title: An introduction to factor VIII inhibitors: the detection and quantitation.
abstract: Spontaneous development of autoantibodies against factor VIII:C (FVIII:C) protein in a nonhemophiliac is a rare but significant clinical occurrence that frequently is associated with life-threatening hemorrhagic complications. These autoantibodies often arise as an epiphenomenon of various disease states that are autoimmune or manifest a component of immune dysfunction. The present symposium reviews the immunochemistry of FVIII:C auto-antibodies and describes ways in which this knowledge has been applied to gain insight into the structure-function relationship of the FVIII:C protein. Also discussed are the etiology and natural history of acquired FVIII:C inhibition as well as evolving approaches to its treatment. Therapeutic options for this condition continue to expand, and choice of the optimal regimen for each patient is based on many considerations, including the level of the inhibitor, the underlying disease state, clinical responses to previous treatment, and degree of antibody interaction with heterologous purified FVIII:C protein. Acquired FVIII:C autoantibodies isolated from nonhemophiliacs are characterized as heterogeneous, noncomplement-fixing, nonprecipitating immunoglobulins directed against functional epitopes (antigenic sites) of FVIII:C in a time- and temperature-dependent manner. The clinical significance of these inhibitors is determined qualitatively by studying in vivo survival of FVIII:C activity with infused replacement materials or quantitatively by laboratory mixing tests that measure the capacity of the inhibitor to neutralize FVIII:C activity. In the United States inhibitor potency is expressed most commonly in Bethesda Units (BU), where 1.0 BU is the reciprocal dilution of patient test plasma, permitting detection of 50% residual FVIII:C activity in a mixture with normal pooled plasma. In Europe, FVIII inhibitors are now often quantitated in New Oxford Units, which are derived from neutralizing-mixing studies of patient test plasma with diluted FVIII concentrate. One Oxford unit is equivalent to approximately 0.83 BU. Although analyses that measure functional inhibition of FVIII:C activity by the autoantibody provide a useful tool to assess clinical efficacy of therapeutic regimens, these assays may not recognize nonactivating antibodies. These immunoglobulins may bind to alternative epitopes and significantly influence plasma clearance, survival times, and circulating levels of infused FVIII:C protein. Finally, this symposium will speculate on the potential application of innovative approaches to inhibitor therapy, based on results from numerous provocative studies on the nature of the human immune response.
authors.affiliation: Department of Medicine, George Washington University School of Medicine, Washington, D.C. 20037.
authors.forename: C M
authors.initials: CM
authors.lastname: Kessler
mesh_terms: D001323:Autoantibodies / Q000032:analysis*; D005169:Factor VIII / Q000276:immunology*; D006467:Hemophilia A / Q000097:blood / Q000276:immunology; D006801:Humans; D008722:Methods; D010314:Partial Thromboplastin Time
chemical_list: D001323:Autoantibodies; D005169:Factor VIII