Factor VIII Inhibitor Profile, Comprehensive

Factor inhibitors (also called circulating anticoagulants or inactivators) are endogenously produced antibodies that interfere with coagulation in vivo or in vitro.⁶ These inhibitors are frequently specific for their respective coagulation factors. Specific factor inhibitors can be classified as neutralizing or non-neutralizing. Neutralizing inhibitors interact with the functional component of the coagulant protein while non-neutralizing antibodies react with the protein somewhere other than the functional epitopes. Factor inhibitors are not normally present in plasma. When present, factor inhibitors are measured by Bethesda titer units (BU). Titers <5 BUs are classified as low responders, titers >10 BUs as high responders. Factor VIII inhibitors may arise as IgG4 (noncomplement fixing) alloantibodies or autoantibodies. Factor VIII alloimmunization occurs in 15% to 20% of hemophilia, when the patient's plasma factor VIII concentration is <1%. Alloimmunization is idiosyncratic, affecting some, but not all, severe hemophilia A patients. Autoimmune factor VIII inhibitors occur in 1 of 1,000,000 individuals, primarily in pregnancy and the postpartum period, in patients older than 55 years of age, and in people with primary autoimmune disorders.

Porcine factor VIII inhibitors may arise in hemophilia A patients treated with porcine factor VIII (HyateC®) therapy. HyateC® is no longer available from the manufacturer. Alloimmune factor VIII inhibitors are suspected when hemophilia A patients' symptoms increase in severity, or bleeding continues despite infusion of ever-increasing dosages of factor concentrates. The normal plasma half-life of factor VIII, is 12 hours; however, hemophilia A patients with inhibitors may have undetectable factor VIII levels a few minutes after factor VIII-concentrate infusion and may require specialized therapy to halt acute bleeding. Neutralizing factor inhibitors form covalent complexes with their target coagulant factor molecules, rendering the factors nonfunctional. For alloimmune factor VIII inhibitor, this is a first order reaction with complete in vitro inactivation of available factor VIII. Autoimmune factor VIII inhibitors generally exhibit in vitro second order kinetics, achieving equilibrium with factor VIII leaving some residual factor VIII unbound in the plasma. In vivo, however, autoimmune factor VIII inhibitors cause “acquired hemophilia” with symptoms as severe as the more common congenital severe hemophilia. The mortality rate for acquired hemophilia is up to 22%.