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Thromb Haemost 1999; 82(02): 531-539
DOI: 10.1055/s-0037-1615876
Research Article
Schattauer GmbH

Treatment of Patients with Factor VIII and Factor IX Inhibitors with Special Focus on the Use of Recombinant Factor VIIa

Ulla Hedner
1   Department of Coagulation Disorders, University Hospital of Malmö, University of Lund, SWEDEN
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Publication Date:
09 December 2017 (online)

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Introduction

In caring for patients with hemophilia, the development of inhibitors against the missing coagulation protein remains a significant problem. Such inhibitors occur in about 15% of patients with severe hemophilia1 and are directed against the procoagulant part of the factor VIII or factor IX molecules. The goal in the treatment of patients with hemophilia is to achieve high enough levels of the missing factor to induce hemostasis in case of bleeding or to prevent bleeding during surgery. Patients with a low inhibitor titer, and especially those with a low anamnestic response, can be given high doses of the coagulation factor concentrate to induce hemostasis. However, for patients with high inhibitor levels, or high-responders, other treatments must be used, including procedures to decrease the antibody titers. To minimize the booster effect of high doses of antigen, immunosuppressive treatment may be added. Because such treatment procedures are complicated and associated with a number of potential side effects, they are not often used to treat mild-to-moderate bleeding episodes or to cover elective, less urgent surgery for inhibitor patients. As a result, a great deal of effort has been devoted to finding more convenient treatment modalities and to inducing immunologic tolerance to permanently eradicate the inhibitors.

 

