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.

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

“…The infusion of r-hu-FVIII in FVIII Ϫ/Ϫ mice normalized the occlusion time to WT values ( Figure 5B), whereas in the VWF Ϫ/Ϫ mice infused with the same amount of r-hu FVIII, 8 of 9 vessels remained patent ( Figure 5A). As would be expected from the asymptomatic state of human carriers of type 3 von Willebrand disease, 22 venules in mice containing half the level of VWF (VWF ϩ/Ϫ mice) occluded, at times similar to WT mice ( Figure 5A). …”

Laboratory Diagnosis of von Willebrand Disease Type 1/2E (2A Subtype IIE), Type 1 Vicenza and Mild Type 1 Caused by Mutations in the D3, D4, B1–B3 and C1–C2 Domains of the von Willebrand Factor Gene

“…The FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag ratios remain within the normal range before and after DDAVP, indicating that VWD Vicenza and CVWD Rotterdam belong to type 1 and not 2M of VWD [10, 18, 24]. Congenital VWD type 1 Vicenza due to a single mutation (R1205H) in the D3 domain clearly differs from 2M and 2U due to a mutation in the A1 domain with loss of VWF:RCo function [24,25,26]. The absence of increased triplet structure seen in type 2A and type 2B (fig.…”

“…VWD type 1 Vicenza is caused by the R1205H mutation and featured by equally low levels of FVIII:C, VWF:Ag and VWF:RCo, and the presence of unusually large vWF multimers in plasma [18,19,20,21,22,23,24,25,26]. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by unexplained very short half-lives of less than a few hours for FVIII:C and all VWF parameters, indicating a rapid clearance defect as the cause of a hemophilia-like phenotype of VWD (CVWD Rotterdam) [18, 20, 24].…”

Dominant von Willebrand Disease Type 2M and 2U Are Variable Expressions of One Distinct Disease Entity Caused by Loss-of-Function Mutations in the A1 Domain of the von Willebrand Factor Gene

“…Patients with type 1 VWD present a partial deficiency in qualitatively normal VWF, type 2 VWD is caused by functionally abnormal VWF, and type 3 VWD is characterized by a virtual absence of the VWF protein. The diagnosis and classification of VWD relies on the phenotypic characterization and is complemented by genetic analysis of causative mutations [4,5,6,7]. Laboratory phenotyping and classification of patients with VWD type 1 and 2 according to the recommendations of the Scientific Standardization Committee (SSC)/International Society on Thrombosis and Hemostasis (ISTH) are based on rather insensitive routine laboratory measurements of VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo), ristocetin-induced platelet aggregation (RIPA) and low-resolution VWF multimer analysis [1, 2].…”