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Thromb Haemost 2013; 109(03): 440-449
DOI: 10.1160/TH12-06-0383
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Sara C. M. Stoof
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
,
Yvonne V. Sanders
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
,
Fred Petrij
2   Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
,
Marjon H. Cnossen
3   Department of Pediatric Hematology and Oncology, Erasmus University Medical Center/ Sophia Children’s Hospital, Rotterdam, the Netherlands
,
Moniek P. M. de Maat
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
,
Frank W. G. Leebeek
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
,
Marieke J. H. A. Kruip
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
› Author Affiliations
Further Information

Publication History

Received: 11 June 2012

Accepted after minor revision: 27 January 2012

Publication Date:
01 December 2017 (online)

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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.

Keywords

Desmopressin - haemophilia A - blood coagulation factor VIII - mutation - sustainment of response

 

  • References

  • 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.
    PubMedSearch in Google 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.
    CrossrefPubMedSearch in Google Scholar
  • 3 Vehar GA, Keyt B, Eaton D. et al. Structure of human factor VIII. Nature 1984; 312: 337-342.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google Scholar
  • 6 Kaufmann JE, Vischer UM. Cellular mechanisms of the haemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: 682-689.
    CrossrefPubMedSearch in Google Scholar
  • 7 Kaufmann JE, Vischer UM. Cellular mechanisms of the haemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: 682-689.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google Scholar
  • 9 World Federation of Haemophilia.. Plasma Factor Level and Duration of Administration. In: Guidelines for the management of haemophilia. 2005. pp. 45-46
    Search in 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
    Search in 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
    Search in Google Scholar
  • 12 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
    PubMedSearch in Google Scholar
  • 13 Franchini M, Favaloro EJ, Lippi G. Mild haemophilia A. J Thromb Haemost 2010; 8: 421-432.
    CrossrefPubMedSearch in Google Scholar
  • 14 Castaman G. Desmopressin for the treatment of haemophilia. Haemophilia 2008; 14 (Suppl. 01) 15-20.
    PubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google Scholar
  • 19 den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000; 15: 7-12.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    PubMedSearch in Google 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.
    CrossrefPubMedSearch in Google 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.
    PubMedSearch in Google Scholar
  • 24 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418-435.
    CrossrefPubMedSearch in Google 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.
    CrossrefPubMedSearch in Google Scholar
  • 26 Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 1998; 4: 558-563.
    CrossrefPubMedSearch in Google Scholar
  • 27 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22.
    PubMedSearch in Google 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.
    Thieme ConnectPubMedSearch in Google Scholar