Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses. © Schattauer 2011.1053501508Sadler, J.E., Rodeghiero, F., Provisional criteria for the diagnosis of VWD type 1 (2005) Journal of Thrombosis and Haemostasis, 3 (4), pp. 775-777. , DOI 10.1111/j.1538-7836.2005.01245.xTitani, K., Kumar, S., Takio, K., Amino acid sequence of human von Willebrand factor (1986) Biochemistry, 25 (11), pp. 3171-3184Mancuso, D.J., Tuley, E.A., Westfield, L.A., Worrall, N.K., Shelton-Inloes, B.B., Sorace, J.M., Alevy, Y.G., Sadler, J.E., Structure of the gene for human von Willebrand factor (1989) Journal of Biological Chemistry, 264 (33), pp. 19514-19527Federici, A.B., Mannucci, P.M., Stabile, F., Canciani, M.T., Di, R.N., Miyata, S., Ware, J., Ruggeri, Z.M., A type 2b von Willebrand disease mutation (lle 546 &gtVal) associated with an unusual phenotype (1997) Thrombosis and Haemostasis, 78 (3), pp. 1132-1137Casonato, A., Sartorello, F., Pontara, E., Gallinaro, L., Bertomoro, A., Cattini, M.G., Daidone, V., Pagnan, A., A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: An elusive phenotype and a difficult diagnosis (2007) Thrombosis and Haemostasis, 98 (6), pp. 1182-1187. , DOI 10.1160/TH07-05-0347Baronciani, L., Federici, A.B., Beretta, M., Cozzi, G., Canciani, M.T., Mannucci, P.M., Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding (2005) Journal of Thrombosis and Haemostasis, 3 (12), pp. 2689-2694. , DOI 10.1111/j.1538-7836.2005.01638.xTakimoto, Y., Imanaka, F., Type 2B Hiroshima: A variant of von Willebrand disease characterized by chronic thrombocytopenia and the presence of all von Willebrand factor multimers in plasma (1999) Int J Hematol, 70, pp. 127-131Poon, M.C., Rand, M.L., Jackson, S.C., 2B or not to be - The 45-year saga of the Montreal Platelet Syndrome (2010) Thromb Haemost, 104, pp. 903-910Weiss, H.J., Meyer, D., Rabinowitz, R., Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers (1982) New England Journal of Medicine, 306 (6), pp. 326-333Miller, J.L., Castella, A., Platelet-type von Willebrand's diseaseCharacterization of a new bleeding disorder (1982) Blood, 60 (3), pp. 790-794Miller, J.L., Platelet-type von Willebrand disease (1996) Thrombosis and Haemostasis, 75 (6), pp. 865-869Favaloro, E.J., Bonar, R., Meiring, M., Street, A., Marsden, K., 2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD (2007) Thrombosis and Haemostasis, 98 (2), pp. 346-358. , DOI 10.1160/TH06-12-0693Whalley, I.N., Perry, D.J., 2B or not 2B? Differential identification of Type 2B, versus pseudo-,von Willebrand disease (2007) Br J Haematol, 136, p. 345. , author reply -346Othman, M., Lillicrap, D., Distinguishing between non-identical twins: Platelet type and type 2B von Willebrand disease [2] (2007) British Journal of Haematology, 138 (5), pp. 665-666. , DOI 10.1111/j.1365-2141.2007.06690.xEnayat, M.S., Guilliatt, A.M., Lester, W., Wilde, J.T., Williams, M.D., Hill, F.G.H., Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importance (2006) British Journal of Haematology, 133 (6), pp. 664-666. , DOI 10.1111/j.1365-2141.2006.06078.xMathew, P., Greist, A., Maahs, J.A., Lichtenberg, E.C., Shapiro, A.D., Type 2B vWD: The varied clinical manifestations in two kindreds (2003) Haemophilia, 9 (1), pp. 137-144Saba, H.I., Saba, S.R., Dent, J., Type IIB tampa: A variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation (1985) Blood, 66 (2), pp. 282-286Olson, J.D., Preston, F.E., Nichols, W.L., External quality assurance in thrombosis and hemostasis: An international perspective (2007) Seminars in Thrombosis and Hemostasis, 33 (3), pp. 220-225. , DOI 10.1055/s-2007-971207Othman, M.L.J., Notley, C., James, P., Platelet Type von Willebrand disease: An under diagnosed cause of excessive mucocutanous bleeding (2007) J Thromb Haemost, 5 (SUPPL. 1). , Abstract P-W-167Othman, M., Ozelo, M., Brown, H., Canadian Platelet-type von Willebrand disease (PT-VWD) project: Progress and update (2009) J Thromb Haemost, 7 (SUPPL. 