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Thromb Haemost 2011; 105(01): 59-65
DOI: 10.1160/TH10-04-0231
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction

Camila Caram
1   Grupo de Estudo da Hemostasia e Trombose – GETHe/UFMG, Belo Horizonte, Brazil
,
Roberta Grazielle de Souza
2   Prefeitura de Pará de Minas, Pará de Minas, Brazil
,
Júlio Carepa de Sousa
3   Target M&E Consultoria, Belo Horizonte, Brazil
,
Tatiana Araújo Pereira
4   Sulamérica, São Paulo, Brazil
,
Ana Maria do Amaral Cerqueira
5   Fundação HEMOMINAS, Belo Horizonte, Brazil
,
Johanna G. van Der Bom
6   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Suely Meireles Rezende
7   Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
› Author Affiliations Financial support: This study was supported by FAPEMIG and CNPq.
Further Information

Publication History

Received: 15 April 2010

Accepted after major revision: 01 October 2010

Publication Date:
22 November 2017 (online)

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Summary

The development of alloantibodies that inhibit or neutralise the function of factor VIII is considered the most serious complication of the treatment of congenital haemophilia A. In order to describe their course without immune tolerance induction (ITI), we documented data on all performed inhibitor tests with dates as well as on clotting factor infusions of all consecutive patients who were treated in our centre between 1993 and 2006. Patients were tested every 7.1 months (95% confidence interval [CI], 6.6–7.8). A ‘sustained negative inhibitor status’ was defined as consistent non-positive inhibitor measurements for two years or longer. A total of 60/486 (12%) patients tested had a positive inhibitor titre in two or more occasions. Most of the patients (56%) with a maximum inhibitor titre of < 5 Bethesda unit (BU)/ml (named “low titre inhibitor”) developed a sustained negative inhibitor status. Among patients with high (5–9.9 BU/ml) and very high (≥ 10 BU/ ml) inhibitor titres, the proportions were 50% and 3%, respectively. Our findings suggest that ITI might not be needed for all patients with non-transient inhibitors, especially when their maximum inhibitor titre is below 10 BU/ml. Further studies in countries where ITI is not available are needed to examine predictors of the natural sustained negative inhibitor status.

Keywords

Haemophilia - inhibitor - alloantibody - factor VIII - natural history
 

  • References

  • 1 Ehrenforth SKW, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
    CrossrefPubMedGoogle Scholar
  • 2 Kempton CL SJ, Abshire TC. Incidence of inhibitors in a cohort of 838 males with haemophilia A previously treated with factor VIII concentrates. J Thromb Haemost 2006; 04: 2576-2581.
    CrossrefPubMedGoogle Scholar
  • 3 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-435.
    CrossrefPubMedGoogle Scholar
  • 4 DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87: 52-57.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Mariani G, Kroner B. Immune tolerance in haemophilia with factor VIII inhibitors: predictors of success. Haematologica 2001; 86: 1186-1193.
    PubMedGoogle Scholar
  • 6 Rezende SM, Pinheiro K, Caram C. et al. Registry of inherited coagulopathies in Brazil: first report. Haemophilia 2009; 15: 142-149.
    CrossrefPubMedGoogle Scholar
  • 7 Astermark J, Oldenburg J, Carlson J. et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with haemophilia A. Blood 2006; 108: 3739-3745.
    CrossrefPubMedGoogle Scholar
  • 8 Astermark J, Oldenburg J, Pavlova A. et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with haemophilia A. Blood 2006; 107: 3167-3172.
    CrossrefPubMedGoogle Scholar
  • 9 Gouw SC, van der Bom JG, Auerswald G. et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe haemophilia A: the CANAL cohort study. Blood 2007; 109: 4693-4697.
    CrossrefPubMedGoogle Scholar
  • 10 Gouw SC, van der Bom JG, van den Berg MH. Treatment-related risk factors of inhibitor development in previously untreated patients with haemophilia A: the CANAL cohort study. Blood 2007; 109: 4648-4654.
    CrossrefPubMedGoogle Scholar
  • 11 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22.
    PubMedGoogle Scholar
  • 12 Astermark JWX, Oldenburg J, Berntorp E. et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe haemophilia. A J Thromb Haemost 2007; 05: 263-265.
    PubMedGoogle Scholar
  • 13 Lorenzo JI LA, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600-603.
    CrossrefPubMedGoogle Scholar
  • 14 Oldenburg JSJ, Brackmann HH, Muller-Reible C. et al. Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004; 41: 82-88.
    CrossrefPubMedGoogle Scholar
  • 15 van der Bom JG M-BE, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe haemophilia. Thromb Haemost 2003; 89: 475-479.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Gilbert C, White I, Rosendaal Frits. et al. on behalf of the Factor VIII and Factor IX Subcommittee.. Scientific and Standardization Committee Communication: Definitions in Haemophilia. ISTH Website 29 November, 2000; Available at: http://www.isth.org.
    PubMedGoogle Scholar
  • 17 Kasper CK, Aledort L, Aronson D. et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 612.
    PubMedGoogle Scholar
  • 18 McMillan CW, Shapiro SS, Whitehurst D. et al. The natural history of factor VIII: C inhibitors in patients with haemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII: C inhibitors. Blood 1988; 71: 344-348.
    PubMedGoogle Scholar
  • 19 Yee TT, Pasi KJ, Lilley PA. et al. Factor VIII inhibitors in haemophiliacs: a single-centre experience over 34 years, 1964–97. Br J Haematol 1999; 104: 909-914.
    CrossrefPubMedGoogle Scholar
  • 20 Rasi VIE. Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 1990; 76: 369-371.
    CrossrefPubMedGoogle Scholar
  • 21 Schwarzinger IPI, Korninger C, Haschke F. et al. Incidence of inhibitors in patients with severe and moderate haemophilia A treated with factor VIII concentrates. Am J Hematol 1987; 24: 241-245.
    CrossrefPubMedGoogle Scholar
  • 22 Canada AoHCDo.. Canadian Haemophilia Registry and Inherited Bleeding Disorders Registry. Available at http://www.fhs.mcmaster.ca/chr/data.html. Last update on May 13, 2010.
    PubMedGoogle Scholar
  • 23 Services DoHah.. Bleeding and Clotting Disorders Surveillance. Center for Diseases control. Available at http://www.cdc.gov/ncbddd/blooddisorders/udc/index.html. Last update on May 1, 2010.
    PubMedGoogle Scholar
  • 24 Lenk H. The German Registry of immune tolerance treatment in haemophilia--1999 update. Haematologica 2000; Oct 85 (Suppl. 10) 45-47.
    PubMedGoogle Scholar
  • 25 Kroner B. Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry. Vox Sang 1999; 77: 33-37.
    CrossrefPubMedGoogle Scholar
  • 26 Kasper CK. Effect of prothrombin complex concentrates on factor VIII inhibitor levels. Blood 1979; 54: 1358-1368.
    PubMedGoogle Scholar
  • 27 Strauss HS, Merler E. Characterization and properties of an inhibitor of factor 8 in the plasma of patients with haemophilia A following repeated transfusions. Blood 1967; 30: 137-150.
    PubMedGoogle Scholar
  • 28 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII: C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
    Article in Thieme ConnectPubMedGoogle Scholar