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Classification and Characterization of Hereditary Types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (Unclassifiable) von Willebrand Disease

Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium, Hemostasis and Thrombosis Research Science Center, Goodheart Institute, Rotterdam, The Netherlands, jan.michiels{at}uza.be

Zwi Berneman, MD, PhD

Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium

Alain Gadisseur, MD

Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium

Marc van der Planken, MD

Hemostasis and Thrombosis Research, Laboratory of Hematology and Hemostasis, Department of Clinical Pathology, University Hospital Antwerp, Belgium

Wilfried Schroyens, MD, PhD

Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium

Ann van de Velde, MD

Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium

Huub van Vliet, PhD

Hemostasis Thrombosis Research, Erasmus Medical Center, Academic Hospital Dijkzigt, Rotterdam, The Netherlands

All variants of type 2 von Willebrand disease (VWD) patients, except 2N, show a defective von Willebrand factor (VWF) protein (on cross immunoelectrophoresis or multimeric analysis), decreased ratios for VWF:RCo/Ag and VWF:CB/Ag and prolonged bleeding time. The bleeding time is normal and FVIII:C levels are clearly lower than VWF:Ag in type 2N VWD. High resolution multimeric analysis of VWF in plasma demonstrates that proteolysis of VWF is increased in type 2A and 2B VWD with increased triplet structure of each visuable band (not present in types 2M and 2U), and that proteolysis of VWF is minimal in type 2C, 2D, and 2E variants that show aberrant multimeric structure of individual oligomers. VWD 2B differs from 2A by normal VWF in platelets, and increased ristocetine-induced platelet aggregation (RIPA). RIPA, which very likely reflects the VWF content of platelets, is normal in mild, decreased in moderate, and absent in severe type 2A VWD. RIPA is decreased or absent in 2M, 2U, 2C, and 2D, variable in 2E, and normal in 2N. VWD 2M is usually mild and characterized by decreased VWF:RCo and RIPA, a normal or near normal VWF multimeric pattern in a low resolution agarose gel. VWD 2A-like or unclassifiable (2U) is distinct from 2A and 2B and typically featured by low VWF:RCo and RIPA with the relative lack of high large VWF multimers. VWD type 2C is recessive and shows a characteristic multimeric pattern with a lack of high molecular weight multimers, the presence of one single-banded multimers instead of triplets caused by homozygosity or double hereozygosity for a mutation in the multimerization part of VWF gene. Autosomal dominant type 2D is rare and characterized by the lack of high molecular weight multimers and the presence of a characteristic intervening subband between individual oligimers due to mutation in the dimerization part of the VWF gene. In VWD type 2E, the large VWF multimers are missing and the pattern of the individual multimers shows only one clearly identifiable band, and there is no intervening band and no marked increase in the smallest oligomer. 2E appears to be less well defined, is usually autosomal dominant, and accounts for about one third of patients with 2A in a large cohort of VWD patients.

Key Words: von Willebrand factor • von Willebrand disease • Ristocetin cofactor activity • von Willebrand collagen binding activity • Factor VIII:C • Bleeding time • DDAVP

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