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Twenty to 33% of patients with hemophilia A develop antibodies to Factor VIII that neutralize or inhibit coagulant activity, making replacement therapy ineffective. These antibodies are referred to as inhibitors and occur almost exclusively in patients with severe hemophilia A (Factor VIII < 1%). Inhibitors usually develop early in the course of treatment, after approximately 10 days. The presence of an inhibitor does not increase the frequency of bleeding, but does increase morbidity and mortality including less well controlled hemorrhage, more joint damage, and increased hospitalizations. The strength of an inhibitor is measured with the Bethesda assay. This assay determines the dilution of patient plasma that decreases normal plasma Factor VIII activity by 50%. The result is expressed as Bethesda units and classified as low ( < 10 BU), intermediate (10-20 BU), and high (>20 Bu) titers. Hemophiliacs with antibody are often classified as having high or low responding inhibitors. High responders have brisk anamnestic responses with repeat exposures to Factor VIII concentrates. They consequently develop high titer antibodies that may persist for months to years. Low responders have minimal anamnestic response to repeat Factor VIII exposure. Historically, more than 80% of patients with inhibitors have developed high responder antibody. With the exclusive use of recombinant Factor VIII, less than 50% have become high responders and many have been transient. Treatment of Patients with Inhibitors The treatment of bleeding in the presence of an inhibitor is challenging. Treatment strategies include infusing sufficient quantities of Factor VIII to neutralize the inhibitor and bypassing factor VIII activity in the coagulation cascade. Hemophiliacs with low level inhibitor ( < 10 BU) who do not have a history of high level inhibitor can be treated with high doses of Factor VIII concentrate. Inhibitor levels of 10 BU or higher usually preclude high dose Factor VIII therapy. In hemophiliac patients with a history of high titer inhibitor, this approach should be tried only in life-threatening or limb-threatening bleeding situations because the patient will have an anamnestic response that will result in the recurrence of high level inhibitor. The initial treatment goal is to neutralize the inhibitor. Once the inhibitor is overwhelmed, maintenance therapy is similar to patients without inhibitors.
Recombinant Factor VIIa (NovoSeven) received FDA approval and became commercially available on April 19, 1999. It has been available in Europe and Canada since the 1980s. NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. Factor VIIa complexes with tissue factor at the site of injury and induces activation of Factor X, resulting in clot formation. Recombinant Factor VIIa is supplied in three sizes: 1200, 2400 and 4800 ug/vial. The recommended dose is 90 ug/kg by IV bolus given every two hours for 24 hours or until hemostasis is achieved. Once the patient is stabilized, the interval between treatments can be lengthened to 3-6 hours. This dosage schedule can be used for patients undergoing major surgery or treatment of serious CNS, intraperitoneal, retroperitoneal or intramuscular bleeding. A dosage of 90 ug/kg corresponds to plasma levels of 2 ug per mL, assuming 100% recovery. The goal of therapy should be to increase peak levels of FVII functional clotting activity (FVII: C), measured immediately after the initial dose, to above 30 U/mL and preferably between 60 and 90 U/mL. Steady state levels measured 2 hours after 90 ug/kg NovoSeven administration following two days of dosing at 2-hour intervals average 28 U/mL. The protime shortens significantly and often plateaus around 7 seconds. The aPTT may shorten as much as 15 to 20 seconds, but usually does not completely normalize. An advantage of Factor VIIa is its lower risk DIC. However, DIC may occur if a patient is first treated with APCC and then switched to Factor VIIa. DIC can be prevented by waiting several hours between discontinuing APCC and starting Factor VIIa infusions. Factor Concentrates for Treatment of Factor VIII Inhibitors
Acquired Hemophilia A Autoantibodies to factor VIII occasionally develop in healthy elderly adults, postpartum women, and patients with autoimmune diseases or cancer. The majority of cases, however, have no known etiology. Patients with acquired factor VIII deficiency are at risk for spontaneous intramuscular hematomas, soft tissue hemorrhage, and mucosal bleeding. They have a lower incidence of hemarthroses compared to congenital hemophiliacs. Spontaneous remission occurs in 30 to 40% of patients. Remission rates are highest for postpartum and normal healthy elderly adults. Elective surgical procedures should be postponed while the patient is observed for possible spontaneous remission. Treatment options include DDAVP, high dose Factor human VIII, Factor VIIa and immunosuppressive drugs. Patients with low levels of acquired inhibitor may respond to DDAVP. DDAVP should be more successful in acquired hemophilia since these patients can synthesize factor VIII. DDAVP dose is 0.3 ug/Kg. Patients with autoantibodies usually do not mount an anamnestic response to factor VIII infusion. Dosage is calculated as for congenital inhibitors. Immunosuppressive therapy with cyclophosphamide and corticosteroids can also be used to manage acquired hemophilia if the patient does not have contraindication such as malignancy or infection. More recently, Rituximab has been used to reduce inhibitor levels. |
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