Pathophysiology underlying genetic clinical-grade variants (CGV) responsible for the phenotypes type 2A and 2M of von Willebrand disease (VWD).

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

Melbourne

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

International Society on Thrombosis and Hemostasis

In von Willebrand Disease (VWD), different pathophysiological mechanisms have been described: high FVIII:C/VWFAg, associated with decreased VWF synthesis and/or secretion, high VWFpp/Ag, with shortened VWF survival.We have shown that most CGV in VWD2A are associated with shortened VWF survival, whereas those in VWD2M showed different pathophysiological mechanisms according to the affected domain (D).In VWD2A(n:30) and 2M(n:71) patients (Pts) genotypically diagnosed, we evaluated the pathophysiological mechanisms involved in the effect of each CGV on the resulting phenotype.Methods: VWF parameters: FVIII:C; VWF:Ag (Ag); propeptide (VWFpp). Ratios calculated: FVIII:C/Ag and VWFpp/Ag.Results: FVIII/Ag, VWFpp/Ag and percentage of Pts with high or normal ratios within CGV are shown in table 1.VWD2A CGV: p.C1272F(n:2), p.G1505R(n:3), p.Y1542D(n:1), p.R1597W(n:16), p.I1628T(n:6), p.F1654L(n:2).VWD2M 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), p.L1503P(n:2), p.E1549K(n:32), p.R1564W(n:1), p.I1628T(n:4). Discussion: VWD2A:Decreased VWF synthesis and/or secretion was observed in Pts with in p.Y1542D. Normal VWF synthesis, in Pts with p.C1272F and p.F1654L, and some Pts with p.G1505R, p.R1597W and p.I1628T.Shortened VWF survival (group 2A-II) was observed in Pts with p.C1272F, p.G1505R, p.R1597W and in some Pts with p.I1628T.Normal VWD survival (group 2A-I): in p.Y1542D and p.F1654L.Both pathophysiological mechanisms would be involved in some Pts with p.G1505R, p.R1597W, and p.I1628T.VWD2M:Decreased VWF synthesis and/or secretion: in all Pts with p.R1374L and p.R1564W, and in some Pts with p.L1503P.Shortened VWF survival: in some cases of p.E1549K and p.I1628T.Both pathophysiological mechanisms would be involved in p.F1293C and in most of cases of p.R1374C and some ones of p.I1628T.Other non-identified pathophysiological mechanisms neither related to synthesis nor survival, would explain both normal ratios in 100% of Pts with p.F1654L (VWD2A), and p.P1266Q, p.G1324S, p.S1325F, p.R1334Q, p.T1468I, and in some cases of p.L1503P, p.E1549K and p.I1628T (VWD2M).