Discussion

This patient was found to have an inhibitor of Factor VIII (FVIII). In Hemophilia A, FVIII inhibitors are primarily IgG alloantibodies that occur following initiation of treatment with FVIII infusions. Patients with severe (<1% FVIII activity) or moderately severe (2-5% FVIII activity) disease are most at risk for the development of an inhibitor. Twenty-five percent of patients with severe Hemophilia A may develop a FVIII Inhibitor.1,2 They may initially be high (high responders) and persist for up to several years, or be initially low (low responders) and persist at very low levels and become undetectable after several weeks. Patients with large deletions in the FVIII gene or those with nonsense mutations (stop codons) are most at risk for inhibitor development.3 The inhibitors are directed, most commonly, against epitopes in the C2 domain of the Factor VIII protein. The C2 domain is normally responsible for binding FVIII to the phospholipid surface of platelets or endothelium, thereby inducing its procoagulant effects. By binding to the C2 region, the antibodies render the FVIII molecule unable to bind to the phospholipid surface (see Figure II). In some cases, the antibody has been found to have proteolytic activity directly against the FVIII protein. Certainly, the lack of circulating normal factor VIII in patients with severe disease may predispose them to antibody formation after exposure to normal factor VIII. Interestingly, there appears to be a familial predisposition to factor VIII inhibitors, as siblings of patients with hemophilia have an increased risk of developing inhibitors.4 Patients with mild to moderate Hemophilia may be “converted” to severe disease because of the development of an inhibitor. As a result, there is an increased risk of hemorrhage and musculoskeletal complications. 

The diagnosis may be suspected when a patient is refractory to FVIII infusions and there is an isolated prolonged activated partial thromboplastin (aPTT) time. After a heparin effect has been ruled out (by adding heparinase to the sample) an inhibitor screen should be performed to confirm the presence of an inhibitor. Briefly, the patient’s plasma is mixed with plasma containing a known amount of Factor VIII and incubated for at least 60 minutes. As the patient is FVIII deficient, the addition of the FVIII-containing plasma should allow for the correction of the aPTT. When correction of the aPTT does not occur and increases after incubation, i.e., allowing time for the inhibitor to take effect, the presence of an inhibitor to FVIII is confirmed. A Bethesda Assay is then performed in order to quantitate the inhibitor. Here, serial dilutions of the patient’s plasma are made with normal pooled plasma until 50% of the initial FVIII activity of the normal pooled plasma is detected. The reciprocal of this dilution (e.g., 1:20 = 20) is the Bethesda titer in Bethesda Units, BU.5 A titer < 5 - 10 BU may be effectively treated by “overriding” the inhibitor with large doses of Factor VIII. In patients with higher inhibitor titers, however, “bypass products” are necessary. These include prothrombin complex concentrates and activated Factor VII, and “bypass” the need for Factor VIII in the coagulation cascade. Factor VIIa is preferred due to its dependence on tissue factor, and therefore, its local coagulation effects. The prothrombin complex concentrates act systemically and carry increased risks for thrombotic events.6 FVII:C levels have been suggested as a means of monitoring FVIIa treatment, although success with this has varied.7-9 Other methods of monitoring FVIIa treatment have been studied10 but not established. Factor VIIa inhibitors have been identified in patients treated with Factor VIIa. While these antibodies appear to not affect the function of FVIIa, they may increase clearance of the protein.11