Semin Thromb Hemost 2009; 35(8): 760-768
DOI: 10.1055/s-0029-1245108
© Thieme Medical Publishers

Laboratory Identification of Factor Inhibitors: The Perspective of a Large Tertiary Hemophilia Center

Geoffrey Kershaw1 , Dayani Jayakodi1 , Scott Dunkley1
  • 1Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia
Further Information

Publication History

Publication Date:
18 February 2010 (online)

ABSTRACT

Coagulation factor inhibitors are antibodies that bind and neutralize specific procoagulant plasma proteins. The identification of coagulation factor inhibitors by the hemostasis laboratory requires a careful and systematic approach that excludes other possible causes of prolonged screening tests such as the activated partial thromboplastin time and prothrombin time. Once the laboratory is confident that a specific coagulation factor inhibitor is present in a sample, its strength or titer must be measured. The clinician will use this information as a treatment guide. The most frequently occurring factor inhibitors encountered in the hemostasis laboratory are those directed against factor VIII (FVIII), which can arise in individuals with inherited hemophilia A as an immune response to factor replacement therapy or as an autoantibody leading to the condition of acquired hemophilia A. The Bethesda assay is the most widely used test for measuring the FVIII inhibitor titer. The Bethesda assay has several components that must be carefully controlled to achieve consistent results. This overview examines the behavior of various coagulation inhibitors and laboratory tests with an emphasis on the Bethesda assay for factor inhibitors.

