Semin Thromb Hemost 2009; 35(8): 806-813
DOI: 10.1055/s-0029-1245113
© Thieme Medical Publishers

Recent Improvements in the Clinical Treatment of Coagulation Factor Inhibitors

Massimo Franchini1 , 2 , Giuseppe Lippi2 , 3
  • 1Immunohematology and Transfusion Center, University Hospital of Parma, Parma, Italy
  • 2Department of Pathology and Laboratory Medicine, University Hospital of Parma, Parma, Italy
  • 3Clinical Chemistry Laboratory, University Hospital of Parma, Parma, Italy
Further Information

Publication History

Publication Date:
18 February 2010 (online)

ABSTRACT

The mainstay of therapy in patients with congenital hemophilia is factor replacement. However, the development of inhibitors in these patients is a major complication that represents an important challenge in hemophilia care. Development of inhibitors complicates the clinical course of severe hemophilia in up to 30% of patients with hemophilia A and up to 5% of patients with hemophilia B. Although the main short-term objective of the treatment of alloantibodies against factors VIIII and IX is to control the bleeding diathesis, the eradication of the inhibitor is the leading long-term goal. The management of severe bleeding episodes and the definitive eradication of the autoantibody are also the two main options of the clinical management of patients with acquired hemophilia, a rare but life-threatening hemorrhagic condition. The most recent options available for treating patients with acquired hemophilia and congenital hemophilia with inhibitors are addressed in this review.

