Genotype-phenotype and pathophysiological mechanisms involved in patients with von Willebrand disease (VWD) type 2A and 2M according to domains affected by genetic clinical-grade variants (CGV).

WOODS AI; BLANCO AN, ; SANCHEZ-LUCEROS A. ; PAIVA J,; CASINELLI MM, ; KEMPFER AC,; ,LAZZARI MA,

Melbourne

Congreso; XXVII|to Congreso de ISTH y 65to Reunión Anual del Comité Científico y de estandarización; 2019

International Society on Thrombosis and Hemostasis

Background : VWD type 2A and 2M are defined by RCo/Ag< 0.6, decreased/absent RIPA, absence of large/intermediate multimers in VWD2A and normal multimers in VWD2M. Two main pathophysiological mechanisms were described: decreased VWF synthesis and/or secretion expressed as high FVIII:C/VWF:Ag; shortened VWFsurvival expressed as high VWFpp/Ag.Aims : In VWD2A( n:30 ) and 2M( n:73 ) patients genotypically diagnosed,we studied the genotype/phenotype and pathophysiological mechanisms involved according to domains (D) affected by CGV responsible for phenotype.Methods : Bleeding score(ISTH- BAT), bleeding time(BT); FVIII:C; VWF:Ag(Ag); VWF:CB1(CB1) (type- 1 collagen); propeptide(VWFpp) were performed. FVIII:C/Ag, CB/Ag, VWFpp/Ag were calculated. Informed consent and ethical approval were obtained.Results : Phenotypic characteristics of the patients and the distributionof respective ratios, according to the affected D are described in Table 1 and 2, respectively.VWD2A: A1-D (n:2): CGV: p.C1272F. Patients showed higher BAT, BT and VWFpp/Ag, lower levels of FVIII:C and Ag than those in A2- D(p=ns). A2-D (n:28): CGV: p.G1505R(n:3), p.Y1542D(n:1), p.R1597W(n:16), p.I1628T(n:6), p.F1654L(n:2). Patients showed lower CB1/Ag than those in A1- D(p=0.000).VWD-2M: A1-D (n:34): CGV: p.P1266Q(n:1), p.F1293C(n:2), p.G1324S(n:1), p.S1325F(n:1), p.R1334Q(n:1), p.R1374C(n:21), p.R1374L(n:1), p.A1437T(n:5), p.T1468I(n:1). Patients showed lower Ag(p=0.0001) and higher VWFpp/Ag(p=0.0021) than those in A2- D.A2-D (n:39): CGV: p.L1503P(n:2), p.E1549K(n:32), p.R1564W(n:1), p.I1628T(n:4).Patients showed lower CB1/Ag than those in A1- D(p:0.000).Conclusions: VWD2A: A1- D: CGV were mostly associated with shortened VWF survival and correlated to more severe phenotype. VWD2M: A1- D: CGV were not only responsible for decreased VWF synthesis but also for shortened VWF survival; A2- D: CGV were responsible for shortened VWF survival. CGV in A2- D would affect the function of adjacent A1- D and the resulting phenotype. Similarly, our results suggest that changes in A2- D structure by CGV, observed in both VWD2A and 2M, would influence the adjacent A3- D, altering its ability to bind type- 1 collagen, resulting in low VWF:CB1. Other non- identified pathophysiological mechanisms would explain both normal ratios seen mostly in VWD2M pts with CGV in A2- D.