title: 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.
abstract: 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 deficiency 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.
authors.affiliation: Department of Hematology, Hemostasis and Thrombosis Research, University Hospital Antwerp.
authors.forename: Jan Jacques
authors.initials: JJ
authors.lastname: Michiels
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.forename: Alain
authors.initials: A
authors.lastname: Gadisseur
authors.forename: Marc
authors.initials: M
authors.lastname: van der Planken
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schroyens
authors.forename: Ann
authors.initials: A
authors.lastname: van de Velde
authors.forename: Huub
authors.initials: H
authors.lastname: van Vliet
mesh_terms: D000017:ABO Blood-Group System; D003937:Diagnosis, Differential; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006470:Hemorrhage; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense; D014842:von Willebrand Diseases / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics
chemical_list: D000017:ABO Blood-Group System; D014841:von Willebrand Factor