REFERENCES

  • 1 Kasper C K, Aledort L M, Counts R B et al.. Letter: A more uniform measurement of factor VIII inhibitors.  Thromb Diath Haemorrh. 1975;  34(3) 869-872
  • 2 Favaloro E J, Bonar R, Duncan E et al.. Identification of factor inhibitors by diagnostic haemostasis laboratories: a large multi-centre evaluation.  Thromb Haemost. 2006;  96(1) 73-78
  • 3 Favaloro E J, Bonar R, Kershaw G, Mohammed S, Duncan E, Marsden K. (on behalf of RCPA Haematology QAP Haemostasis Committee) . Laboratory identification of factor VIII inhibitors in the real world: the experience from Australasia.  Haemophilia. 2010;  , In press
  • 4 Meijer P, Verbruggen B. The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment programme of the ECAT Foundation.  Semin Thromb Hemost. 2009;  35(8) 786-793
  • 5 Kitchen S, Jennings I, Preston F E, Kitchen D P, Woods T AL, Walker I D. Inter-laboratory variation in factor VIII:C inhibitor assay results is sufficient to influence patient management: data from the UK NEQAS for blood coagulation.  Semin Thromb Hemost. 2009;  35 778-785
  • 6 Favaloro E J, Bonar R, Kershaw G, Duncan E, Sioufi J, Marsden K. Investigations from external quality assurance driven cross-laboratory studies reveal a high degree of variation in the identification of coagulation factor inhibitors.  Semin Thromb Hemost. 2009;  35(8) 794-805
  • 7 DiMichele D M. Inhibitor treatment in haemophilias A and B: inhibitor diagnosis.  Haemophilia. 2006;  12(Suppl 6) 37-41 discussion 41-42
  • 8 White II G C, Kempton C L, Grimsley A, Nielsen B, Roberts H R. Cellular immune responses in hemophilia: why do inhibitors develop in some, but not all hemophiliacs?.  J Thromb Haemost. 2005;  3(8) 1676-1681
  • 9 Key N S. Inhibitors in congenital coagulation disorders.  Br J Haematol. 2004;  127(4) 379-391
  • 10 Towfighi F, Gharagozlou S, Sharifian R A et al.. Comparative measurement of anti-factor VIII antibody by Bethesda assay and ELISA reveals restricted isotype profile and epitope specificity.  Acta Haematol. 2005;  114(2) 84-90
  • 11 Oldenburg J, Tuddenham E. Inhibitors to factor VIII-molecular basis. In: Lee C, Berntorp E, Hoots KW Textbook of hemophilia. Oxford, United Kingdom; Blackwell 2005: 59-63
  • 12 Gouw S C, van den Berg H M. The multifactorial etiology of inhibitor development in hemophilia: genetics and environment.  Semin Thromb Hemost. 2009;  35(8) 723-734
  • 13 Lusher J. Natural history of inhibitor development in children with severe hemophilia A treated with FVIII products. In: Lee C, Berntorp E, Hoots KW Textbook of hemophilia. Oxford, United Kingdom; Blackwell 2005: 34-38
  • 14 Gouw S C, van den Berg H M, le Cessie S, van der Bom J G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.  J Thromb Haemost. 2007;  5(7) 1383-1390
  • 15 Lillicrap D, Nair S C, Srivastava A, Rodeghiero F, Pabinger I, Federici A B. Laboratory issues in bleeding disorders.  Haemophilia. 2006;  12(suppl 3) 68-75
  • 16 Dunkley S, Kershaw G, Young G et al.. Rituximab treatment of mild haemophilia A with inhibitors: a proposed treatment protocol.  Haemophilia. 2006;  12(6) 663-667
  • 17 Ma A D, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment.  Hematology (Am Soc Hematol Educ Program). 2006;  432-437
  • 18 Kasper C K, Ewing N P. Acquired inhibitors of plasma coagulation factors.  J Med Technol. 1986;  3 431-439
  • 19 Mannucci P M, Peyvandi F. Autoimmune hemophilia at rescue.  Haematologica. 2009;  94(4) 459-461
  • 20 Collins P W, Hirsch S, Baglin T P UK Haemophilia Centre Doctors' Organisation et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.  Blood. 2007;  109(5) 1870-1877
  • 21 Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII.  Thromb Haemost. 1981;  45(3) 200-203
  • 22 Warrier I. Inhibitors in hemophilia B. In: Lee C, Berntorp E, Hoots WK Textbook of hemophilia. Oxford, United Kingdom; Blackwell 2005
  • 23 Ljung R, Petrini P, Tengborn L, Sjörin E. Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity.  Br J Haematol. 2001;  113(1) 81-86
  • 24 Brown S A. Treatment of inhibitors in hemophilia B. In: Lee C, Berntorp E, Hoots WK Textbook of hemophilia. Oxford, United Kingdom; Blackwell 2005: 101-105
  • 25 Kessler C, Asatiani E. Acquired inhibitors to factor VIII. In: Lee C, Berntorp E, Hoots WK Textbook of hemophilia. Oxford, United Kingdom; Blackwell 2005: 86-90
  • 26 Lossing T S, Kasper C K, Feinstein D I. Detection of factor VIII inhibitors with the partial thromboplastin time.  Blood. 1977;  49(5) 793-797
  • 27 Kazmi M A, Pickering W, Smith M P, Holland L J, Savidge G F. Acquired haemophilia A: errors in the diagnosis.  Blood Coagul Fibrinolysis. 1998;  9(7) 623-628
  • 28 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability.  Thromb Haemost. 1995;  73(2) 247-251
  • 29 Giles A R, Verbruggen B, Rivard G E, Teitel J, Walker I. Association of Hemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis . A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor VIII:C inhibitors in the haemophilia A population of Canada.  Thromb Haemost. 1998;  79(4) 872-875
  • 30 Verbruggen B, van Heerde W, Novákovà I, Lillicrap D, Giles A. A 4% solution of bovine serum albumin may be used in place of factor VIII:C deficient plasma in the control sample in the Nijmegen Modification of the Bethesda factor VIII:C inhibitor assay.  Thromb Haemost. 2002;  88(2) 362-364
  • 31 Kitchen S, McCraw A. Diagnosis of haemophilia and other bleeding disorders: a laboratory manual. Montreal, Quebec, Canada; World Federation of Hemophilia 2000: 72-76
  • 32 Gadarowski Jr J J, Czapek E E, Ontiveros J D, Pedraza J L. Modification of the Bethesda assay for factor VIII or IX inhibitors to improve efficiency.  Acta Haematol. 1988;  80(3) 134-138

Geoffrey KershawF.A.I.M.S. 

Institute of Haematology, Royal Prince Alfred Hospital

Missenden Road, NSW 2050 Australia

Email: geoffrey.kershaw@email.cs.nsw.gov.au