Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Abstract

Summary. Background: The relationship of the biologic response to desmopressin with the F8 mutation and physiological characteristics has been poorly investigated in patients with mild hemophilia A. Objectives: We prospectively assessed the molecular and phenotypic determinants of the biologic response to desmopressin in a cohort of 50 patients with mild hemophilia A. Methods: Up to 24 h after desmopressin, blood samples were serially obtained and factor (F)VIII and von Willebrand factor (VWF) measured. The promoter region, all exons and exonintron boundaries of the F8 gene were screened using denaturing high-performance liquid chromatography (DHPLC). Direct sequencing was done when DHPLC screening was normal. Genomic DNA was also sequenced for exons 18-21, 24 and 27 of VWF. Results: Mean basal FVIII:C was 19 ± 9 IU dL )1 (range 6-37) and the median postdesmopressin peak increase was 2.5-fold (range 1.1-7.1). Eleven patients with a cross-reacting material positive (CRM + ) phenotype had similar basal levels and relative increases of FVIII:C to the remaining patients with low FVIII:Ag. Using multivariate regression, FVIII:C half-life was positively related to basal and peak VWF:Ag levels (P = 0.008) and patient age (P = 0.004). Eleven patients had evidence of reduced FVIII survival. While 27 different gene mutations were identified in 41 patients, nine patients had no detectable mutation. These patients had significantly smaller peaks and smaller relative increase of postdesmopressin FVIII:C (median FVIII:C 26 IU dL )1 vs. IU dL )1; P < 0.001; fold 1.8 ± 0.6 vs. 2.9 ± 0.8; P = 0.002). Conclusions: In this cohort of patients with mild hemophilia A, a poor biologic response to desmopressin was frequently associated with the absence of detectable F8 mutations.

Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A

“…In patients with mild VWD or hemophilia A, administration of the vasopressin analog DDAVP causes an almost immediate and parallel rise (2-to 5-fold) in both VWF and FVIII, but no FVIII or VWF is released in type 3 VWD. 6,40 Studies done by our laboratory have demonstrated that FVIII is not internalized from culture media by endothelial cells in vitro 41 and transfused FVIII does not reestablish the releasable pool in vivo. 6 Taken together, our data support the notion that the DDAVP-releasable pool of FVIII in humans originates from endothelial cells.…”

Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A

“…Although FVIII increase occurs in most cases, only 50% to 60% of patients achieve FVIII levels higher than 50 U/dL. 3,[23][24][25][26] The peak postdesmopressin depends in part on the patient's basal FVIII level 24,25 and age. Young children often have markedly lower responses to desmopressin than adults, but they may become responsive at an older age.…”

“…[27][28][29] The FVIII half-life, typically around 6 to 8 hours, is positively associated with basal and peak VWF antigen levels and patient age. 24 Some mutations are consistently associated with favorable responses (in particular, several of those at risk for inhibitor development; Table 1), whereas promoter, splicing, or intronic mutations respond poorly, and some missense mutations show a reduced FVIII survival 3,24-27 ( Figure 1). Although there is a certain consistency of the response within the same mutation, the response to desmopressin is somehow heterogeneous.…”

“…Although there is a certain consistency of the response within the same mutation, the response to desmopressin is somehow heterogeneous. [24][25][26][27]29 Therefore, the individual response should always be assessed by a test infusion of desmopressin with FVIII measured at least 1 and 4 hours after its administration to ascertain the pattern of response and the rate of clearance.…”

“…30 Although there is scarce published evidence for possible increased clearance of FVIII after desmopressin in MHA, nevertheless, as in a few patients there is evidence of fast FVIII clearance 24 ( Figure 1), it seems advisable to test at least after 4 hours after desmopressin. Tachyphylaxis (ie, a reduced response on repeated administration) should be considered when using desmopressin at closely spaced intervals during surgical procedures.…”