Response to desmopressin in patients with mild hemophilia A caused by the F 8 c.1910 A > G , p. A sn637 S er mutation

Therapy for mild hemophilia A consists of desmopressin acetate (1-deamino[8-D-arginine]-vasopressin; desmopressin; DDAVP), which increases factor VIII and von Willebrand factor antigen (VWF:Ag) levels two-fold to six-fold through endogenous release from endothelial cells [1]. The effect of desmopressin varies between patients, and has been suggested to depend on the hemophilia-causing mutation [2–4]. Mild hemophilia is generally caused by F8 missense mutations. One of these mutations is c.1910A>G, p.Asn637Ser. In our hemophilia treatment center (the Van Creveldkliniek, University Medical Center Utrecht, The Netherlands), a large cohort of patients with this particular mutation is known. To investigate the variability in the increase in FVIII levels after desmopressin infusion in this cohort of patients, a retrospective single-center study was performed. All male patients with the F8 c.1910A>G, p.Asn637Ser mutation treated at the Van Creveldkliniek at any time during the past 20 years were included. Baseline characteristics, including residual FVIII level, VWF:Ag level, and blood group, were collected. Age at the time of desmopressin testing and FVIII levels after 30–60 min of intravenous desmopressin infusion were recorded. The dose of desmopressin was 0.3 lg kg , which was infused over a period of 20–30 min. The study was approved by the medical ethics review board of the University Medical Center Utrecht. For statistical analysis, the mean lowest known FVIII level, baseline FVIII level at the start of desmopressin testing and mean lowest known VWF:Ag level were calculated. For six patients for whom baseline FVIII levels were not measured, the lowest known FVIII levels were imputed. The effects of VWF:Ag levels and blood group on baseline FVIII levels were assessed with linear regression analysis. Determinants with a P-value of < 0.15 in the univariate analysis were included in the multivariate analysis. The mean FVIII level, mean absolute increase in FVIII level and mean proportional increase in FVIII level within 60 min of desmopressin infusion were calculated for our patients. When FVIII levels were measured more than once between 30 and 60 min after the end of desmopressin infusion, the highest level was used for analysis. The effects of age, baseline FVIII level, VWF:Ag level and blood group on the absolute increase in FVIII levels within 60 min after desmopressin infusion were assessed with univariate and multivariate linear regression analysis. P-values of < 0.05 were considered to be statistically significant. Data were analyzed with IBM SPSS 20 statistical software (IBM Corporation, Armonk, NY, USA). In 115 patients, mild hemophilia was caused by the F8 c.1910A>G, p.Asn637Ser mutation. In 77 of these patients, a desmopressin test was performed, and 68 of these could be analyzed. The mean age at desmopressin testing was 21.7 years (range, 3–70 years). The mean lowest FVIII level was 0.19 IU dL , but varied greatly, between 6 and 36 IU dL . The mean VWF:Ag level was 101 IU dL 1 (range, 20–235 IU dL ). Forty-nine per cent of patients had blood group O, 35% had blood group A, 11% had blood group AB, and 5% had blood group B. We found a strong association between VWF:Ag and FVIII levels (b = 0.06, P = 0.003). There was no effect of blood group (O vs. non-O) on FVIII levels (P = 0.64). No association was found between age and baseline FVIII level at the time of desmopressin testing (P = 0.58). The mean FVIII level before desmopressin infusion was 20 IU dL 1 (range, 13–39 IU dL ). After desmopressin infusion, the mean absolute increase in FVIII levels was 79 IU dL 1 (range, 36–171 IU dL ; interquartile range [IQR] 57–98), resulting in a mean FVIII peak level of 102 IU dL 1 (range, 53–196 IU dL ; IQR 80–124). The relative FVIII increase after desmopressin infusion varied Correspondence: Eveline P. Mauser-Bunschoten, Van Creveldkliniek, University Medical Center Utrecht, HP C01 425, Postbox 85500, 3508 GA Utrecht, the Netherlands. Tel.: +31 88 7558450; fax: +31 88 7555438. E-mail: E.mauserbunschoten@umcutrecht.nl