Semin Thromb Hemost 2003; 29(1): 077-086
DOI: 10.1055/s-2003-37972
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Treatment of the Bleeding Inhibitor Patient

Jan Astermark
  • Associate Professor, Department of Coagulation Disorders, Malmö University Hospital, Malmö, Sweden
Further Information

Publication History

Publication Date:
17 March 2003 (online)

ABSTRACT

The development of inhibitory antibodies to factor (F) VIII and FIX continues to be a major challenge in the treatment of patients with hemophilia. In patients with low-responding inhibitors, it is usually possible to saturate the inhibitor with the deficient factor and to achieve hemostasis, but in patients with high-responding inhibitors, two major tasks have to be considered. One is how to treat the acute bleedings and the other is how to permanently eliminate the immune response, in other words, to induce tolerance. There are several hemostatic agents available for bleeding patients with high-responding inhibitors. Nonactivated and activated prothrombin complex concentrates (PCCs) have been used for almost 30 years, and since the beginning of the 1980s, porcine FVIII has also been used. In more recent years, recombinant FVIIa has been added to the therapeutic armamentarium and has been shown to control hemostasis in most patients. Immunoadsorption may temporarily reduce the inhibitor, enabling replacement therapy for several days. Available data on these alternative regimens will be discussed with a focus on the mechanisms of action, pharmacokinetics, safety, monitoring, and clinical experience.

