Inhibitor Antibodies to Factor VIII and Factor IX: Management

 

 Buy Article Permissions and Reprints

ABSTRACT

Inhibitor antibodies directed against factor VIII or factor IX present challenges to the clinician. Fortunately, several management options are available, although each has disadvantages as well as advantages. Alloantibodies against factor VIII (which develop in 25 to 50% of children with severe hemophilia A, as well as in a small percentage of children with mild or moderate hemophilia A) may be low titer and transient or may be high titer. Most patients with high-titer problematic inhibitors now try to eliminate the inhibitor by using one of several immune tolerance induction (ITI) regimens. For treatment of bleeding episodes in patients who have high-titer (≥ 5 Bethesda units) inhibitors, one can use a prothrombin complex concentrate (PCC) (preferably an activated PCC [APCC]), recombinant (r) factor VIIa, or porcine factor VIII. The choice of product is generally dependent on the type and severity of the patient's bleeding, degree of cross-reactivity of the patient's inhibitor with porcine factor VIII, physician familiarity with the product, product availability, and cost.

In persons with hemophilia B, alloantibodies occur in only 1 to 3% of severely affected individuals. However, in roughly half of those who develop inhibitors, anaphylaxis or severe allergic reactions occur on infusion of any type of factor IX-containing product. This phenomenon usually develops after relatively few exposures to factor IX; thus it is recommended that the first 10 to 20 infusions of factor IX given to children with severe hemophilia B be given in a setting equipped for treatment of shock. For treatment of bleeding episodes in patients with severe allergic reactions, rF VIIa is the treatment of choice. ITI has been less successful in hemophilia B patients with inhibitors than in those with hemophilia A, and in a subgroup of patients with severe allergic reactions who were desensitized to factor IX and then tried on ITI, results were even poorer. Additionally, several developed nephrotic syndrome while on ITI. For hemophilia B patients with inhibitors who do not have allergic reactions to factor IX, bleeding episodes can be treated with PCC or APCC or with rF VIIa.

Autoantibodies directed against factor VIII are rare but can occur in a variety of settings. They occur mainly in adults, and bleeding is often severe and life threatening. Although some factor VIII autoantibodies disappear spontaneously, most require immunosuppression. Corticosteroids and cyclophosphamide are generally recommended. For treatment of bleeding, therapeutic options include (human) factor VIII concentrates, porcine factor VIII, APCC, and rFVIIa. The choice of product is generally determined by the consulting hematologist's familiarity with the product, product availability and cost, as well as response to treatment.

