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Haematologica 2000; 85(suppl. to n.10) p. 57-63 Acquired Factor VIII Inhibitors Acquired factor VIII autoantibody inhibitors: current concepts and potential therapeutic strategies for the future CRAIG M. KESSLER Division of Hematology and Oncology, the Vincent T. Lombardi Cancer Center; Georgetown University Medical Center, Washington, DC, USA The extremely low incidence of acquired autoantibody inhibitors directed against factor VIII procoagulant activity (estimated at 0.2-1 case per one million population per year) belies its importance as a clinical complication and socioeconomic burden. Furthermore, insight into the pathogenesis of this disease entity may provide clues as to how the immune system responds to factor VIII and how the immune system can be manipulated for treatment. This review will examine current therapeutic concepts and will speculate on future approaches to treatment based on emerging information about immune responses to the factor VIII protein. Correspondence: Craig M. Kessler, Division of Hematology and Oncology, the Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA. Clinical presentation Acquired factor VIII inhibitors occur predominantly in previously non-coagulopathic young adults (peaking 20-30 years of age) and the elderly (peaking at 60-80 years of age), assuming an approximate biphasic age distribution. Whereas almost half of these individuals present with no identifiable underlying medical condition, the majority do have defined or evolving autoimmune or lymphoproliferative disorders. Immunologic based diseases, usually observed in younger patients, have included systemic lupus erythematosys, rheumatoid arthritis, dermatomyositis, myasthenia gravis, multiple sclerosis, and graft-versus-host disease after allogeneic bone marrow transplantation. Asthma, chronic inflammatory bowel disease, and pemphigus also have been reported; several antibiotics, particularly the penicillins and sulfonamides, and BCG vaccination have been implicated. Several cases of autoantibody inhibitors have been described in association with chronic interferon-alpha therapy. In older individuals, malignant lymphoproliferative disorders, such as chronic lymphocytic leukemia and lymphomas, predominate. These underlying diseases occur in the context of a dysregulated immune system and suggest that an otherwise silent lymphoid clone has been induced or that a previously suppressed lymphoid clone has emerged from its inhibited state. The end result is the production of a humoral immunoglobulin, which interacts with specific epitope(s) on the factor VIII protein molecule and neutralizes its procoagulant function (see below). Very recently, a number of solid tumor malignancies have been accompanied by autoantibody inhibitors; however, it is unclear whether these are coincidental or causal events. In favor of the latter possibility are: (1) the frequently close temporal relationship between inhibitor and tumor detection, and (2) the absence of other conditions known to be associated with factor VIII autoantibody formation. Inhibitors of coagulation may be an additional example of the numerous autoimmune paraneoplastic phenomena which have previously been observed with solid tumor malignancies, e.g. autoimmune thrombocytopenic purpura, hemolytic anemia, pemphigus. On the other hand, successful treatment of these tumors with surgery, chemotherapy, or radiation therapy usually does not result in inhibitor disappearance. The appearance of autoantibody inhibitors against factor VIII during the post-partum period is a rare but serious condition, which most usually occurs in primiparas within 3 months after delivery. 1,2 Low titer inhibitors (10 BU) may persist for years and may be particularly resistant to the typical immunosuppressive treatment modalities employed in this disease, e.g. corticosteroids, intravenous gammaglobulin, cytotoxic/myelosuppressive agents. Whether the post-partum autoantibody antedates the development of an autoimmune syndrome or represents an epiphenomenon related to the immunosuppressive factors synthesized by the placenta remains unclear. Acquired autoantibody inhibitors against factor VIII appear spontaneously in otherwise normal non-bleeding patients 3,4 and, similar to the alloantibody situation in individuals with severe Haematologica vol. 85(supplement to n. 10):October 2000
