Inhibitors may be detected due to inadequate response to infusion therapy or through routine screening. Repeated testing may be required to determine the type of inhibitor present, the need for alternative treatment strategies and its ultimate impact on the clinical course.
The presence of inhibitors in patients with hemophilia A or B significantly negatively impacts overall prognosis and is correlated to the type of inhibitor (high versus low responding) present. Treatment is determined by the type of inhibitor with high-responding patients requiring some form of bypassing therapy for control of hemorrhagic episodes. These bypassing products produce hemostasis in the presence of an inhibitor through activation of the coagulation system through alternate mechanisms and have reduced overall efficacy compared to replacement of the deficient factor and hence increase in overall morbidity and mortality. The development of disabilities is more common and often accompanied by social and psychological sequelae.
Treatment options for high-responding inhibitor patients
Treatment for high-responding inhibitor patients is a continuing challenge and presents the need for very individualized physician care.
Prothrombin complex concentrates (PCCs) and activated prothrombin complex concentrates (APCCs)
Treatment with PCCs and APCCs has been used to control bleeding episodes in high-responding inhibitor patients. The use of APCCs is more common at this time compared to PCCS. These products result in hemostasis in approximately 50% to 75% with each infusion. Because of their unpredictable efficacy, PCCs and aPCCs often require repeated infusions. The use of these products is associated with sequelae including infusion reactions if infused too quickly; ineffective hemostasis leading to risk of uncontrolled hemorrhage; and thrombotic episodes. Thrombotic episodes have been reported in young patients in unusual sites including myocardial infarction, despite appropriate dose level and interval, but appear more frequent in patients who are immobile, use large or repetitive doses, are undergoing surgery, or have suffered crush injuries or bleeding events where tissue is damage has occurred. Therefore these products require ongoing surveillance and should be used with caution in surgical settings. Also of note, approximately a third of patients treated with PCCs and aPCCs will experience an increase in level of their inhibitor titers or a failure of their titers to fall over time.
Recombinant factor VIIa
Another product utilized to treat high-responding inhibitor patients also in the bypassing treatment category is recombinant activated factor VII (rFVIIa). RFVIIa appears to have a mechanism of action different from PCCs and APCCs through either a platelet surface action or through binding with exposed tissue factor at areas of injury utilizing the extrinsic pathway of coagulation. Through both of these proposed mechanisms of action, the site of activity tends to be localized to the area of injury, theoretically decreasing the risk of complications.
Other forms of therapeutic interventions:
Plasmapheresis, either with or without protein-A immunoabsorption, may lower inhibitor levels so that factor replacement therapy can be used. However, this technique is time consuming and thus has limited applications to situations that involve life- or limb-threatening hemorrhages. This modality will not result in a lasting decrease of inhibitor titer and may be required frequently to maintain a titer low enough to obtain hemostasis with normal replacement therapy. Once discontinued, the titer will rapidly increase.
Porcine factor has many of the same qualities as human factor and its antigenic differences are small enough to allow it to be less recognized by the antibody or inhibitor compared to the human factor VIII. Unfortunately, some patients’ inhibitors to human factor VIII will not have a deceased recognition of the porcine factor VIIII to preclude use of this product. Therefore a specific porcine inhibitor titer will need to be performed to determine whether this product will be of value in any particular patient or circumstance. The majority of patients will subsequently develop an immune response to the porcine factor VIII prohibiting its further use at that time.
Immune Tolerance Therapy (ITT)
Immune tolerance therapy (ITT) is the only method known to eliminate inhibitors in patients with hemophilia A or B. Different regimens have been proven to be effective and range from three times weekly to twice daily infusions of the deficient coagulation factor and the use of immunosuppressive agents such as Cyclophosphomide and intravenous immune globulin and Rutuxan. At this time there is no one best proven regimen for a particular patient or circumstance, however an international randomized trial is underway to evaluate at least two of the commonly used regimens. ITT regimens are expensive and often very demanding for the patient. ITT lasts a variable period of time from a few months to years. Predictors of success include time from detection of inhibitor to time to start of ITT, peak level of inhibitor titer, and factor deficiency with factor IX deficient patients having a much lower rate of success.