REFERENCES

• 1 Hay C RM, Ludlam C A, Colvin B T. Factor VIII inhibitors in mild and moderate severity haemophilia A.  Thromb Haemost . 1998;  79 762-766
  PubMedGoogle Scholar
• 2 Schwaab R, Brackmann H-H, Meyer C. Haemophilia A: Mutation type determines risk of inhibitor formation.  Thromb Haemost . 1995;  74 1402-1406
  PubMedGoogle Scholar
• 3 Addiego J E, Kasper C K, Abildgaard C F. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII.  Lancet . 1993;  342 462-464
  CrossrefPubMedGoogle Scholar
• 4 Lusher J M, Courter S, Spira J. Safety, efficacy and inhibitor development in previously untreated patients (PUPs) treated exclusively with recombinant B domain deleted F VIII (rVIII SQ).  Haemophilia . 1998;  4 (Abstract) 227
  CrossrefPubMedGoogle Scholar
• 5 Hay C RM, Ollier W, Pepper L. HLA class II profile: A weak determinant of factor VIII inhibitor development in severe haemophilia A.  Thromb Haemost . 1997;  77 234-237
  PubMedGoogle Scholar
• 6 Oldenburg J, Picard J K, Schwaab R. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors to factor VIII.  Thromb Haemost . 1997;  77 238-242
  PubMedGoogle Scholar
• 7 Kasper C K, Aledort L M, Counts R B. A more uniform measurement of factor VIII inhibitors.  Thrombosis et Diathesis Haemorrhagica . 1975;  34 869-872
  PubMedGoogle Scholar
• 8 Verbruggen B, Novakova I, Wessels H. The Nijmegen modification of the Bethesda assay for factor VIII inhibitors: Improved specificity and reliability.  Thromb Haemost . 1995;  73 247-251
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Bray G L, Gomperts E D, Courter S. A multicenter study of recombinant factor VIII (Recombinate): Safety, efficacy and inhibitor risk in previously untreated patients.  Blood . 1994;  83 2428-2435
  PubMedGoogle Scholar
• 10 Lusher J M, Arkin S, Abildgaard C F. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A.  N Engl J Med . 1993;  328 453-459
  CrossrefPubMedGoogle Scholar
• 11 Ehrenforth S, Kreuz W, Scharrer I. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs.  Lancet . 1992;  339 594-598
  CrossrefPubMedGoogle Scholar
• 12 Brackmann H H. Induced immunotolerance for factor VIII inhibitor patients.  Prog Clin Biol Res . 1984;  150 181-195
  PubMedGoogle Scholar
• 13 Aznar J A, Jorquera J L, Peiro A. Suppression of inhibitors in haemophilia with corticoids and factor VIII.  Thromb Haemost . 1983;  49 241-243
  PubMedGoogle Scholar
• 14 Nilsson I M, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia A and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide and factor VIII.  N Engl J Med . 1988;  328 947-950
  PubMedGoogle Scholar
• 15 Ewing N P, Sanders N L, Dietrich S L, Kasper C K. Induction of immune tolerance to factor VIII in hemophiliacs with inhibitors.  JAMA . 1988;  259 65-68
  CrossrefPubMedGoogle Scholar
• 16 Unuvar S, Warrier I, Lusher J M. Immune tolerance induction in the treatment of pediatric hemophilia A patients with factor VIII inhibitors.  Haemophilia (in press).
  PubMedGoogle Scholar
• 17 Gruppo R A, Valdez L P, Stout R D. Induction of immune tolerance in patients with hemophilia A and inhibitors.  Am J Pediatr Hematol Oncol . 1992;  14 82-87
  PubMedGoogle Scholar
• 18 Mauser-Bunschoten E P, Nieuwenhius H K, Roosendaal G, van den Berg M H. Low dose immune tolerance induction in hemophilia A patients with inhibitors.  Blood . 1995;  86 983-988
  PubMedGoogle Scholar
• 19 Kreuz W, Ehrenforth S, Funk M. Immune tolerance therapy is paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up.  Haemophilia . 1995;  1 24-32
  PubMedGoogle Scholar
• 20 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia. Principal results from the International Registry.  Thromb Haemost . 1994;  72 155-158
  PubMedGoogle Scholar
• 21 DiMichele D M, Kroner B L, the ISTH Factor VIII/IX Subcommittee. Analysis of the North American Immune Tolerance Registry (NAITR) (1993-1997): Current practice implications.  Blood . 1997;  90(suppl 1) (Abstract) 156A
  PubMedGoogle Scholar
• 22 Lenk H. The German National immune tolerance registry-1997 update. Vox Sang 1998
  Google Scholar
• 23 Nilsson I M, Berntorp E, Freiburghaus C. Treatment of patients with factor VIII and IX inhibitors.  Thromb Haemost . 1993;  70 56-59