REFERENCES

  • 1 Haya S, Moret A, Cid A R et al.. Inhibitors in haemophilia A: current management and open issues.  Haemophilia. 2007;  13(Suppl 5) 52-60
  • 2 Lusher J M. Inhibitor antibodies to factor VIII and factor IX: management.  Semin Thromb Hemost. 2000;  26(2) 179-188
  • 3 Franchini M, Targher G, Montagnana M, Lippi G. Laboratory, clinical and therapeutic aspects of acquired hemophilia A.  Clin Chim Acta. 2008;  395(1-2) 14-18
  • 4 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review.  Haemophilia. 2003;  9(4) 418-435
  • 5 Scandella D H. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients.  Semin Thromb Hemost. 2000;  26(2) 137-142
  • 6 Moreau A, Lacroix-Desmazes S, Stieltjes N et al.. Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG.  Blood. 2000;  95(11) 3435-3441
  • 7 Spiegel Jr P C, Jacquemin M, Saint-Remy J M, Stoddard B L, Pratt K P. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII.  Blood. 2001;  98(1) 13-19
  • 8 Lee C A, Lillicrap D, Astermark J. Inhibitor development in hemophiliacs: the roles of genetic versus environmental factors.  Semin Thromb Hemost. 2006;  32(Suppl 2) 10-14
  • 9 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
  • 10 Gill J C. The role of genetics in inhibitor formation.  Thromb Haemost. 1999;  82(2) 500-504
  • 11 Astermark J, Berntorp E, White G C, Kroner B L. MIBS Study Group . The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.  Haemophilia. 2001;  7(3) 267-272
  • 12 Aledort L M, Dimichele D M. Inhibitors occur more frequently in African-American and Latino haemophiliacs.  Haemophilia. 1998;  4(1) 68
  • 13 Hay C R, Ollier W, Pepper L UKHCDO Inhibitor Working Party et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A.  Thromb Haemost. 1997;  77(2) 234-237
  • 14 Oldenburg J, Schröder J, Brackmann H H, Müller-Reible C, Schwaab R, Tuddenham E. Environmental and genetic factors influencing inhibitor development.  Semin Hematol. 2004;  41(Suppl 1) 82-88
  • 15 Santagostino E, Mancuso M E, Rocino A et al.. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study.  Br J Haematol. 2005;  130(3) 422-427
  • 16 Gouw S C, van der Bom J G, Auerswald G, Ettinghausen C E, Tedgård U, van den Berg H M. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study.  Blood. 2007;  109(11) 4693-4697
  • 17 Goudemand J, Rothschild C, Demiguel V et al.. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A.  Blood. 2006;  107(1) 46-51
  • 18 Chalmers E A, Brown S A, Keeling D Paediatric Working Party of UKHCDO et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.  Haemophilia. 2007;  13(2) 149-155
  • 19 Berntorp E, Shapiro A, Astermark J et al.. Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference.  Haemophilia. 2006;  12(Suppl 6) 1-7
  • 20 Jadhav M, Warrier I. Anaphylaxis in patients with hemophilia.  Semin Thromb Hemost. 2000;  26(2) 205-208
  • 21 Warrier I. Management of haemophilia B patients with inhibitors and anaphylaxis.  Haemophilia. 1998;  4(4) 574-576
  • 22 Astermark J. Treatment of the bleeding inhibitor patient.  Semin Thromb Hemost. 2003;  29(1) 77-86
  • 23 von Depka M. Managing acute bleeds in the patient with haemophilia and inhibitors: options, efficacy and safety.  Haemophilia. 2005;  11(Suppl 1) 18-23
  • 24 Parameswaran R, Shapiro A D, Gill J C, Kessler C M. HTRS Registry Investigators . Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.  Haemophilia. 2005;  11(2) 100-106
  • 25 Santagostino E, Mancuso M E, Rocino A, Mancuso G, Scaraggi F, Mannucci P M. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.  J Thromb Haemost. 2006;  4(2) 367-371
  • 26 Young G, Shafer F E, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.  Haemophilia. 2008;  14(2) 287-294
  • 27 Franchini M, Sassi M, Dell'Anna P et al.. Extracorporeal immunoadsorption for the treatment of coagulation inhibitors.  Semin Thromb Hemost. 2009;  35(1) 76-80
  • 28 Fischer K, Valentino L, Ljung R, Blanchette V. Prophylaxis for severe haemophilia: clinical challenges in the absence as well as in the presence of inhibitors.  Haemophilia. 2008;  14(Suppl 3) 196-201
  • 29 Franchini M, Manzato F, Salvagno G L, Montagnana M, Zaffanello M, Lippi G. Prophylaxis in congenital hemophilia with inhibitors: the role of recombinant FVIIa.  Semin Thromb Hemost. 2009;  35(8) 814-819
