Inhibitor levels are quantified in Bethesda units (BU). The Bethesda assay measures the amount of factor (FVIII or FIX) inactivated when the plasma from the patient is incubated with an external source of factor for 2 hours at 37ºC. Patients with hemophilia A or B who have Type 1 inhibitors can be definitively measured in BUs because factor antibodies result in a complete inactivation of factor in the presence of excess inhibitor. Patients who have Type 2 inhibitors pose a greater challenge in terms of establishing actual inhibitor levels as in these cases the results are displayed in nonlinear and incomplete inactivation of FVIII.
Patients with inhibitor levels less than 5 BU are defined as low responders. Those with a BU measure of greater than 5 are classified as high responders. Inhibitor levels in high responders can spontaneously decrease if there is no further exposure to the deficient factor. After reexposure, titers often increase within 5 to 7 days. Inhibitor levels usually peak between one and three weeks after factor exposure.
Of all patients who develop inhibitors, 41% to 53% are high responding, 20% to 55% low responding with the remaining being transient. Persistent inhibitors, especially of the high-responding type result in increased risk of morbidity and mortality for the affected individual and pose significant challenges for the treatment team. For high-responding inhibitor patients, use of normal replacement therapy is reserved for life- or limb-threatening bleeding complications and may only be efficacious when the titer is less than or equal to 10 BU. For low-responding patients, treatment consists of the use of the normal replacement therapy at higher doses calculated to overcome and neutralize the inhibitor titer and achieve a level adequate for hemostasis. However, the half-life may be altered in these patients and therefore repeated doses may be required for resolution of the bleeding event.
Transient inhibitors may be detected at some time during treatment, and are often at levels below 5 BU. These inhibitors resolve without any specific intervention. Any inhibitor that is detected in a patient requires close follow-up to determine the appropriate treatment.
Patients with moderate and mild deficiency may also develop an inhibitor, but this is more common among factor VIII deficiency than factor IX deficiency. The incidence appears to be approximately between 3% and 13%. These inhibitors tend to occur but are limited to during an intensive course of therapy, for example, during treatment for major bleeding episodes or for surgical interventions. These inhibitors may recognize the patient’s low level of factor VIII as well as the infused replacement therapy, and therefore convert the patients from a moderate or mild deficient state to that of severe deficiency. However, the inhibitor may only be directed against the infused replacement therapy and, therefore, the patient’s baseline level may not be significantly altered but there will be a detectable inhibitor titer that affects the amount and often frequency of required replacement therapy.
Most patients with factor IX deficiency and inhibitors tend to be of the high-responding type. These patients pose a unique set of issues in that the development of an inhibitor may be associated with infusion and anaphylactoid reactions which may preclude use of any product containing factor IX including PCCs and their activated counterparts, APCCs. Some patients with these reactions have been successfully desensitized thus allowing immune tolerance treatment. Despite this, some of these patients develop nephrosis 6 to 8 months into therapy, which may be associated with reemergence of the infusion reactions. The nephrosis is unlike childhood nephrosis in that it is steroid resistant and may require withdrawal of the antigen (factor IX) for symptoms to abate.