Factor VIII Activity With Inhibitor Reflex

Factor VIII inhibitors are antibodies directed against coagulation FVIII, which may then manifest clinically as a bleeding tendency in a patient without a previous bleeding history.^2-12 Factor VIII inhibitors are polyclonal immunoglobulins that can develop in patients with congenital FVIII deficiency (hemophilia A) as a response to treatment with either plasma-derived or recombinant FVIII. In these patients, inhibitory antibodies can render treatment with exogenous factor VIII ineffective. Early detection and alteration of treatment in their presence is crucial to effective patient care. 

Because FVIII inhibitor levels can fluctuate over time, surveillance for inhibitor concentration in patients treated with factor replacement therapy must be undertaken on a regular basis. These antibodies may develop in a variety of circumstances including 1) patients with congenital FVIII deficiency (hemophilia A) in response to therapeutic infusions of factor VIII concentrate, 2) elderly non-hemophiliac patients (not previously factor VIII deficient), 3) women in postpartum period and 4) patients with other autoimmune illnesses. Specific coagulation Factor VIII inhibitors can develop in patients with hemophilia after exposure to replacement factor.⁷ Factor inhibitors may also develop as an autoimmune phenomenon in individuals without congenital factor deficiency.^8-12 

Acquired hemophilia A (AHA) caused by these autologous inhibitors produce a serious bleeding disorder and can result in spontaneous, life-threatening bleeding diathesis. The prevalence of this condition is one to two cases per million persons per year. AHA should be suspected in patients with a new onset of bleeding and an isolated prolongation of activated partial thromboplastin time (with normal prothrombin time). Approximately 10% of patients do not bleed at the time of diagnosis but are at risk of future bleeding, particularly during interventions or surgery. Acquired factor VIII inhibitors are most commonly seen in the elderly (though these antibodies may occur in children and young adults) and can be (though not always) be associated with underlying conditions such as the post-partum period, malignancies, autoimmune diseases or drug exposure. Development of factor VIII inhibitors necessitates specific therapy in a timely fashion. Patient management can be clinically difficult, as patients may not respond to conventional therapies.

Factor VIII inhibitors can be detected by a combination of prolonged coagulation screening tests, such as the activated partial thromboplastin time, plus a non-correcting mixing test. Non-correction may only be evident, or else may be extenuated, with incubation at 37°C. The Bethesda assay for quantitation of inhibitor strength is based on a combination of mixing tests followed by specific factor assays.¹ The Bethesda Titer (BT) procedure is designed to determine the strength (i.e., concentration or potency) of factor VIII (FVIII) inhibitors that bind and neutralize the activity of the essential blood-clotting protein, FVIII. Inhibitors that bind and clear the factor from the patient’s circulation rather than neutralize the factor will not be detected by the Bethesda assay. 

In congenital hemophilia A, patients with BT up to five Bethesda Units (BU) per mL can often be successfully treated with high-dose FVIII replacement therapy, whereas inhibitors with BT >5 BU/mL may require bypassing agents to control acute bleeds. However, in AHA, residual FVIII activity and inhibitor BT levels do not generally correlate with the risk of bleeding or the response to hemostatic treatment.