absence from plasma of high-molecular-weight VWF multimers, positive ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.4 mg/mL, VWF ristocetin cofactor (VWF:RCo) < 10 IU/dL, and VWF:RCo to VWF antigen (VWF:Ag) ratio of less than 0.2. The authors initiated the diagnosis via meticu- lous laboratory assessment, including RIPA mixing tests and cryoprecipitate challenge tests, and ultimately providing comprehensive laboratory discrimination from type 2B VWD. In addition, they confirmed their diagnosis by DNA analysis, by revealing a c.3805 G >T GP1BA gene mutation that predicted the protein change Try246Leu. This mutation was absent in the unaffected mother and also in 100 healthy control subjects. Second, in that report, 1 an attempt was made to quantify the bleeding symptoms in a patient with PT-VWD (bleeding score of 13). The knowledge about variation in bleeding symptoms and the ability to objectively assess these symp- toms have proven to be important in management of bleeding disorders and can help predict disease outcome and also aid in treatment. 10 The only other such attempt was in a small case series reported recently. This series showed considerable variability in bleeding severity among PT-VWD that is inde- pendent of age or gender. The phenotypic variability in type 2B VWD has been reviewed in relation to various mutations and different patients’ cohorts. 12 However, a systematic analysis of PT-VWD phenotype and the genotype–phenotype relationship remains to be investigated. Third, for the first time, the level of VWF propeptide (VWFpp) and VWFpp/VWF:Ag ratio was reported in a patient with PT-VWD. 1 VWFpp is a 741 amino acid portion that gets cleaved from mature VWF by proteolysis. After cleavage, the VWFpp remains in noncovalent association with the VWF multimers, and both are stored together in the α-granules (megakaryocytes/platelets) or Weibel–Palade bodies (endo- thelial cells). Upon release and under physiologic pH, the VWF multimers and VWFpp dissociate and are secreted in 1:1 stoichiometric amounts. 13 Studies have shown a regulatory role for VWFpp as an intramolecular chaperone for the mature VWF protein and an aid to its storage and multi- merization. 14,15 The VWFpp circulates in the plasma for a short time, with a half-life of approximately 2 to 3 hours and plasma levels of approximately 1 μg/mL, whereas multimeric VWF circulates with a half-life of approximately 8 to 12 hours and plasma levels of approximately 10 μg/mL. 16,17 Recent Issue Theme Quality in Hemostasis and Thrombosis, Part III; Guest Editors, Emmanuel J. Favaloro, PhD, FFSc (RCPA), Giuseppe Lippi, MD, and Mario Plebani, MD. Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI http://dx.doi.org/ 10.1055/s-0033-1364182. ISSN 0094-6176. Editorial Focus