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

Abstract

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.

Acquired von Willebrand syndrome associated with left ventricular assist device

“…This shear-induced cleavage reduces VWF size and adhesive activity in a pattern similar to patients with type 2A VWD. 31,79,107,108,116 However, this tentative mechanism has not been experimentally validated, and significant gaps remain. First, there is no direct evidence that VWF multimers are excessively cleaved by ADAMTS-13 in patients on LVAD support.…”

Type 2M von Willebrand disease: a variant of type 2A?

“…An important example of a limitation of the current classification system is the R1374C mutation [5,6]. The phenotype associated with this mutation shows several characteristics that we have confirmed in 23 members of three unrelated families.…”

“…In light of the most recently published physiopathological hypotheses that may provide an explanation for the differing incidence between products, we suggested to the authors to repeat their analyses without inclusion of the patient follow-up after the first switch [5]. In their response, van der Bom et al [6] tested this alternative analytical option, but unfortunately only for its impact on the search for an effect of von Willebrand factor on the immunogenicity of FVIII. Their response shows that to not include follow-up of patients after the first switch increases by 0.3 the risk estimation of rFVIII vs, pdFVIII with high VWF content (the crude RR increased from 1.0 to 1.3 and the adjusted RR from 1.2 to 1.5).…”

Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis

“…The D-domains of MUC2 share very high homology with the blood clotting glycoprotein von Willebrand Factor (vWF) which also forms homo-oligomers. Autosomal dominant and recessive mutations in all four Ddomains of vWF cause von Willebrand disease [69], typically via altered homo-oligomerisation, and are therefore analogous to the Win and Eey Muc2 mutations. A single genomewide scan has identified an IBD susceptibility locus at Chromosome 11p, which contains MUC2 within a cluster of four mucin genes at 11p15.5 [70].…”