Final Diagnosis -- Acquired inhibitors (autoantibodies) to factor VIII (Acquired Hemophilia)


I. Background:

Inhibitors (autoantibodies) to factor VIII create a state of functional coagulation factor VIII deficiency in individuals with no prior history of bleeding (hence the name acquired hemophilia). With an incidence of 1-5 per million, it occurs mostly in the elderly (over 60 years of age). The generation of the autoantibodies has been associated with certain underlying conditions such as autoimmune disorder, lymphoproliferative disorder, malignancy, pregnancy, and certain drugs. But 50% of the time, no underlying cause can be identified (1, 2). Factor VIII inhibitors are associated with severe bleeding episodes in almost 90% of the patients because the antibodies are constantly present in excess over antigen (factor VIII) in the plasma (3). Management of such hemorrhage can be challenging since the bleeding may be life threatening, refractory to local treatment, respond poorly to conventional clotting factor concentrates and is associated with high mortality rate (10-12%) (2, 3). Therefore early diagnosis and optimal treatment are crucial in such patients.

The inhibitors (autoantibodies) are usually polyclonal IgG with specificity against various epitopes on factor VIII. The binding of autoantibodies partially or completely neutralizes the action of factor VIII molecules. Antibodies in hemophiliacs have broad specificity while the autoantibodies in non-hemopheliacs has narrower specificity (ie, against fewer epitopes on Factor VIII) (4). Asymptomatic healthy blood donors may have a low titer factor VIII inhibitor (<2 Bethesda Unite or lower) (1). Such inhibitors are kept in check at least in part by the production of corresponding anti-idiotypic antibodies. Normal homeostasis of this network of interacting molecules, idiotypies and anti-idiotypes is disrupted by the overproduction of inhibitors; the development of hemophilia follows (3, 5).

II. Laboratory Diagnosis:

The presence of a factor VIII inhibitor should be suspected in an elderly patient with sudden onset of severe bleeding without a prior bleeding history. Laboratory testing should include mixing studies, single factor activity level and a Bethesda inhibitor assay. Initial coagulation studies will typically show a prolonged APTT and normal PT. This pattern can also be characteristic of heparin contamination or lupus anticoagulant (LA). The presence of heparin can be excluded by treating the plasma with Hepzyme (to inactivate the heparin) and then repeating the APTT, or a Thrombin time performed. Heparin would prolong the Thrombin time but a factor VIII inhibitor would have no affect on the assay. APTT mixing studies (1:1 of patient's plasma with normal plasma) should then be performed to demonstrate the presence of an inhibitor or anticoagulant. In the presence of an inhibitor the APTT mix is often prolonged. Since the reaction between factor VIII and its inhibitor is time dependent, the 1:1 mix should be incubated at 370C for 1 to 2 hours, then the APTT repeated (6). Since an APTT mixing study may also be prolonged in the presence of an LA, specific factor assays, in particular factor VIII, is prudent when the clinical presentation is that of bleeding. In the presence of an autoantibody to factor VIII, the factor VIII activity level is markedly decreased or often undetectable (<1%). Although with some LA the factor VIII level may be low, it is rarely less than 10% (9). Also, other factor level assays based on APTT test system such as IX, XI, and XII may be low, and the "inhibitor effect" of the LA can be diluted out (6, 9). A newly developed ELISA assay appears to discriminate mild, moderate, or severe factor VIII antibodies (allo- or auto-) from other circulating inhibitors such as LA (7).

Confirmation of the factor VIII inhibitor is achieved by the employment of the Bethesda assay. This assay, which was standardized by a group of hematologists meeting in Bethesda, Maryland in the mid-1970's, is based on the ability of the patient's plasma containing the factor VIII inhibitor to inactivate factor VIII present in normal pooled plasma. Dilutions of the patient's plasma are incubated with normal pooled plasma for 2 hours at 370C, and then the residual factor VIII is measured. One Bethesda unit (BU) is defined as the quantity of inhibitor that neutralizes 50% of the factor VIII in normal plasma in 2 hours at 370C. For consistency, the least dilution of patient's plasma that inactivates exactly or almost exactly half the factor VIII in the incubation mixture is used in the calculation of Bethesda unit (6). The Bethesda method assumes a linear relationship between the patient's plasma dilution and residual factor VIII activity, and thus is best suited for measuring the amount of inhibitor in hemophiliacs. However, spontaneous (acquired) factor VIII inhibitors in non-hemophiliacs often demonstrate a complex, non-linear relationship and the Bethesda assay may underestimate the potency of the inhibitor. (6, 8). Unfortunately, there is no strict correlation between the titer levels and severity of disease (1).

III. Treatment:

Treatment strategies have two goals: to stop the bleeding and to eradicate the inhibitor (2). During the acute phase, effective control of bleeding is the foremost goal. DDAVP and human FVIII are effective in patients with low (<5 BU) FVIII inhibitor titers. In patients with high titer it is not possible to overcome the inhibiting activity by raising the FVIII level. These patients require the administration of porcine FVIII, activated prothrombin complex concentrates (APCC), or recombinant human activated factor VII (rFVIIa) (NovoSeven). Porcine factor VIII is effective regardless of antihuman factor VIII titer, and response rates are up to 80% (1). APCC may be effective during an acute hemorrhagic event, but the reported associated thromboembolic events warrants use with caution (10).

NovoSeven was approved by FDA in 1999 for the treatment of bleeding in patients with hemophilia A and B inhibitors (alloantibodies), acquired inhibitors (autoantibodies) to factor VIII, and congenital factor VII deficiency. The site of action of NovoSeven is through the extrinsic pathway, therefore bypassing the intrinsic pathway (factors VIII and IX). Approximately 70% of patients with acquired inhibitors to Factor VIII or IX and acute bleeding will respond to NovoSeven. NovoSeven has been shown to be safe to use. There has been no evidence of allergic reaction, thrombosis, thrombocytopenia, or disseminated intravascular coagulation. A drawback of NovoSeven is that it requires frequent dosing due to its short half-life (2-3 hours) (4, 10).

The ultimate therapeutic goal is eradication of the inhibitor (autoantibodies), therefore the cure of the disease. Immunosuppresive regimen with corticosteroids, cyclosporine, and cyclophosphamide, alone or in combination, lead to remission in 50-70% cases (11). Intravenous immunoglobulin may decrease the circulating autoantibody level by modulating the immune system through idiotype/anti-idiotype interaction (1, 5). In summary, management of patients with inhibitors to factor VIII requires the combined approaches of achieving hemostasis and immunosuppressive (immumodulating) therapy to eradicate the inhibitor.


  1. Shwaiki, A. et al. Acquired inhibitor to factor VIII in small cell lung cancer: a case report and review of the literature. Ann Hematol (2001) 80:124-126.
  2. Ragni, M. Acquired inhibitors to factor VIII. Transfusion medicine update. Aug/Sep 1998. URL:
  3. Negrier C. And A. Lienhart. Overall experience with Novoseven. Blood Coagulation and Fibrinolysis. (2000) 11(suppl 1):S19-S24.
  4. Colman RW, Hirsh J, Marder VJ, et al. Thrombosis and Hemostasis 4th Ed. Lippincott Williams & Wilkins, Philadelphia, PA 2001:1003-1009.
  5. Gilles, J et al. Nature autoantibodies and anti-idiotypes. Seminars in thrombosis and hemostasis. (2000) 26:151-155.
  6. Kessler C, et al. Aquired Hemophilia 2nd Ed. Escerpta Medica, Inc. Princeton, NJ. 1995:9-24.
  7. Sahud M. Laboratory Diagnosis of Inhibitors. Seminars in thrombosis and Hemostasis. (2000) 26:195-203.
  8. Loscalzo J, and Schafer Al. Thrombosis and Hemorrhage 2nd Ed. Williams and Wilkins, Baltimore, MD, 1998:526-527:803-808.
  9. Goodnight SH, Hathaway WE. Disorders of Hemostasis & Thrombosis. A Clinical Guide 2nd Ed. McGraw-Hill, New York, NY 2001:192-201, 407-409.
  10. Ragni, M. Recombinant factor VIIa. Transfusion medicine update. Nov/Dec. 1999. URL:
  11. Gruneward, M et al. Acquired haemophilia: experiences with a standardized approach. Haemophilia (2001) 7:164-169.

Contributed by Lirong Qu, MD, Ph.D, Kathy Puca, MD, Joseph Kiss, MD and Darrel Triulzi, MD

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