58 C.M. Kessler hemophilia A, have been characterized predominantly as polyclonal IgG4 and occasionally as IgG1. In contrast to congenital hemophilia, IgM and IgA monoclonal inhibitors have been reported in acquired hemophilia. Approximately 15- 17% of normal, healthy individuals with no evidence of a coagulopathy possess low titers of clinically irrelevant anti-factor VIII antibodies in their plasmas. They are predominantly of the IgG1 and IgG2 variety and may exert detectable inhibitory activity against factor VIII in in vitro mixing studies with normal plasma. Kazatchkine et al. have hypothesized the presence of anti-idiotypic antibodies in these healthy individuals, which neutralize the inhibitory potential of any circulating anti-factor VIII autoantibodies. Thus, there is no clinical evidence of bleeding but the existence of autoantibodies against this self-antigen suggests the presence of factor VIII-specific CD4+ T-helper lymphocytes in the normal immunologic repertoire. Autoantibody inhibitors are predominantly directed against single epitopes on the factor VIII molecule, contained in either the amino terminal end of the A2 domain, or much more frequently (around 50%), in the carboxyl end of the C2 domain of the factor VIII protein. In contrast to the alloantibody situation, autoantibodies to factor VIII are not directed to both sites. Alloantibody inhibitors are usually directed against both the A2 and C2 domains and sometimes against the A3 domain. The low titer, clinically irrelevant autoantibodies found in normal individuals are also directed primarily against the A3 domain. As with alloantibodies, autoantibodies can also be directed against the B domain and other areas of the factor VIII protein; however, they convey no inhibitory activity. Recent data suggest that anti-B domain antibodies may influence the circulating half-life of the factor VIII protein, but this remains to be confirmed. Anti-A2 autoantibodies interfere with factor activation by the factor VIIIa-IXa-phospholipid complex; anti-C2 autoantibodies interfere with the binding of von Willebrand factor protein and/or phospholipid to factor VIII; and anti-A3 autoantibodies block interactions between factor IXa and factor VIII. How these autoantibodies determine the pharmacokinetics of factor VIII remains to be elucidated; however, it is apparent that autoantibodies typically produce a type II pattern with non-linear inactivation and the presence of residual factor VIII activity despite very high titers of the inhibitor. Rarely, autoantibodies possess a type I pattern of inhibition, in which there is total and linear inactivation of factor VIII activity. This is the characteristic pattern for alloantibodies. Treatment Individuals with autoantibody inhibitors of coagulation tend to present with spontaneous bruising and/or serious bleeding. Their hemorrhagic manifestations are typically more dramatic and are more likely to be life- and limbthreatening than compared with alloantibody inhibitor associated bleeds. The mortality rate of patients with acquired hemophilia approaches 15%, due primarily to bleeding complications occurring early in the course of the disease. With time, infectious complications, mediated by the myelosuppressive effects of cytotoxic agents intended to repress inhibitor formation, contribute to morbidity and mortality. The choice of treatment modalities for acquired inhibitors is predicted on the acuity and severity of bleeding and the BU titer. Acute bleeds occurring in association with low titer inhibitors (10 BU) are high responders and will mount an anamnestic antibody increase after re-exposure to the specific coagulant antigen. The high titer inhibitor characteristically cannot be overwhelmed by large amounts of high purity human factor concentrates. Rather, acute bleeds associated with this type of inhibitor must be treated with bypassing agents, which circumvent the site of antibody neutralization within the intrinsic pathway of the coagulation cascade, or heterologous porcine factor VIII concentrate, which has reduced cross-reactivity with anti-human factor VIII antibodies and is not neutralized by them. None of these products produces universal hemostasis. By-pass products include prothrombin (factor IX) complex concentrates of the unactivated (PCC) (Konyne-80 {Bayer, Inc.}, Bebulin {Alpha Therapeutics, Inc.}, etc.) or activated (APCC) (FEIBA{Baxter-Immuno, Inc.} or Autoplex{NABI, Inc.}) varieties, all of which are plasma-derived, or the new genetically engineered recombinant factor VIIa (rFVIIa) concentrate. The mecha- Haematologica vol. 85(supplement to n. 10):October 2000
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Acknowledgments We wish to thank th
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Haematologica 2000; 85(suppl. to n.
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4 J.M. Lusher (range 1-34) for pati
Page 9 and 10: 6 J.M. Lusher ALEDORT: I’d just l
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II Immune Tolerance and the Treatme
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