title: 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. Role of von Willebrand factor multimers and the von Willebrand factor propeptide/antigen ratio.
abstract: Autosomal dominant von Willebrand disease (VWD) type 1/2E is a quantitative/qualitative defect in the von Willebrand factor (VWF) caused by heterozygous cysteine and non-cysteine mutations in the D3 domain of the VWF gene and results in a secretion-multimerization-clearance defect in mutant VWF with the loss of large VWF multimers not due to proteolysis. The multimers of patients with dominant VWD type 1/2E due to mutations in the D3 domain show an aberrant triplet structure with lack of outer bands but with pronounced inner bands of the triplet structure combined with a relative decrease in large multimers reflecting heterozygosity for multimerization defects. There is a good response to desmopressin (DDAVP) followed by rapid clearance of VWF:antigen (Ag), factor VIII coagulant activity (FVIII:C) and VWF:ristocetin cofactor activity (RCo) as the main cause of VWD type 1 or 2 with typical 2E multimeric pattern (VWD type 1/2E). Cysteine mutations in the D3 domains (C1130, C1149 and C1190) show pronounced features of VWD 1/2E with the relative loss of large and relative increase in small VWF multimers with abnormal triplet structure in heterozygotes. Such abnormalities are less pronounced in patients with a milder form of VWD type 1 due to non-cysteine mutations W1144G, T1156M and W1120S in the D3 domain. VWD type 1 Vicenza is caused by the R1205H mutation in the D3 domain and characterized by equally low levels of FVIII:C, VWF:Ag and VWF:RCo. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by a rapid clearance in less than a few hours of FVIII:C and VWF parameters. The ratios for FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag remain normal before and after DDAVP indicating that VWD Vicenza clearly differs from VWD type 1, 1/2E and 2M. A new set of missense mutations in D4, B1-B3 and C1-C2 domains has been discovered as the cause of a mild VWD type 1 secretion defect with normal VWF multimers or smeary VWF multimeric pattern. Cysteine mutations in exons 38, 40, 42 and 43 (D4, B1-B3 and C1 domain), show smeary patterns (either smf or sm), with the presence of large VWF multimers and a laboratory phenotype of mild VWD type 1 with variable penetrance of bleeding manifestations. Recent studies showed that the ratio of VWF propeptide (pp) to VWF:Ag can be used to predict a shorter than normal half-life for VWF:Ag. There is a strong inverse correlation between rapid clearance of VWF:Ag after DDAVP and increased VWFpp/Ag ratios >10 in VWD type 1 Vicenza, and >2 in VWD type 1/2E but normal or slightly increased (1-<2) VWFpp/Ag ratios in mild-type VWD due to nonsense or missense mutations in the D1, D2, D4, B and C domains.
authors.affiliation: Hemostasis and Thrombosis Research Center, Antwerp University Hospital, Wilrijkstraat 10, Edegem, Belgium. alain.gadisseur@uza.be
authors.forename: Alain
authors.initials: A
authors.lastname: Gadisseur
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schroyens
authors.forename: Jan Jacques
authors.initials: JJ
authors.lastname: Michiels
mesh_terms: D001760:Bleeding Time; D003894:Deamino Arginine Vasopressin / Q000627:therapeutic use; D003937:Diagnosis, Differential; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D014842:von Willebrand Diseases / Q000145:classification / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D014841:von Willebrand Factor / Q000032:analysis / Q000737:chemistry / Q000235:genetics*
chemical_list: D011498:Protein Precursors; D014841:von Willebrand Factor; D003894:Deamino Arginine Vasopressin