  • References

  • 1 Hoyer WL. The incidence of factor VIII inhibitors in patients with severe hemophilia A. In: Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White II GC. eds. Inhibitors to Coagulation Factors. New York: Plenum Press; 1995: 35-45.
    Google Scholar
  • 2 Nilsson IM, Hedner U. Immunosuppressive treatment in haemophiliacs with inhibitors to factor VIII and factor IX. Scand J Haematol 1976; 16: 369-382.
    PubMedGoogle Scholar
  • 3 Nilsson IM, Berntorp E, Zetterwall O. Induction of immune tolerance in patients with haemophilia 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
  • 4 Hedner U, Tengborn L. Management of haemophilia A with antibodies: The effect of combined treatment with factor VIII, hydrocortisone and cyclophosphamide. Thromb Haemost 1985; 54: 776-779.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Green D. Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide. Blood 1971; 37: 381-387.
    PubMedGoogle Scholar
  • 6 Hedner U, Nilsson IM. Induced tolerance in hemophilia patients with antibodies against IX:C. Acta Med Scand 1983; 214: 191-197.
    PubMedGoogle Scholar
  • 7 Colvin BT. Role of plasma-exchange in the management of patients with factor VIII inhibitors. La Ricerca Clin Lab 1983; 13: 85-93.
    PubMedGoogle Scholar
  • 8 Révész T, Mátyus J, Goldschmidt B, Harsanyi V. Control of life-threatening bleeding by combined plasmapheresis and immunosuppressive treatment in a haemophiliac with inhibitors. Arch Dis Child 1980; 55: 641-643.
    CrossrefPubMedGoogle Scholar
  • 9 Nilsson IM, Jonsson S, Sundqvist S-B, Ahlberg A, Bergentz SE. A procedure for removing high titer antibodies by extracorporeal protein-A-sepharose adsorption in hemophilia: Substitution therapy and surgery in a patient with hemophilia B and antibodies. Blood 1981; 58: 38-43.
    PubMedGoogle Scholar
  • 10 Theodorsson B, Hedner U, Nilsson IM, Kisiel W. A technique for specific removal of factor IX alloantibodies from human plasma: Partial characterization of the alloantibodies. Blood 1983; 61: 973-981.
    PubMedGoogle Scholar
  • 11 Macik BG. Treatment of factor VIII inhibitors: Products and strategies. Semin Thromb Hemost 1993; 19: 13-24.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Nilsson IM, Berntorp E, Zettervall O, Dahlback B. Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients. Blood 1990; 75: 378-383.
    PubMedGoogle Scholar
  • 13 Brackman HH, Gormsen J. Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder. Lancet 1977; 2: 933.
    PubMedGoogle Scholar
  • 14 Brackman HH. Induced immunotolerance in factor VIII inhibitor patients. Prog Clin Biol Res 1986; 150: 180-195.
    PubMedGoogle Scholar
  • 15 Gomperts ED, Jordan S, Church JA, Sakai R, Lemire J. Induction of tolerance to factor VIII in a child with a high-titer inhibitor: In vitro and in vivo observations. J Pediatr 1984; 104: 70-75.
    CrossrefPubMedGoogle Scholar
  • 16 White GC, Taylor RE, Blatt PM, Roberts HR. Treatment of a high titer anti-factor-VIII antibody by continuous factor VIII administration: Report of a case. Blood 1983; 58: 141.
    PubMedGoogle Scholar
  • 17 Scheibel E, Ingerslev J, Dalsgaard-Nielsen J, Stenbjerg S, Knudsen JB. Continuous high-dose factor VIII for the induction of immune tolerance in haemophilia A patients with high responder state: A description of eleven patients treated. Thromb Haemost 1987; 58: 1049-1052.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Sultan Y, White GC, Aronstam A. et al. Hemophilic patients with an inhibitor to factor VIII treated with high dose factor VIII concentrate. Nouv Rev Fr Hematol 1986; 28: 85-89.
    PubMedGoogle Scholar
  • 19 Mauser-Bunschoten EP, Niewenhuis HK, Rosendaal G, van den Berg HM. Low-dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86: 983-988.
    PubMedGoogle Scholar
  • 20 Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance of factor VIII in hemophiliacs with inhibitors. JAMA 1988; 259: 65-68.
    CrossrefPubMedGoogle Scholar
  • 21 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia. Principal results from the international registry. Thromb Haemost 1994; 72: 155-158.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Warrier I, Lusher JM. Development of anaphylactic shock in haemophilia B patients with inhibitors. Blood Coagul Fibrinolysis 1998; 9: S125-S128.
