Type 2N von Willebrand Disease (VWD2N): Is it Always a Recessive Trait?

ROSSETTI L.C.; ROMERO MC; SÁNCHEZ-LUCEROS A.; WOODS A.I.; DE BRASI CD; BLANCO AN; PAIVA J.; CASINELLI MM

Milano

Congreso; Virtual Meeting of the International Society on Thrombosis and Haemostasis ISTH 2020 Congress; 2020

International Society on Thrombosis and Haemostasis, ISTH

Background: VWD2N is a rare form of VWD, described as a recessive disease due to disease-causing variant (DCV) in homozygous or double/compound-heterozygous state. Heterozygotes individuals are considered carriers, and mostly asymptomatic; those homozygotes and double/compound-heterozygotes have clinical manifestations and laboratory phenotype frequently mistaken for those of mild hemophilia A.Aims: To show the variable inheritance of VWD2N according to the DCV in a selected group of patientsphenotypic and genotypically diagnosed.Methods: We studied the F8 in five symptomatic patients with heterozygous DCV in VWF associated toVWD2N (Table 1). The severity of bleeding symptoms was evaluated by the ISTH/SSC bleeding assessment tool (ISTH/SSC BAT).Patients were studied after signing the written-informed consent. The study was approved by local Ethics Committee.Laboratory tests: FVIII:C (one-stage method), VWF:Ag (ELISA), VWF:RCo (aggregometry). Mixing studies of the patient/control plasmas to evaluate the presence of inhibitors were undertaken by APTT and VWF:RCo. FVIII:C/VWF:Ag (normal value [nv]>0.8) and VWF:RCo/VWF:Ag (nv>0.6) were calculated in each patient. Genomic DNA was extracted from peripheral blood. Exons 17-27 of the VWF and all 26 exons of F8 werePCR-amplified and directly sequenced (Sanger method). F8 exons were previously heteroduplex-analysed by conformation sensitive gel electrophoresis.Results: Both normal VWF:Ag and VWF:RCo levels, and normal VWF:RCo/VWF:Ag were observed in all patients. No DCV were observed in F8 (Table 1). Patients with p.Arg816Trp had very low FVIII (< 12 IU/dL) and FVIII/VWF:Ag< 0.11, abnormal BAT; 2 out of 3 patients had major bleeding episodes.Patients with p.Arg854Gln had low FVIII levels (40-45 IU/dL) and FVIII/VWF:Ag< 0.7, and abnormal BAT. One patient had a major bleeding episode. Conclusions: According to the FVIII levels and FVIII/VWF:Ag values of the patients, heterozygous p.Arg816Trp appears to cause a clearly dominant VWD2N. Patients with p.Arg854Gln should be considered as VWD2N in spite of their heterozygous state in VWF given their bleeding tendency.