title: Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A.
abstract: 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.
  
  
  OBJECTIVE
  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 exon-intron 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. 54 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.
authors.affiliation: Department of Cell Therapy and Hematology, Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza, Italy. castaman@hemato.ven.it
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.forename: M E
authors.initials: ME
authors.lastname: Mancuso
authors.forename: S H
authors.initials: SH
authors.lastname: Giacomelli
authors.forename: A
authors.initials: A
authors.lastname: Tosetto
authors.forename: E
authors.initials: E
authors.lastname: Santagostino
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
authors.forename: F
authors.initials: F
authors.lastname: Rodeghiero
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology* / Q000627:therapeutic use; D005169:Factor VIII / Q000032:analysis / Q000187:drug effects* / Q000235:genetics*; D040461:Gene Components; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin