Factor Viii Inhibitors

Acquired hemophilia is due to the development of an autoantibody to factor VIII (FVIII). The estimated incidence is approximately 1 per 1 000 000 per annum. Most cases occur in healthy individuals without discernible risk factors, but the condition is associated with autoimmune conditions such as rheumatoid arthritis and SLE, inflammatory bowel disease, multiple sclerosis and malignancies. In up to 11% of cases, the associated factor is a recent or ongoing pregnancy50.

Acquired hemophilia may occur in relation to any pregnancy, but the risk appears to be greatest after the first delivery. Onset is usually at term or within 3 months postpartum, but may only become evident 12 months post-delivery51. Clinical manifestations do not necessarily correlate with inhibitor levels and can range from spontaneous bruising to life-threatening hemorrhage. FVIII inhibitors may cross the placenta and persist in the neonate for up to 3 months, but neonatal complications are rare51. Spontaneous resolution occurs in almost 100% of women first diagnosed in the postpartum period after 30 months50.

Basic coagulation studies in acquired hemophilia demonstrate a prolonged APPT with a normal PT and thrombin time (TT). If plasma from the patient is mixed with normal plasma, the APPT remains prolonged due to the inhibitor antibody neutralizing the FVIII in the normal plasma. FVIII inhibitors must be differentiated from a lupus inhibitor by specific tests because the clinical implications are profoundly different. Quantification of FVIII inhibitor is by the Bethesda assay, and checking this level may help in determining the choice of therapy and monitoring the progress of the patient.

Treatment is aimed at control of bleeding and accelerating the elimination of inhibitors. Hematological measures to minimize blood loss aim to compensate for the loss of FVIII. Choice of product to attempt to normalize hemostasis depends on various considerations, including the severity of bleeding, availability of clotting factor concentrates, inhibitor level and cross-reactivity of inhibitor to porcine FVIII. Human FVIII may be effective if the titer of inhibitor is low, i.e. less than 10 Bethesda units. At higher levels, use of porcine FVIII which may not cross-react with the inhibitor, and recombinant FVIIa or prothrombin complex concentrate (PCC) becomes necessary52.

Inhibiting the production of the inhibitor is the second management aim. Prednisolone at dose of 1 mg/kg is associated with a loss of inhibitor in 50% of patients with acquired hemophilia52. Other immunosuppressives should be considered if there is no response to steroids. Addition of cyclophosphamide (2.0-3.0 mg/kg) should be considered at 3 weeks if there is no decline in the inhibitor titer, or earlier if there is continued bleeding. Other methods to reduce inhibitor levels include azathioprine, plasma exchange or infusion of IVIg.

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