August / September, 1998
An Update On Diagnosis and Treatment Of Autoantibody to FVIII Margaret V. Ragni, M.D., M.P.H., Director, Hemophilia Center Of Western Pennsylvania
INTRODUCTION One of the most difficult coagulation disorders to manage is an acquired autoantibody to coagulation factor VIII. Occurring most commonly in the elderly with no prior bleeding history, the onset of an acquired auto-anti-VIII is usually heralded by the occurrence of a severe hemorrhage, which is dramatic, poorly responsive to treatment, and associated with a high mortality rate. This syndrome is the equivalent to developing severe hemophilia A in later life, but without the capacity to respond to clotting factor VIII. Recent clinical trials have shown that low-dose, daily oral immunosuppression with cyclophosphamide and prednisone followed by a very slow taper is not only well-tolerated, but also an effective approach to treatment of anti-VIII inhibitors. Because the dosing and taper of these drugs differ from that used in many other autoimmune diseases, and because the success of treatment depends on the dosing and duration of treatment, the purpose of this update is to review the basis for an optimal management of acquired anti-VIII inhibitors.
BACKGROUND Antibodies directed against coagulation factor VIII, which is the largest coagulation factor at over 2 million daltons, may be of two types, either alloantibodies or autoantibodies. In contrast to alloantibodies, which are directed against foreign, infused factor VIII and occur in about 15% of children with hemophilia A, autoantibodies to factor VIII are rare and directed against endogenous factor VIII and primarily occur in the elderly, with no prior bleeding history. Anti-VIII autoantibodies may be associated with autoimmune disorders, lymphoproliferative disorders, pregnancy, or drugs: however, in the majority of cases, there is no associated disease.
CLINICAL PRESENTATION Typically, the patient with an autoantibody to factor VIII presents with a severe, spontaneous, usually massive hemorrhage, such as a retroperitoneal hematoma, hematuria, epistaxis, or postpartum hemorrhage. These hemorrhages are refractory to local measures, may be worsened by surgical intervention, and are poorly responsive to clotting factor concentrates. In addition, hemorrhages occurring in patients with autoantibodies to factor VIII have a 10-12% fatality rate. Thus, early detection and optimal treatment are crucial to the outcome in such patients.
LABORATORY DIAGNOSIS Autoantibodies to factor VIII are suspected when the APTT is prolonged and does not correct in a 1:1 mix with normal plasma, associated with a very low factor VIII level, usually <0.01 U/ml. The inhibitor is confirmed by demonstrating an elevated anti-FVIII titer by the Bethesda assay. These inhibitors are heterologous antibodies of the IgG class, either IgG1 or IgG4, irreversible, non-complement-fixing, and directed against the A2 heavy chain and the C2 light chain of the Factor VIII molecule. Specifically, these inhibitors interfere with normal coagulation and normal activation of factor VIII, by interfering with thrombin cleavage in the A2 heavy chain (activates factor VIII) and by interfering with factor VIII interaction with phospholipid on platelets and cells in the C2 light chain (promotes clot formation). The precise mechanism by which inhibitor formation occurs is unknown, but appears to involve T cell activation and T cell proliferative responses to factor VIII.
TREATMENT Treatment of individuals with autoantibodies to FVIII is complex, difficult, and costly. There are two main goals of treatment: 1) to stop the hemorrhage and 2) to eradicate the inhibitor. In general, hemorrhages are treated with conservative measures, including immobilization, rest, ice, avoidance of surgery, and avoidance of anti-platelet drugs, e.g. aspirin or nonsteroidal anti-inflammatory agents, which may worsen bleeding. Because the inhibitor prevents factor VIII activation and increases the anti-VIII titer, factor VIII concentrate is used only for life-threatening situations, and, then, only for the short time until anamnesis occurs. Thus, agents which bypass the inhibitor effect, including prothrombin complex concentrates (Konyne®), activated factor IX complex (Autoplex® , FEIBA®), or factor IX concentrates, are the main treatment for bleeding symptoms; however, these are effective in only 50% of bleeding episodes and may cause thrombosis or anaphylaxis. Other treatment approaches have been suboptimal: factor VIIa and recombinant FVIIa are not FDA-approved and have a short half-life, <3 hours, limiting availability and requiring frequent dosing; porcine FVIII is complicated by allergic reactions, thrombocytopenia, and anamnesis; removal of the antibody by immunoadsorption is costly and often ineffective; and induction of immune tolerance, with cytotoxic agents, gamma globulin is costly and slow, taking months. Successful eradication of the anti-VIII has been achieved by combining daily oral cyclophosphamide, 100 mg., with daily oral prednisone, 50 mg, starting at the time of diagnosis and continuing until the inhibitor becomes undetectable, followed by a very slow taper, e.g. 5 mg weekly. Using this regimen, the nine consecutive patients studied by Shaffer and Phillips had cessation of bleeding after 3 weeks, and all achieved a complete remission by 12 weeks (defined as a normal factor VIII level in the absence of inhibitor). The total treatment duration was 91 weeks (range: 61 to 164). In patients in whom relapse occurred with too rapid a taper of cyclophosphamide or prednisone, reinduction with the original treatment dose resulted in reattainment of remission.
REFERENCES Shaffer LG and Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 1997; 127:206-09. For questions regarding Acquired Inhibitors to Factor VIII, please
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