2). , Abstract OC-WE-134Othman, M., Hamilton, A., Platelet-type von Willebrand disease: Results of a worldwide survey from the Canadian PT-VWD project (2010) Acta Haematol, 123, pp. 126-128James, P.D., Notley, C., Hegadorn, C., Leggo, J., Tuttle, A., Tinlin, S., Brown, C., Lillicrap, D., The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study (2007) Blood, 109 (1), pp. 145-154. , http://www.bloodjournal.org/cgi/reprint/109/1/145, DOI 10.1182/blood-2006-05-021105Othman, M., Notley, C., Lavender, F.L., White, H., Byrne, C.D., Lillicrap, D., O'Shaughnessy, D.F., Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease (2005) Blood, 105 (11), pp. 4330-4336. , DOI 10.1182/blood-2002-09-2942Favaloro, E.J., 2B or not 2B? Differential identification of type 2B, versus pseudovon Willebrand disease (2006) Br J Haematol, 135, pp. 141-142. , author reply -143Favaloro, E.J., Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: A question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin? (2008) Semin Thromb Hemost, 34, pp. 113-127Frontroth, J.P., Hepner, M., Sciuccati, G., Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children (2010) Thromb Haemost, 104, pp. 1158-1165Favaloro, E.J., Patterson, D., Denholm, A., Mead, S., Gilbert, A., Collins, A., Estell, J., Smith, M.P., Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis [3] (2007) British Journal of Haematology, 139 (4), pp. 623-626. , DOI 10.1111/j.1365-2141.2007.06850.xScepansky, E., Othman, M., Smith, H., Acquired von Willebrand syndrome with a type 2B phenotype: Diagnostic and therapeutic dilemmas (2009) J Thromb Haemost, 5 (SUPPL. 1). , Abstract PP-MO-632Chegeni, R., Vickars, L., Favaloro, E.J., Functional analysis of three recombinant A1 -VWF domain mutants in comparison to wild type and plasma-derived VWF facilitates subtyping in type 2 von Willebrand disease (2010) Thromb Res, , published onlineOthman, M., Differential identification of PT-VWD from type 2B VWD and GP1BA nomenclature issues (2008) Br J Haematol, 142, pp. 312-314. , author reply 314-315Facey, D.A., Favaloro, E.J., Maxwell, E., Baker, R., Hertzberg, M., Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families: Phenotype and genotype correlations (2000) American Journal of Hematology, 63 (4), pp. 197-199. , DOI 10.1002/(SICI)1096-8652(200004)63:4<197::AID-AJH6>3.0.CO;2-2Favaloro, E.J., Koutts, J., Brighton, T., Genetic testing for the diagnosis of von Willebrand Disease: Benefits and limitations (2010) J Coagul Dis, 2, pp. 37-47Corrales, I., Ramirez, L., Altisent, C., Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene (2009) Thromb Haemost, 101, pp. 570-576James, P., Lillicrap, D., The role of molecular genetics in diagnosing von Willebrand disease (2008) Semin Thromb Hemost, 34, pp. 502-508Othman, M., Favaloro, E.J., Genetics of type 2B von Willebrand disease: "true 2B", "tricky 2B", or "not 2B". What are the modifiers of the phenotype? (2008) Semin Thromb Hemost, 34, pp. 520-531Federici, A.B., Mannucci, P.M., Castaman, G., Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: A cohort study of 67 patients (2009) Blood, 113, pp. 526-534Lopez-Fernandez, M.F., Lopez-Berges, C., Martin-Bernal, J.A., Type IIB von Willebrand's disease associated with a complex thrombocytopenic thrombocytopathy (1988) Am J Hematol, 27, pp. 291-298Nurden, P., Debili, N., Vainchenker, W., Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia (2006) Blood, 108, pp. 2587-2595Nurden, P., Chretien, F., Poujol, C., Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease (2000) Br J Haematol, 110, pp. 704-714Nurden, A.T., Federici, A.B., Nurden, P., Altered megakaryocytopoiesis in von Willebrand type 2B disease (2009) J Thromb Haemost, 7 (SUPPL. 1), pp. 277-281Nurden, P., Gobbi, G., Nurden, A., Abnormal VWF modifies megakaryocytopoiesis: Studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B (2010) Blood, 115, pp. 2649-2656Ragni, M.V., Bontempo, F.A., Cortese, H.A., Von Willebrand disease and bleeding in women (1999) Haemophilia, 5 (5), pp. 313-317. , DOI 10.1046/j.1365-2516.1999.00342.xNovelli, E.M., Ragni, M.V., Genetics of bleeding disorders in women (2008) Semin Thromb Hemost, 34, pp. 509-519