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Characterization of Recessive Severe Type 1 and 3 von Willebrand Disease (VWD), Asymptomatic Heterozygous Carriers Versus Bloodgroup O-Related von Willebrand Factor Deficiency, and Dominant Type 1 VWD

Department of Hematology, Hemostasis and Thrombosis Research, Erasmus Medical Center, Academic Hospital Dijkzigt; Hemostasis and Thrombosis Research Science Center, Goodheart Institute, Rotterdam

Zwi Berneman, MD, PhD

Alain Gadisseur, MD

Department of Hematology, Hemostasis and Thrombosis Research, Erasmus Medical Center, Academic Hospital Dijkzigt, Rotterdam

Marc van der Planken, MD

Laboratory of Hematology and Hemostasis, Department of Clinical Pathology, University Hospital Antwerp, Hemostasis and Thrombosis Research, Erasmus Medical Center, Academic Hospital Dijkzigt, Rotterdam

Wilfried Schroyens, MD, PhD

Ann van de Velde, MD

Department of Hematology, Hemostasis and Thrombosis Research, Erasmus Medical Center, Academic Hospital Dijkzigt, Rotterdam

Huub van Vliet, PhD

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

Recessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation (RIPA), absence of von Willebrand factor (VWF) protein, and prolonged activated partial thromboplastin time (aPTT) due to factor VIII:coagulant (FVIII:C) deficiency. VWD type 3 is associated with a pronounced tendency to mucocutaneous and musculoskeletal bleedings since early childhood. Carriers of one null allele are usually asymptomatic at VWF levels of 50% of normal. Recessive severe type 1 VWD is caused by homozygosity or double heterozygosity for a missense mutation. Recessive type 1 VWD differs from type 3 VWD by the presence of detectable von Willebrand factor: antigen VWF:Ag and FVIII:C levels between 0.09 and 0.40 U/mL. Patients with recessive type 1 VWD show an abnormal VWF multimeric pattern in plasma and/or platelets consistent with severe type 2 VWD. Carriers of a missense mutation may have mild bleeding and mild VWF deficiency and can be diagnosed by a double VWF peak on cross immunoelectrophoresis (CIE). There will be cases of mild and moderate recessive type 1 VWD due to double heterozygosity of two missense mutations, or with the combination of one missense mutation with a non-sense or bloodgroup O. Mild deficiency of VWF in the range of 0.20 to 0.60 U/mL, with normal ratios of von Willebrand factor: ristocetine cofactor/antigen VWF:RCo/Ag and VWF:collagen binding/antigen (VWF:CB/Ag), normal VWF multimers, and a completely normal response to desmopressin acetate (DDAVP) with VWF level rising from below to above 1.00 U/mL are very likely cases of so-called pseudo-VWF defienciecy in individuals with normal VWF protein and gene. Autosomal dominant type 1 VWD variants are in fact type 2 variants caused by a heterozygous missense mutation in the VWF gene that produces a mutant VWF protein that has a dominant effect on normal VWF protein produced by the normal VWF allele with regard to the synthesis, processing, storage, secretion, and/or proteolysis of VWF in endothelial cells. A DDAVP challenge test clearly differentiates between dominant type 1 VWD phenotype and dominant type 2 M VWD.

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

Clinical and Applied Thrombosis/Hemostasis, Vol. 12, No. 3, 277-295 (2006)
DOI: 10.1177/1076029606291401


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