REFERENCES

  • 1 van Leeuwen F E, Mauser-Bunschoten E P, van Kijken J P. et al . Disappearance of factor VIII:C antibodies in patients with haemophilia A upon frequent administration of factor VIII in intermediate or low dose.  Br J Haematol . 1996;  64 291-297
  • 2 Berntorp E, Björkman S, Carlsson M, Lethagen S, Nilsson I M. Biochemical and in vivo properties of high purity factor IX concentrates.  Thromb Haemost . 1993;  70 768-773
  • 3 Hoyer L W, Gawryl M S, de la Fuente B. Immunological characterization of factor VIII inhibitors. In: Hoyer LW, ed. Factor VIII Inhibitors New York: Liss 1984: 73-85
  • 4 Gjörstrup P, Berntorp E, Larsson L, Nilsson I M. Kinetic aspects of the removal of IgG and inhibitors in hemophiliacs using protein A immunoadsorption.  Vox Sang . 1991;  61 244-250
  • 5 Nilsson I M, Jonsson S, Sundqvist S B, Ahlberg Å, Bergentz S E. 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 38-44
  • 6 Freiburghaus C, Berntorp E, Ekman M. et al . Immunoadsorption for removal of inhibitors: update on treatments in Malmö-Lund between 1980 and 1995.  Haemophilia . 1998;  4 16-20
  • 7 Hedner U, Schulman S, Alberts K A. et al . Successful use of rFVIIa in a patient with severe hemophilia A subjected to synovectomy.  Lancet . 1988;  2 1193
  • 8 Wildgoose P, Berkner K L, Kisiel W. Synthesis, purification, and characterization of an Arg152 → Glu-site-directed mutant of recombinant human blood clotting factor VII.  Biochemistry . 1990;  29 3413-3420
  • 9 Hoffman M, Monroe D M, Roberts H R. Human monocytes support factor X activation by factor VIIa, independent of tissue factor: implications for the therapeutic mechanism of high-dose factor VIIa in hemophilia.  Blood . 1994;  83 38-42
  • 10 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;  9(Suppl 1) S61-S65
  • 11 Hedner U. NovoSeven as a universal haemostatic agent.  Blood Coagul Fibrinolysis . 2000;  11(Suppl 1) S107-S111
  • 12 Broze G J, Higuchi D A. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma.  Blood . 1996;  88 3815-3823
  • 13 van't Veer C, Golden N J, Mann K G. Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa.  Blood . 2000;  95 1330-1335
  • 14 Lund-Hansen T. Novoseven-virus safety.  Haemostasis . 1996;  26(Suppl 1) 96-97
  • 15 Nicolaisen E M, Hansen L L, Poulsen F, Glazer S, Hedner U. Immunological aspects of recombinant factor VIIa (rFVIIa) in clinical use.  Thromb Haemost . 1996;  76 200-204
  • 16 Roberts H R. Clinical experience with activated factor VIIa: focus on safety aspects.  Blood Coagul Fibrinolysis . 1998;  9(Suppl 1) S115-S118
  • 17 Hedner U. Treatment of patients with factor VIII and factor IX inhibitors with special focus on the use of recombinant factor VIIa.  Thromb Haemost . 1999;  82 531-539
  • 18 Kitchen S, Malia R G, Preston F E. A comparison of methods for the measurements of activated factor VII.  Thromb Haemost . 1992;  68 301-305
  • 19 Hansen L L, Nielsen F E, Hedner U. Validation of method for determination of recombinant FVIIa coagulant activity in plasma using a one-stage clotting assay (Abst).  Thromb Haemost . 1993;  69 865
  • 20 Morrissey J H, Macik B G, Neuenschwander P F, Comp P C. Quantitation of activated factor VII levels in plasma using tissue factor mutant selectively deficient in promoting factor VII activation.  Blood . 1993;  81 734-744
  • 21 Cid A R, Lorenzo J I, Haya S. et al . A comparison of FVII:C and FVII:a assays for the monitoring of recombinant factor VIIa treatment.  Haemophilia . 2001;  7 39-41
  • 22 Hedner U. Dosing and monitoring Novo-seven treatment.  Haemostasis . 1996;  26(Suppl 1) 103-108
  • 23 Lindley C M, Sawyer W T, Macik G. et al . Pharmacokinetics and pharmacodynamics of recombinant factor VIIa.  Clin Pharmacol Ther . 1994;  55 638-648
  • 24 Erhardtsen E. Pharmacokinetics of recombinant activated factor VII (rFVIIa).  Semin Thromb Haemost . 2000;  26 385-391
  • 25 Hedner U, Kristensen H, Berntorp E. et al . Pharmacokinetics of rFVIIa in children (Abst).  Haemophilia . 1998;  4 244
  • 26 Bech R M. Recombinant factor VIIa in joint and muscle bleeding episodes.  Haemostasis . 1996;  26(Suppl 1) 135-138