    PubMedGoogle Scholar
  • 23 Brettler DB, Forsberg MS, Levine PH, Aledort LM, Hilgartner MW, Kasper CK, Lusher JM, McMIllan C, Roberts H. The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII: A multicenter U.S. experience. Arch Intern Med 1989; 149: 1381-1385.
    CrossrefPubMedGoogle Scholar
  • 24 Lusher JM, Blatt PM, Penner JA, Aledort LM, Levine PH, White GC, Warrier AI, Whitehurst DA. Autoplex versus proplex: A controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood 1983; 62: 1135-1138.
    PubMedGoogle Scholar
  • 25 Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, van Geijlswijk JL, van Houwelingen H, van Asten P, Sizma JJ. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med 1981; 305: 717-721.
    CrossrefPubMedGoogle Scholar
  • 26 Hultin MB. Activated clotting factors in factor IX concentrates. Blood 1979; 54: 1028-1038.
    PubMedGoogle Scholar
  • 27 White II GC, Roberts HR, Kindon HS, Lundblad RL. Prothrombin complex concentrates: Potentially thrombogenic materials and clues to the mechanism of thrombosis in vivo. Blood 1977; 49: 159-170.
    PubMedGoogle Scholar
  • 28 Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol 1991; 28: 3-5.
    PubMedGoogle Scholar
  • 29 Fekete L, Holst S, Peetoom F. et al. ‘Auto’ factor IX concentrate: A new therapeutic approach to treatment of hemophilia A patients with inhibitors. Paper presented at the XIV International Congress of Hematology. 1972
    PubMedGoogle Scholar
  • 30 Lusher JM, Shapiro SS, Palascak JE, Rao AV, Levine PH, Blatt PM. Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies for factor VIII. A multicentre trial. N Engl J Med 1980; 303: 421-425.
    CrossrefPubMedGoogle Scholar
  • 31 Seligsohn U, Kasper CK, Østerud B, Rapaport SI. Activated factor VII: Presence in factor IX concentrate and persistence in the circulation after infusion. Blood 1979; 53: 828-837.
    PubMedGoogle Scholar
  • 32 Rapaport SI, Rao LVM. Initiation and regulation of tissue factor-dependent blood coagulation. Art Thromb 1992; 12: 1111-1121.
    PubMedGoogle Scholar
  • 33 Kasper CK, Feinstein DI. Rising factor VIII inhibitor titers after Konyne factor IX complex. N Engl J Med 1976; 295: 505-506.
    CrossrefPubMedGoogle Scholar
  • 34 Rauch U, Bonderman D, Badimon J. et al. Platelets become tissue factor positive during thrombus formation. Blood 1998; 92: 347a.
    PubMedGoogle Scholar
  • 35 Rapaport SI, Rao LVM. The tissue factor pathway: How it has become a “prima ballerina.”. Thromb Haemost 1995; 74: 7-17.
    PubMedGoogle Scholar
  • 36 Ernofsson M, Siegbahn A. Platelet-derived growth factor-BB and monocyte chemotactic protein-1 induce human peripheral blood monocytes to express tissue factor. Thromb Res 1996; 83: 307-320.
    CrossrefPubMedGoogle Scholar
  • 37 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76: 731-736.
    PubMedGoogle Scholar
  • 38 Hedner U. Factor VIIa in the treatment of haemophilia. Blood Coagul Fibrinolysis 1990; 1: 307-317.
    CrossrefPubMedGoogle Scholar
  • 39 Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542-547.
    CrossrefPubMedGoogle Scholar
  • 40 Le DT, Borgs P, Toneff W, Witte MH, Rapaport SI. Hemostatic factors in rabbit limb lymph: Relationship to mechanism regulating extravascular coagulation. Am J Physiol 1998; 274: H769-H776.
    PubMedGoogle Scholar
  • 41 Dvorak HN, Senger DR, Dvorak AM, Harey VS, McDonagh J. Regulation of extravascular coagulation by microvascular permeability. Science 1985; 227: 1059-1061.
    CrossrefPubMedGoogle Scholar
  • 42 Glazer S, Hedner U, Falch JF. Clinical update on the use of recombinant factor VIIa. In: Aledort SM, Hoyer LW, Lusher JM, Reisner HM, White II GC. eds. Inhibitors to Coagulation Factors. New York: Plenum Press; 1995: 163-174.
    Google Scholar
  • 43 Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experience with recombinant factor VIIa. Blood Coagul Fibrinolysis 1998; 9: 119-128.
    CrossrefPubMedGoogle Scholar
  • 44 Rao LVM, Rapaport SI, Hoang AD. Binding of factor VIIa to tissue factor permits rapid antithrombin III/heparin inhibition of factor VIIa. Blood 1993; 81: 2600-2607.
