Pathogenic antibodies to coagulation factors. Part one: factor VIII and factor IX.

Pathogenic antibodies targeting coagulation factors usually are clinically significant because they inhibit function. Circulating anticoagulants were recognized as early as 1906 ([1], cited in [2]). They interfere with the coagulation of normal blood as well as that of the patient, which is the basis of the classical mixing study. Circulating anticoagulants inhibiting factor (F)VIII and factor (F)IX were identified in the early 1940s and 1950s, nearly as soon as these factors were discovered and differentiated from one another [2], and subsequently were shown to be antibodies [3]. Another circulating anticoagulant was identified in this era that did not appear specific for a single coagulation factor and frequently was associated with systemic lupus erythematosus. Although some of these patients had abnormal bleeding, a paradoxical association of the lupus anticoagulant with thrombosis was subsequently discovered [4]. Both the hemostatic and adaptive immune systems developed rapidly during early vertebrate evolution and then produced no major changes in their principle features over the next 450 million years. Fibrinogen, factor XIII, the vitamin K-dependent proenzymes and their procofactors, factor (F)V and FVIII, are present in fish, which were the first vertebrates [5,6]. The adaptive immune system, characterized by antigenspecific lymphocyte receptors, major histocompatibility class (MHC) molecules, and antibody production, is present in jawed, but not jawless, fishes, indicating that it evolved during the 50 million years between the divergence of these two vertebrate classes [7]. The hemostatic challenge to the early vertebrates was to plug hemorrhagic leaks while maintaining overall patency of the vascular system. This includes allowing effector cells of the immune system to cross the endothelial barrier. The immunological challenge was to kill invading microorganisms and neutralize their toxic products using a defense system that did not produce self-inflicted injury. Vertebrate immune systems possess elaborate mechanisms to tolerate self-molecules and cells. It is interesting to consider hemostasis from the point of view of the immune system. A major hemostatic event is associated with deposition of products derived from fibrinogen and other coagulation factors at potentially immunizing levels. Specific and non-specific proteolytic fragmentation exposes possible neoepitopes, often in the setting of an associated inflammatory process with its attendant adjuvant effects. Thus, it seems surprising that autoantibody formation is not a common sequela to hemorrhage. In fact, autoantibodies to coagulation factors are rare: the incidence of clinically significant autoantibodies to FVIII, which is the most commonly targeted coagulation factor in autoimmunity, is only 0.2–1 per million people per year [8] and the incidence of autoantibodies to the other coagulation factors is considerably lower. Although tolerance to the coagulation proteins has not been studied, experimental models using complement component C5 as a model plasma protein have been developed and may be relevant to the development of inhibitors [9, 10]. Conversely, the recent emergence of methods to study the immunogenicity of FVIII and FIX that are described in this review may contribute to the general understanding of immunological tolerance. Inhibitory antibodies to coagulation factors occur more commonly as an immune response to non-self protein, e.g. during factor replacement therapy for hemophilia A or B or during the use of bovine thrombin products in surgery. Here one may wonder why the incidence is not higher. For example, most patients with hemophilia A and apparent null mutations do not develop a detectable immune response after repeated exposure to FVIII. However, the usual peaceful coexistence of the coagulation and immune systems provides little consolation to the practicing hematologist in a tertiary care center, who sees inhibitor patients often enough. Patients with autoantibodies to FVIII or other coagulation factors often present with severe bleeding that is difficult and expensive to control. The development of inhibitory antibodies in hemophilia A and B frequently transforms these disorders from treatable to refractory and now is considered the most significant complication of treatment. Correspondence: P. Lollar, 1365-B Clifton Road, Suite B5100, Atlanta, GA 30322., USA. Tel.: +1 404 727 5569; fax: +1 404 727 4859; e-mail: jlollar@ emory.edu Journal of Thrombosis and Haemostasis, 2: 1082–1095