  PubMedGoogle Scholar
• 24 Nilsson I M, Berntorp E, Rickard K A. Results in three Australian haemophilia B patients with high-responding inhibitors treated with the Malmö model.  Haemophilia . 1995;  1 59-66
  PubMedGoogle Scholar
• 25 Lusher J M, Blatt P M, Penner J A. Autoplex versus Proplex: A double controlled, double blind study of effectiveness in acute hemarthrosis in hemophiliacs with factor VIII.  Blood . 1983;  62 1135-1138
  PubMedGoogle Scholar
• 26 Sjamsoedin L J, Heijnen L, Mauser-Bunschoten E P. The effect of activated prothrombin complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double blind clinical trial.  N Engl J Med . 1981;  305 717-721
  CrossrefPubMedGoogle Scholar
• 27 Lusher J M. Thrombogenicity associated with factor IX complex concentrates.  Semin Hematol . 1991;  3-4 (3-4)
  PubMedGoogle Scholar
• 28 Chavin S I, Siegel D M, Rocco Jr A T, Olson J P. Acute myocardial infarction during management with an activated prothrombin complex concentrate in a person with factor VIII deficiency and factor VIII inhibitor.  Am J Med . 1988;  85 245-249
  CrossrefPubMedGoogle Scholar
• 29 Kernoff P BA. Porcine factor VIII: Preparation and use in treatment of inhibitor patients.  Prog Clin Biol Res . 1984;  150 207-224
  PubMedGoogle Scholar
• 30 Kernoff P BA. The clinical use of porcine factor VIII. In: Kasper CK, ed. Recent Advances in Hemophilia Care New York: Liss 1990: 47-56
  Google Scholar
• 31 Kernoff P BA, Thomas N D, Lilley P A. Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII.  Blood . 1984;  63 31-41
  PubMedGoogle Scholar
• 32 Brettler D B, Forsberg A D, Levine P H. The use of porcine factor VIII concentrate in the treatment of persons with inhibitor antibodies to factor VIII:C: A multicenter U.S. experience.  Arch Intern Med . 1989;  149 1381-1385
  CrossrefPubMedGoogle Scholar
• 33 Lusher J M. Considerations for current and future management of haemophilia and its complications.  Haemophilia . 1995;  1 2-10
  PubMedGoogle Scholar
• 34 Martinowitz U, Schulman S. Continuous infusion of coagulation products.  Int J Pediatr Hematol Oncol . 1994;  1 47-48
  PubMedGoogle Scholar
• 35 Woloschik D MN, Rubinger M, Israels J J. In vitro stability of porcine factor VIII (Hyate:C®).  Haemophilia . 1997;  3 21-23
  CrossrefPubMedGoogle Scholar
• 36 Hay C RM, Laurian Y, Verroust F. Induction of immune tolerance in patients with haemophilia A and inhibitors treated with porcine factor VIII by home therapy.  Blood . 1990;  76 882-886
  PubMedGoogle Scholar
• 37 Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors.  J Clin Invest . 1983;  71 1836-1841
  CrossrefPubMedGoogle Scholar
• 38 Lusher J M. Recombinant clotting factor concentrates.  Baillieres Clin Haematol . 1996;  9 291-303
  PubMedGoogle Scholar
• 39 Hedner U, Ingerslev J. Clinical use of recombinant F VIIa.  Transfus Sci . 1998;  19 163-176
  CrossrefPubMedGoogle Scholar
• 40 Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experience with recombinant factor VIIa.  Blood Coagul Fibrinolysis . 1998;  9 119-128
  CrossrefPubMedGoogle Scholar
• 41 Hoffman M, Monroe III M D, Roberts H R. Activated factor VII activates factors IX and X on the surface of activated platelets: Thoughts on the mechanism of action of high-dose activated factor VII.  Blood Coagul Fibrinolysis . 1998;  S61-S65 (S61-S65)
  PubMedGoogle Scholar
• 42 Hedner U, Glazer S, Pingel K. Successful use of recombinant factor VIIa in a patient with severe hemophilia A during synovectomy.  Lancet . 1988;  2 1193
  PubMedGoogle Scholar
• 43 Lindley C, Sawyer W T, Macik B G. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa.  Clin Pharmacol Ther . 1994;  55 638-648
  CrossrefPubMedGoogle Scholar
• 44 Lusher J M, Roberts H R, Davignon G. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors.  Haemophilia . 1998;  4 790-798
  CrossrefPubMedGoogle Scholar
• 45 Key N, Aledort L M, Beardsley D. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven) in haemophiliacs with inhibitors.  Thromb Haemost . 1998;  80 912-918
  PubMedGoogle Scholar