    PubMedGoogle Scholar
  • 45 Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, Gilchrist GS, Gill JC, Glader B, Hoots WK, Kisker CT, Lusher JM, Rosenfield CG, Shapiro AD, Smith H, Taft E. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIA (NovoSeven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912-918.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Liesner RJ, Khair K, Hann IM. The impact of prophylactic treatment on children with severe haemophilia. Br J Haematol 1996; 92: 973-978.
    CrossrefPubMedGoogle Scholar
  • 47 Hedner U, Glazer S, Pingel K, Alberts KA, Blomback M, Schulman S, Johnsson H. Successful use of rFVIIa in a patient with severe haemophilia A subjected to synovectomy. Lancet 1988; ii: 1193.
    PubMedGoogle Scholar
  • 48 Gringeri A, Santagostino E, Mannucci PM. Failure of recombinant activated factor VII during surgery in a hemophiliac with high-titer factor VIII antibody. Hemostasis 1991; 21: 1-4.
    PubMedGoogle Scholar
  • 49 Hedner U, Ingerslev J. Clinical use of recombinant FVIIA (rFVIIA). Transfus Sci 1998; 19: 163-176.
    CrossrefPubMedGoogle Scholar
  • 50 Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIA (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 70: 773-778.
    PubMedGoogle Scholar
  • 51 Schulman S, Bech Jensen M, Varon D, Keller N, Gitel S, Horoszowski H, Heim M, Martinowitz U. Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 1996; 75: 432-436.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Vermylen J, Peerlinck K. Optimal care of inhibitor patients during surgery. Eur J Haematol 1998; 61 (Suppl. 63) 15-17.
    PubMedGoogle Scholar
  • 53 Ingram GI, Dykes SR, Crese AL, Mellor P, Swan AV, Kaufert JK, Rizza CR, Spooner RJ, Biggs R. Home treatment in hemophilia: Clinical, social and economic advantages. Clin Lab Haematol 1979; 1: 13-27.
    CrossrefPubMedGoogle Scholar
  • 54 Stein SF, Duncan A, Cutler D. et al. DIC in a hemophiliac treated with recombinant factor VIIa. Blood 1990; 76: 438a.
    PubMedGoogle Scholar
  • 55 Ingerslev J, Freidman D, Gastineau D, Gilchrist G, Johnsson H, Lucas G, McPherson J, Preston E, Scheibel E, Shuman M. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIA. Haemostasis 1996; 26 (Suppl. 01) 118-123.
    PubMedGoogle Scholar
  • 56 Sumner WT, Monroe DM, Hoffman M. Variability in platelet procoagulant activity in healthy volunteers. Thromb Res 1996; 81: 533-543.
    CrossrefPubMedGoogle Scholar
  • 57 Hedner U, Kristensen HI, Berntorp E. et al. Pharmacokinetics of rFVIIA in children. 23rd International Congress of the World Federation of Hemophilia. The Hague, The Netherlands: May 17-21 1998
    Google Scholar
  • 58 Martinowitz U, Schulman S. Continuous infusion of coagulation products. Int J Pediatr Hematol Oncol 1994; 1: 471-478.
    PubMedGoogle Scholar
  • 59 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744.
    PubMedGoogle Scholar
  • 60 Hedner U. Dosing and monitoring NovoSeven treatment. Haemostasis 1996; 26 (Suppl. 01) 102-108.
    PubMedGoogle Scholar
  • 61 Molskov Bech R. Personal communication. 1998
    PubMedGoogle Scholar
  • 62 Beguin S, Keularts I. On the coagulation of platelet rich plasma. Physiological mechanism and pharmacological consequences. In: Lecture Book: 15th International Congress on Thormbosis. October 16-21 1998: 97-101.
    PubMedGoogle Scholar
  • 63 Hoffman M, Monroe DM, Oliver JA. et al. Factor IXa and Xa play distinct roles in tissue factor –dependent initiation of coagulation. Blood 1995; 86: 1794-1801.
    PubMedGoogle Scholar
  • 64 Hansen LL, Nielsen FE, Hedner U. Validation of method for determination of recombinant FVIIa coagulant activity in plasma using a one-stage clotting assay. Thromb Haemostas 1993; 69: 865.
    PubMedGoogle Scholar
  • 65 Nicolaisen EM, Hansen LL, Poulsen F. et al. Immunological aspects of recombinant factor VIIa(rFVIIa) in clinical use. Thromb Haemostas 1996; 76: 200-204.
    PubMedGoogle Scholar
  • 66 Wildgoose P, Nemerson Y, Hansen LL. et al. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood 1992; 80: 25-28.
    PubMedGoogle Scholar
  • 67 Revesz Arets B, Bierings M. et al. Recombinant factor VIIa in severe uremic bleeding. Thromb Haemostas 1998; 80: 353.
    PubMedGoogle Scholar