  • 30 DiMichele D M, Hoots W K, Pipe S W, Rivard G E, Santagostino E. International workshop on immune tolerance induction: consensus recommendations.  Haemophilia. 2007;  (13 Suppl 1) 1-22
  • 31 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia—principal results from the International Registry. Report of the factor VIII and IX Subcommittee.  Thromb Haemost. 1994;  72(1) 155-158
  • 32 DiMichele D M, Kroner B L. North American Immune Tolerance Study Group . The North American Immune Tolerance Registry: practices, outcomes, outcome predictors.  Thromb Haemost. 2002;  87(1) 52-57
  • 33 Lenk H. ITT Study Group . The German Registry of immune tolerance treatment in hemophilia—1999 update.  Haematologica. 2000;  85(10 Suppl) 45-47
  • 34 Kroner B L. Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry.  Vox Sang. 1999;  77(Suppl 1) 33-37
  • 35 Haya S, Quintana M, Aznar J et al.. Registro español de inmunotolerancia en hemofilicos con inhibidores. Actualización a 2005.  Haematologica. 2006;  91(Spanish ed., Suppl 4) 1-5
  • 36 DiMichele D. The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy.  Haemophilia. 2009;  15(1) 320-328
  • 37 Dimichele D M, Hay C R. The International Immune Tolerance Study: a multicenter prospective randomized trial in progress.  J Thromb Haemost. 2006;  4(10) 2271-2273
  • 38 Gringeri A. VWF/FVIII concentrates in high-risk immunotolerance: the RESIST study.  Haemophilia. 2007;  13(Suppl 5) 73-77
  • 39 Hay C R, Brown S, Collins P W, Keeling D M, Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors' Organisation.  Br J Haematol. 2006;  133(6) 591-605
  • 40 Key N S. Inhibitors in congenital coagulation disorders.  Br J Haematol. 2004;  127(4) 379-391
  • 41 Biss T T, Velangi M R, Hanley J P. Failure of rituximab to induce immune tolerance in a boy with severe haemophilia A and an alloimmune factor VIII antibody: a case report and review of the literature.  Haemophilia. 2006;  12(3) 280-284
  • 42 Fox R A, Neufeld E J, Bennett C M. Rituximab for adolescents with haemophilia and high titre inhibitors.  Haemophilia. 2006;  12(3) 218-222
  • 43 Carcao M, St Louis J, Poon M C Inhibitor Subcommittee of Association of Hemophilia Clinic Directors of Canada et al. Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience.  Haemophilia. 2006;  12(1) 7-18
  • 44 Franchini M, Mengoli C, Lippi G et al.. Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients' analysis.  Haemophilia. 2008;  14(5) 903-912
  • 45 Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors.  Br J Haematol. 2003;  121(1) 21-35
  • 46 Cohen A J, Kessler C M. Acquired inhibitors.  Baillieres Clin Haematol. 1996;  9(2) 331-354
  • 47 Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review.  Am J Hematol. 2005;  80(1) 55-63
  • 48 Hay C RM, Baglin T P, Collins P W, Hill F GH, Keeling D M. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO).  Br J Haematol. 2000;  111(1) 78-90
  • 49 Collins P, Macartney N, Davies R, Lees S, Giddings J, Majer R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A.  Br J Haematol. 2004;  124(1) 86-90
  • 50 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
  • 51 Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII.  Thromb Haemost. 1981;  45(3) 200-203
  • 52 Bossi P, Cabane J, Ninet J et al.. Acquired hemophilia due to factor VIII inhibitors in 34 patients.  Am J Med. 1998;  105(5) 400-408
  • 53 Yee T T, Pasi K J, Lilley P A, Lee C A. Factor VIII inhibitors in haemophiliacs: a single-centre experience over 34 years, 1964–97.  Br J Haematol. 1999;  104(4) 909-914
  • 54 Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey.  Am J Hematol. 1998;  59(1) 1-4
  • 55 Franchini M. Postpartum acquired factor VIII inhibitors.  Am J Hematol. 2006;  81(10) 768-773
  • 56 Trotta F, Bajocchi G, La Corte R, Moratelli S, Sun L Y. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosphamide in a patient with systemic lupus erythematosus.  Rheumatology (Oxford). 1999;  38(10) 1007-1009
  • 57 Soriano R M, Matthews J M, Guerado-Parra E. Acquired haemophilia and rheumatoid arthritis.  Br J Rheumatol. 1987;  26(5) 381-383
  • 58 Meiklejohn D J, Watson H G. Acquired haemophilia in association with organ-specific autoimmune disease.  Haemophilia. 2001;  7(5) 523-525
  • 59 Hauser I, Lechner K. Solid tumors and factor VIII antibodies.  Thromb Haemost. 1999;  82(3) 1005-1007
