VWD2M Genotype Carrying Double Heterozygous Mutations with More Severe Phenotype than Classic VWD2M

PAIVA J; SÁNCHEZ LUCEROS A; KEMPFER AC; LAZZARI MA; WOODS AI; BLANCO AN

Berlin

Congreso; 26th Congress of ISTH & 63rd Annual Scientific and Standardization Committee (SSC) Meeting; 2017

International Society on Thrombosis and Haemostasis

Background: We have characterized a group of VWD2M patients (2MC) by VWF:RCo/VWF:Ag (RCo/Ag)< 0,6, normal multimers, DDAVP test and mutations (Mt) in the A1 domain of VWF.Aims: To describe the phenotype resulting from muco-cutaneous bleeding symptoms, in the presence of double heterozygous Mt: a novel missense Mt, and its association with a deletion in a 2M patient (P). To compare the phenotype of P with that of 2MC.Methods: Tests considered for comparison between P and 2MC: FVIII:C (one-stage method), VWF:Ag (Ag) (ELISA), VWF:RCo (RCo) (aggregometry). DDAVP response, tested before and after 90min of intravenous infusion. Exon 28 of VWF gene was analyzed in P and 100 healthy controls (HC).Results: P: boy (8-yr) (blood O group); ISTH bleeding score (BS)=6; epistaxis requiring tamponades; bleeding after tooth eruption and extraction; easy bruising; gum bleeding; normal multimers and VWF:CB (collagen type 1).2MC (n=31): BS=4.6±3.2. Laboratory tests in table 1.P showed lower FVIII:C, VWF:Ag and the DDAVP response than those in 2MC. Two Mt were found in VWF gene: 1) c.4276C>T (p.R1426C) in A1 domain, and 2) c.4944delT (p.P1648fs*45) in A2 domain. p.R1426C was absent in HC, predicted as damaging by in silico analysis (PolyPhen-2, Mutation Tester, SIFT), and submitted by us to the ISTH-SSC-VWF database. Conclusions: We report here a novel Mt: p.R1426C, and its association with a deletion, in a severe VWD2M phenotype. The lower FVIII:C, and VWF:Ag would probably be by the combination of the blood O group and the presence of p.P1648fs*45 which was reported as type 1 (ISTH-SSC-VWF database). In these situations, we should be aware of the selection of appropriate treatment.