A Poor Response to Desmopressin Is Observed in Patients with Mild Hemophilia a and No Detectable FVIII Mutation.

Background. Desmopressin is the treatment of choice for patients with mild hemophilia A (FVIII:C ³; 5 %). However, the range of response is wide and patients with similar basal FVIII:C may respond in a significantly different way. Several clinical studies have demonstrated the clinical efficacy and safety of desmopressin, but few data are available on the relationship of biological response with a given FVIII mutation and physiological characteristics (such as age and blood group, or von Willebrand factor levels). Aim of the study. To evaluate the relationship between type of FVIII mutation, physiological caharacteristics and response to desmopressin

Methods. The biological response to subcutaneous desmopressin was assessed in a group of 51 consecutive patients with FVIII:C ³ 5%. Blood samples were taken at 0, 30, 60, 120 240, 480 minutes and 24 hours after injection. FVIII mutation search strategy was based on DHPLC and gene sequencing.

Results Mean basal FVIII:C was 18 ± 9 U/dL (range 5 – 37) and the median increase at peak was 2.5-fold (range 1.1 – 7.1). Twelve patients with low FVIII:C and normal or increased FVIII:Ag (type II defect) had similar basal and fold increase compared to the remaining patients. By multivariate regression, VWF:Ag peak level reached after desmopressin infusion and patient age were positively related with the FVIII:C half-life (p=0.003 and p=0.002 respectively), but not with FVIII:C peak or AUC. A total of 28 different gene mutations were identified (10 novel) in 42 patients, while 9 had no detectable gene mutations even after two different complete gene sequencing with 2 different sets of primers. No mutations in exons 18–22, 24 and 27 of VWF were identified. Patients with no mutations had similar basal median FVIII:C (15 vs 19 U/dL) and VWF:Ag levels (109.1 ± 31.7 vs 133.1 ± 57.5 U/dL) compared with patients carrying missense mutations. However, the peak of FVIII:C was significantly lower in patients without mutations (median FVIII:C 26 vs 56 U/dL; P < 0.001), with only a 2-fold increase (range 1.1 – 2.7) vs 2.92-fold (range 1.6 – 7.1) in patients with mutations (P < 0.001 by ANOVA).

Conclusions. A poor biological response to desmopressin was associated with the absence of an evident FVIII mutation.