• 46 Shapiro A, Gilchrist G S, Hoots W K, Cooper H A, Gastineau D A. Prospective, randomized trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery.  Thromb Haemost . 1998;  80 773-778
  PubMedGoogle Scholar
• 47 Erhardtsen E, Nony P, Dechavanne M. The effect of recombinant factor VIIa (NovoSeven™) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0  Blood Coagul Fibrinolysis . 1998;  9 741-748
  CrossrefPubMedGoogle Scholar
• 48 Lusher J M. Acute hemarthroses-the benefits of early versus late treatment with recombinant Factor VIIa.  Semin Hematol (in press).
  PubMedGoogle Scholar
• 49 Schulman S, d'Oiron R, Martinowitz U. Experiences with continuous infusion of recombinant activated factor VII.  Blood Coagul Fibrinolysis . 1998;  8(suppl 1) S97-S101
  PubMedGoogle Scholar
• 50 Ljung R C. Gene mutations and inhibitor formation in patients with hemophilia B.  Acta Haematol . 1995;  94(suppl 1) 49-52
  CrossrefPubMedGoogle Scholar
• 51 High K A. Factor IX: Molecular structure, epitopes and mutations associated with inhibitor formation.  Adv Exp Med Biol . 1995;  386 79-86
  PubMedGoogle Scholar
• 52 Giannelli F, Choo K H, Rees D JG. Gene deletions in patients with haemophilia B and anti-Factor IX antibodies.  Nature . 1983;  303 181-182
  CrossrefPubMedGoogle Scholar
• 53 Warrier I, Ewenstein B, Koerper M. Factor IX inhibitors and anaphylaxis in hemophilia B.  J Pediatr Hematol Oncol . 1997;  19 23-27
  CrossrefPubMedGoogle Scholar
• 54 Warrier I. Management of haemophilia B patients with inhibitors and anaphylaxis.  Haemophilia . 1998;  4 574-576
  CrossrefPubMedGoogle Scholar
• 55 Ewenstein B M, Takemoto C, Warrier I. Nephrotic syndrome as a complication of immune tolerance in hemophilia B.  Blood . 1997;  89 115-116
  PubMedGoogle Scholar
• 56 Lenk H, Bierback U, Schille R. Inhibitor to F IX in haemophilia B and nephrotic syndrome in the course of immune tolerance treatment.  Haemophilia . 1996;  2(suppl 1) (Abstract) 104
  PubMedGoogle Scholar
• 57 Pollman H. A haemophilia B patient with complete factor IX gene deletion and a high titer antibody against F IX.  Haemophilia . 1996;  2(suppl 1) (Abstract) 72
  PubMedGoogle Scholar
• 58 Warrier I, Lusher J M. Development of anaphylactic shock in haemophilia B patients with inhibitors.  Blood Coagul Fibrinolysis . 1998;  9(suppl 1) S125-S128
  PubMedGoogle Scholar
• 59 Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII.  Thromb Haemost . 1981;  45 200-203
  PubMedGoogle Scholar
• 60 Cohen A, Kessler C M. Acquired inhibitors.  Baillieres Clin Haematol . 1996;  9 331-354
  CrossrefPubMedGoogle Scholar
• 61 Hausser I, Schneider B, Lechner K. Postpartum factor VIII inhibitors.  Thromb Haemost . 1995;  73 1-5
  PubMedGoogle Scholar
• 62 Kessler C M. An introduction to factor VIII inhibitors: Their detection and quantitation.  Am J Med . 1991;  1-5 (1-5)
  PubMedGoogle Scholar
• 63 Ludlam C A, Morrison A E, Kessler C M. Treatment of acquired hemophilia.  Semin Hematol . 1994;  31 16-69
  PubMedGoogle Scholar
• 64 Macik B G. Treatment of factor VIII inhibitors: Products and strategies.  Semin Thromb Hemost . 1993;  19 13-24
  PubMedGoogle Scholar
• 65 Green D, Rademaker A W, Briet E. A prospective randomized trial of prednisone and cyclophosphamide in the treatment of patients with F VIII autoantibodies.  Thromb Haemost . 1993;  70 753-757
  PubMedGoogle Scholar
• 66 Shaffer L G, Phillips. Successful treatment of high titer acquired factor VIII inhibitors in non-hemophiliacs with oral cyclophosphamide and prednisone.  Blood . 1995;  86(suppl 1) (Abstract) 191
  PubMedGoogle Scholar
• 67 Sultan Y, Maisonneuve P, Kazatchkine M D. Anti idiotypic suppression of autoantibodies to factor VIII by high dose intravenous gamma globulin.  Lancet . 1984;  2 765-781
  PubMedGoogle Scholar
• 68 Schwartz R S, Begriel D A, Aledort L M. A prospective study of treatment of acquired (autoimmune) factor VIII inhibitors with high dose intravenous immunoglobulin.  Blood . 1995;  86 797-804
  PubMedGoogle Scholar
• 69 Pflieger G, Boda Z, Harsfalvi J. Cyclosporine treatment of a woman with acquired haemophilia due to factor VIII:C inhibitor.  Postgrad Med . 1989;  65 400-402
  PubMedGoogle Scholar