  • 27 Laurian Y, Goudemand J, Négrier C. et al . Use of recombinant activated factor VII as first line therapy for bleeding episodes in haemophiliacs with factor VIII or IX inhibitors (NOSEPAC study).  Blood Coagul Fibrinolysis . 1998;  9(Suppl 1) 155-156
  • 28 Lusher J M. Recombinant factor VIIa (NovoSeven(r)) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors.  Haemostasis . 1996;  26(Suppl 1) 124-130
  • 29 Arkin S, Cooper H A, Hutter J J. et al . Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors.  Haemostasis . 1998;  28 93-98
  • 30 Arkin S, Blei F, Fetten J. et al . Human coagulation factor VIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven(r) emergency-use programme in patients with severe haemophilia or with acquired inhibitors.  Blood Coagul Fibrinolysis . 2000;  11 255-259
  • 31 Rice K M, Savidge G F. NovoSeven(r) (recombinant factor VIIa) in central nervous system bleeds.  Haemostasis . 1996;  26(Suppl 1) 131-134
  • 32 Lusher J M, Roberts H R, Davignon G. et al . 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
  • 33 Key N S, Aledort L M, Beardsley D. et al . Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven(r)) in haemophiliacs with inhibitors.  Thromb Haemost . 1998;  80 912-918
  • 34 Lusher J M. Early treatment with recombinant factor VIIa results in greater efficacy with less product.  Eur J Haematol . 1998;  61(Suppl 63) 7-10
  • 35 Santagostino E, Gringeri A, Mannucci P M. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention.  Br J Haematol . 1999;  104 22-26
  • 36 Shirahata A, Kamiya T, Takamatsu J. et al . Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors.  Int J Hematol . 2001;  73 517-525
  • 37 Gringeri A, Santagostino E, Manucci P M. Failure of recombinant activated factor VII during surgery in a hemophiliac with high-titer factor VIII antibody.  Haemostasis . 1991;  21 1-4
  • 38 Ingerslev J, Freidman D, Gastineau D. et al . Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa.  Haemostasis . 1996;  26(Suppl 1) 118-123
  • 39 Shapiro A D, 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
  • 40 Schulman S, Bech Jensen M, Varon D. et al . Feasibility of using recombinant factor VIIa in continuous infusion.  Thromb Haemost . 1996;  75 432-436
  • 41 Baudo F, Redaelli R, Caimi T M. et al . The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications.  Thromb Res . 2000;  99 21-24
  • 42 Kenet G, Lubetsky A, Gitel S. et al . Treatment of bleeding episodes in patients with hemophilia and an inhibitor: comparison of two treatment protocols with recombinant activated factor VII.  Blood Coagul Fibrinolysis . 2000;  11(Suppl 1) S35-S38
  • 43 Kenet G, Lubetsky A, Gitel S. et al . Treatment of inhibitor patients with rFVIIa: continuous infusion protocols as compared to a single, large, dose (Abst).  Haemophilia . 2000;  76 297
  • 44 Lundblad R L, Bergstrom J, Vreker R D. et al . Measurement of active coagulation factors in Autoplex-T with colorimetric active site-specific assay technology.  Thromb Haemost . 1998;  80 811-815
  • 45 Philippou H, Adami A, Lane D A. et al . High purity factor IX and prothrombin complex concentrate (PCC): Pharmacokinetic trigger in PCC.  Thromb Haemost . 1996;  76 23-28
  • 46 Turecek P L, Gritsch H, Richter G, Varadi K, Schwarz H P. Activated prothrombin complex concentrates: a concept for the mechanism of action (Abst).  Thromb Haemost . 2001;  (Suppl) 1772
  • 47 Björkman S, Carlsson M, Berntorp E. Pharmacokinetics of factor IX in patients with haemophilia B. Methodological aspects and physiological interpretation.  Eur J Clin Pharmacol . 1994;  46 325-332
  • 48 Kim H C, McMillan C W, White G C. et al . Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates.  Blood . 1992;  79 568-575
  • 49 Morfini M, Longo G, Berntorp E. et al . Pharmacokinetics, thrombogenicity and safety of a double-treated prothrombin complex concentrate.  Thromb Res . 1993;  71 175-184
  • 50 Sjamsoedin L JM, Heijnen L, Mauser-Bunschoten E P. et al . 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
  • 51 Preiss D U, Eberspächer B, Abdullah D, Rosner I. Safety of vapour heated prothrombin complex concentrate (PCC) Prothromplex S-TIM 4.  Thromb Res . 1991;  63 651-659
  • 52 Kasper C K. Postoperative thrombosis in hemophilia B (Letter).  N Engl J Med . 1973;  289 160