  • 60 Sallah S, Wan J Y. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients.  Cancer. 2001;  91(6) 1067-1074
  • 61 Franchini M, Targher G, Manzato F, Lippi G. Acquired factor VIII inhibitors in oncohematology: a systematic review.  Crit Rev Oncol Hematol. 2008;  66(3) 194-199
  • 62 Sallah S, Nguyen N P, Abdallah J M, Hanrahan L R. Acquired hemophilia in patients with hematologic malignancies.  Arch Pathol Lab Med. 2000;  124(5) 730-734
  • 63 Dentale N, Fulgaro C, Guerra L, Fasulo G, Mazzetti M, Fabbri C. Acquisition of factor VIII inhibitor after acute hepatitis C virus infection.  Blood. 1997;  90(8) 3233-3234
  • 64 Sallah S, Wan J Y. Inhibitors against factor VIII associated with the use of interferon-alpha and fludarabine.  Thromb Haemost. 2001;  86(4) 1119-1121
  • 65 Franchini M, Targher G, Montagnana M, Lippi G. Laboratory, clinical and therapeutic aspects of acquired hemophilia A.  Clin Chim Acta. 2008;  395(1-2) 14-18
  • 66 Kershaw G, Jayakodi D, Dunkley S. Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia centre.  Semin Thromb Hemost. 2009;  35(8) 760-768
  • 67 Scandella D, Gilbert G E, Shima M et al.. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site.  Blood. 1995;  86(5) 1811-1819
  • 68 Franchini M, Lippi G. Acquired factor VIII inhibitors.  Blood. 2008;  112(2) 250-255
  • 69 Kessler C M. Acquired factor VIII autoantibody inhibitors: current concepts and potential therapeutic strategies for the future.  Haematologica. 2000;  85(10, Suppl) 57-61, discussion 61–63
  • 70 Collins P W. Treatment of acquired hemophilia A.  J Thromb Haemost. 2007;  5(5) 893-900
  • 71 Mudad R, Kane W H. DDAVP in acquired hemophilia A: case report and review of the literature.  Am J Hematol. 1993;  43(4) 295-299
  • 72 Sallah S. Treatment of acquired haemophilia with factor eight inhibitor bypassing activity.  Haemophilia. 2004;  10(2) 169-173
  • 73 Hay C R, Negrier C, Ludlam C A. The treatment of bleeding in acquired hemophilia with recombinant factor VIIa: a multicenter study.  Thromb Haemost. 1997;  78 1463-1467
  • 74 Sumner M J, Geldziler B D, Pedersen M, Seremetis S. Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal.  Haemophilia. 2007;  13(5) 451-461
  • 75 Schwartz R S, Gabriel D A, Aledort L M, Green D, Kessler C M. A prospective study of treatment of acquired (autoimmune) factor VIII inhibitors with high-dose intravenous gammaglobulin.  Blood. 1995;  86(2) 797-804
  • 76 Green D. Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide.  Blood. 1971;  37(4) 381-387
  • 77 Spero J A, Lewis J H, Hasiba U. Corticosteroid therapy for acquired F VIII:C inhibitors.  Br J Haematol. 1981;  48(4) 635-642
  • 78 Shaffer L G, Phillips M D. Successful treatment of acquired hemophilia with oral immunosuppressive therapy.  Ann Intern Med. 1997;  127(3) 206-209
  • 79 Lian E C, Larcada A F, Chiu A Y. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor.  Ann Intern Med. 1989;  110(10) 774-778
  • 80 Green D, Rademaker A W, Briët E. A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies.  Thromb Haemost. 1993;  70(5) 753-757
  • 81 Petrovic M, Derom E, Baele G. Cyclosporine treatment of acquired hemophilia due to factor VIII antibodies.  Haematologica. 2000;  85(8) 895-896
  • 82 Lottenberg R, Kentro T B, Kitchens C S. Acquired hemophilia. A natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy.  Arch Intern Med. 1987;  147(6) 1077-1081
  • 83 Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia.  Blood. 2004;  103(12) 4424-4428
  • 84 Wiestner A, Cho H J, Asch A S et al.. Rituximab in the treatment of acquired factor VIII inhibitors.  Blood. 2002;  100(9) 3426-3428
  • 85 Onitilo A A, Skorupa A, Lal A et al.. Rituximab in the treatment of acquired factor VIII inhibitors.  Thromb Haemost. 2006;  96(1) 84-87
  • 86 Franchini M. Rituximab in the treatment of adult acquired hemophilia A: a systematic review.  Crit Rev Oncol Hematol. 2007;  63(1) 47-52
  • 87 Nemes L, Pitlik E. Ten years experience with immune tolerance induction therapy in acquired hemophilia.  Haematologica. 2003;  88(Suppl 12) 106-110
  • 88 Zeitler H, Ulrich-Merzenich G, Hess L et al.. Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept.  Blood. 2005;  105(6) 2287-2293

Massimo FranchiniM.D. 

Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine

University Hospital of Parma, Parma, Italy

Email: mfranchini@ao.pr.it