Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A

 

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Summary

Desmopressin causes two- to six-fold increase of factor VIII (FVIII) in mild or moderate haemophilia A patients. However, responses are variable and little is known whether this is associated with F8 gene mutation. The study objective was to assess the relationship between F8 gene mutation and desmopressin response in haemophilia A patients. Desmopressin response (absolute and relative) was determined in 97 hemophilia A patients. Four amino acid changes (Arg2169His, Pro149Arg, Asn637Ser, and Arg612Cys) and a number of other mutations leading to an aberrant FVIII protein or FVIII deficiency were analysed. Patients with Arg2169His showed significantly lower FVIII levels before and after desmopressin compared to all other mutations (p<0.001). Pro149Arg amino acid change showed significantly lower FVIII levels 1 hour after desmopressin compared to all other mutations (p<0.005). An absolute response with FVIII ≥0.50 IU/ml after 1 hour was observed in 41% (9 of 22) of patients with Arg2169His; however, this was not sustainable after 6 hours in any of these subjects. No patients with Pro149Arg mutation (n=6) showed an absolute response with FVIII _0.50 IU/ml. Patients with other mutations showed significantly more complete and partial responses. Relative responses did not differ between mutations. Our study shows that haemophilia A patients with amino acid change Arg2169His or Pro149Arg have a decreased desmopressin response with regard to FVIII levels as compared to other mutations. Our results indicate that response to desmopressin is dependent on the F8 gene mutation type, despite the fact that multiple factors influence the desmopressin response, even within families.

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• 1 Freije D, Schlessinger D. A 1.6-Mb contig of yeast artificial chromosomes around the human factor VIII gene reveals three regions homologous to probes for the DXS115 locus and two for the DXYS64 locus. Am J Hum Genet 1992; 51: 66-80.
  PubMedGoogle Scholar
• 2 Poustka A, Dietrich A, Langenstein G. et al. Physical map of human Xq27-qter: localizing the region of the fragile X mutation. Proc Natl Acad Sci USA 1991; 88: 8302-8306.
  CrossrefPubMedGoogle Scholar
• 3 Vehar GA, Keyt B, Eaton D. et al. Structure of human factor VIII. Nature 1984; 312: 337-342.
  CrossrefPubMedGoogle Scholar
• 4 d’Oiron R, Pipe SW, Jacquemin M. Mild/moderate haemophilia A: new insights into molecular mechanisms and inhibitor development. Haemophilia 2008; 14 (Suppl. 03) 138-146.
  CrossrefPubMedGoogle Scholar
• 5 Repesse Y, Slaoui M, Ferrandiz D. et al. Factor VIII (FVIII) gene mutations in 120 patients with haemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost 2007; 5: 1469-1476.
  CrossrefPubMedGoogle Scholar
• 6 Kaufmann JE, Vischer UM. Cellular mechanisms of the haemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: 682-689.
  CrossrefPubMedGoogle Scholar
• 7 Kaufmann JE, Vischer UM. Cellular mechanisms of the haemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: 682-689.
  CrossrefPubMedGoogle Scholar
• 8 Lethagen S, Frick K, Sterner G. Antidiuretic effect of desmopressin given in haemostatic dosages to healthy volunteers. Am J Hematol 1998; 57: 153-159.
  CrossrefPubMedGoogle Scholar
• 9 World Federation of Haemophilia.. Plasma Factor Level and Duration of Administration. In: Guidelines for the management of haemophilia. 2005. pp. 45-46
  Google Scholar
• 10 Australian Haemophilia Centre Directors’ Organisation.. Surgical Management. In: Guideline for the management of patients with haemophilia undergoing surgical procedures. 2010. pp. 7-10
  Google Scholar
• 11 Kruip MJ, Leebeek FW. Behandeling van haemofilie-A en -B. In: Richtlijn diagnostiek en behandeling van haemofilie en aanverwante haemostasestoornissen. Van Zuiden Communications B.V.. 2009. pp. 25-38
  Google Scholar
• 12 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
  PubMedGoogle Scholar
• 13 Franchini M, Favaloro EJ, Lippi G. Mild haemophilia A. J Thromb Haemost 2010; 8: 421-432.
  CrossrefPubMedGoogle Scholar
• 14 Castaman G. Desmopressin for the treatment of haemophilia. Haemophilia 2008; 14 (Suppl. 01) 15-20.
  PubMedGoogle Scholar
• 15 Castaman G, Mancuso ME, Giacomelli SH. et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild haemophilia A. J Thromb Haemost 2009; 7: 1824-1831.
  CrossrefPubMedGoogle Scholar
• 16 Nolan B, White B, Smith J. et al. Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders. Br J Haematol 2000; 109: 865-869.
  CrossrefPubMedGoogle Scholar
• 17 Revel-Vilk S, Blanchette VS, Sparling C. et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J Haematol 2002; 117: 947-951.
  CrossrefPubMedGoogle Scholar
• 18 Seary ME, Feldman D, Carcao MD. DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype. Haemophilia 2012; 18: 50-55.
  CrossrefPubMedGoogle Scholar
• 19 den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000; 15: 7-12.
  CrossrefPubMedGoogle Scholar
• 20 Castaman G, Lethagen S, Federici AB. et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111: 3531-3539.
  CrossrefPubMedGoogle Scholar
• 21 Jacquemin M, Lavend’homme R, Benhida A. et al. A novel cause of mild/moderate haemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood 2000; 96: 958-965.
  PubMedGoogle Scholar
• 22 d’Oiron R, Lavergne JM, Peynet J. Response to DDAVP in mild/moderate haemophilia A patients according to the underlying factor VIII genotype. J Thromb Haemost 2003; 1 (Suppl. 01) OC214.
  CrossrefPubMedGoogle Scholar
• 23 Gill JC, Endres-Brooks J, Bauer PJ. et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
  PubMedGoogle Scholar
• 24 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418-435.
  CrossrefPubMedGoogle Scholar
• 25 Eckhardt CL, Menke LA, van Ommen CH. et al. Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate haemophilia A. J Thromb Haemost 2009; 7: 930-937.
  CrossrefPubMedGoogle Scholar
• 26 Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 1998; 4: 558-563.
  CrossrefPubMedGoogle Scholar
• 27 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22.
  PubMedGoogle Scholar
• 28 Lethagen S, Harris AS, Sjorin E. et al. Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58: 1033-1036.
  Article in Thieme ConnectPubMedGoogle Scholar

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