  • 53 Blatt P M, Lundblad R L, Kingdon H S, McLean G, Roberts H R. Thrombogenic materials in prothrombin complex concentrates.  Ann Intern Med . 1974;  81 766-770
  • 54 Cederbaum A L, Blatt P M, Roberts H R. Intravascular coagulation with use of human prothrombin complex concentrates.  Ann Intern Med . 1976;  84 683-687
  • 55 Campbell E W, Neff S, Bowdler A J. Therapy with factor IX concentrate resulting in DIC and thromboembolic phenomena.  Transfusion . 1978;  18 94-97
  • 56 Chavin S I, Siegel D M, Rocco Jr A T, Olson H P. Acute myocardial infarction during treatment with an activated prothrombin complex concentrate in a patient with factor VIII deficiency and FVIII inhibitors.  Am J Med . 1988;  85 245-249
  • 57 Köhler M. Thrombogenicity of prothrombin complex concentrates.  Thromb Res . 1999;  95 S13-S17
  • 58 Leissinger C A. Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors.  Haemophilia . 1999;  5(Suppl 3) 25-32
  • 59 Penner J A. Management of haemophilia in patients with high-titre inhibitors: focus on the evolution of activated prothrombin complex concentrate Autoplex-T.  Haemophilia . 1999;  5(Suppl 3) 1-9
  • 60 Lusher J M, Shapiro S S, Palascak J E. et al . Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII. A multicenter therapeutic trial.  N Engl J Med . 1980;  303 421-425
  • 61 Lusher J M, Blatt P M, Penner J A. et al . 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
  • 62 Abildgaard C H, Penner J A, Watson-Williams E J. Anti-inhibitor coagulant complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia.  Blood . 1981;  56 978-984
  • 63 Kantrowitz J L, Lee M L, McClure D A, Kingdon H S, Thomas W R. Early experience with the use of anti-inhibitor coagulant complex to treat bleeding in hemophiliacs with inhibitors to factor VIII.  Clin Ther . 1987;  9 405-419
  • 64 Hilgartner M, Aledort L, Gill A J, and the members of the FEIBA Study Group. Efficacy and safety of vapor-heated anti-inhibitor coagulant complex in hemophilia patients.  Transfusion . 1990;  30 626-630
  • 65 Negrier C, Goudemand J, Sultan Y. et al . Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII deficiency and a factor VIII inhibitor.  Thromb Haemost . 1997;  77 1113-1119
  • 66 Chang H, Mody M, Lazarus A H. et al . Platelet activation induced by porcine factor VIII (Hyate:C).  Am J Hematol . 1998;  57 200-205
  • 67 Gribble J, Garvey M B. Porcine factor VIII provides clinical benefit to patients with high levels of inhibitors to human and porcine factor VIII.  Haemophilia . 2000;  6 482-486
  • 68 Hay C RM, Lozier J N, Lee C A. et al . Safety profile of porcine factor VIII and its use as hospital and home-therapy for patients with haemophilia A and inhibitors: the results of an international survey.  Thromb Haemost . 1996;  75 25-29
  • 69 Soucie J M, Erdman D D, Evatt B L. et al . Investigation of porcine parvovirus among persons with hemophilia receiving hyate:C porcine factor VIII concentrate.  Transfusion . 2000;  40 708-711
  • 70 Gringeri A, Santagostino E, Tradati F, Giangrande P LF, Mannucci P M. Adverse effects of treatment with porcine factor VIII.  Thromb Haemost . 1991;  65 245-247
  • 71 Altieri D C, Capitanio A M, Mannucci P M. Von Willebrand factor contaminating porcine factor VIII concentrate (hyate:C) causes platelet aggregation.  Br J Haematol . 1986;  63 703-711
  • 72 Brettler D B, Forsberg A D, Levine P H. et al . The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience.  Arch Intern Med . 1989;  149 1381-1385
  • 73 Lozier J N, Santagostino E, Kasper C K, Teitel J M, Hay C RM. Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors.  Semin Hematol . 1993;  30(Suppl 1) 10-21
  • 74 Bona R D, Riberio M, Klatsky A U. et al . Continuous infusion of porcine factor VIII for the treatment of patients with factor VIII inhibitors.  Semin Hematol . 1993;  30(Suppl 1) 32-35
  • 75 Hay C RM. Porcine factor VIII: continuous infusion, immune tolerance induction and prophylaxis.  Haemophilia . 1997;  3 (Suppl 1) 24-30
  • 76 Rubinger M, Houston D S, Schwetz N. et al . Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors.  Am J Hematol . 1997;  56 112-118
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