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Whereas inherited clotting-factor deficiencies are typically clinically evident from birth, the sudden appearance of a bleeding diathesis in a previously healthy adult is suggestive of an acquired factor inhibitor. Although inhibitors to most of the major clotting factors have been described, factor VIII inhibitors are the most common; however, factor VIII inhibitors are still rare, with an estimated incidence of one to two persons per million per year.
A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention. A new Clinical Problem-Solving summarizes.
Clinical Pearl
• What laboratory findings suggest the presence of a factor inhibitor?
A factor inhibitor should be suspected in any patient who has spontaneous bruising and an unexplained new elevation in aPTT (activated partial-thromboplastin time), particularly if the aPTT fails to be corrected after the patient’s plasma is mixed in a 1:1 ratio with normal plasma. The appearance of factor VIII inhibitors in postpartum women (usually after the first or second child), is classic. They have also been described in patients who have an underlying autoimmune disease or an underlying malignant condition, or in older patients in the absence of recognized diseases.
Clinical Pearl
• What is the Bethesda assay?
The titer of the factor VIII inhibitor is determined through the use of the Bethesda assay, in which the patient’s plasma is serially diluted with normal plasma to measure the potency of anticlotting factor activity. One Bethesda unit is defined as the inverse of the dilution of the patient’s plasma that results in 50% residual factor activity when the patient’s plasma is mixed with fixed amounts of normal plasma; any value over 5 Bethesda units is considered to be a high titer.
Morning Report Questions
Q: What is the treatment for acquired factor VIII inhibitors?
A: Treatment of patients who have acquired factor VIII inhibitors is initially directed at controlling bleeding; longer-term therapy is also initiated to suppress inhibitor production. Whereas patients with congenital hemophilia in whom acquired inhibitors develop have a response to high doses of factor VIII, this treatment is rarely useful for acquired inhibitors that develop in patients without congenital hemophilia. Instead, treatment with recombinant factor VIIa or activated prothrombin complex concentrates should be used. Both compounds effectively negate the need for intrinsic factor VIII activity, which acts to amplify the activation of factor X; this step is not absolutely required for the generation of thrombin and can be bypassed either by adding activated factor VII plus inactive factors IX, X, and prothrombin, as in activated prothrombin complex concentrates, or by adding supraphysiologic doses of activated factor VII alone. Both agents have been associated with serious thromboembolic events, including catastrophic strokes, even in patients with severe bleeding. The rarity of these events has precluded the identification of risk factors for thrombosis, but given the risk, the agents should not be continued once the bleeding has stopped. Glucocorticoid therapy plus cyclophosphamide is the traditional first-line approach to therapy aimed at suppressing inhibitor production, but rituximab also appears to have efficacy. Patients with very high titers of inhibitors (>100 Bethesda units) may require more aggressive therapy, with all three agents simultaneously, with intravenous immunoglobulin, or with both approaches.
Figure 1. Mechanism of Factor VIII Inhibitors and Therapeutic Agents.
Q: Do factors VIII inhibitors ever clear without therapy?
A: The natural history of spontaneously acquired factor VIII inhibitors varies. A report published before the introduction of immunosuppressive therapy described rare cases in which factor VIII inhibitors acquired post partum spontaneously cleared in patients within 12 to 18 months after presentation, but the accumulated data suggest that this outcome is much more the exception than the rule.