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Clinically significant autoantibodies to coagulation factors are uncommon, but can produce life-threatening bleeding and death. The most commonly targeted coagulation factor by an autoantibody is factor VIII. Acquired hemophilia A, which results from these antibodies, can either be idiopathic or associated with other autoimmune disorders, malignancy, the postpartum period, and the use of drugs such as penicillin and sulfonamides. Idiopathic autoantibodies occur most often in older persons. Bleeding in acquired hemophilia A is treated with factor VIII bypassing agents. The underlying autoimmune disorder frequently responds to immunosuppressive drugs or to the induction of immune tolerance. Antiprothrombin antibodies found in patients with lupus anticoagulant are often associated with bleeding. Antibodies to factor V can occur as autoantibodies or as cross-reacting antibovine factor V antibodies that develop after exposure to bovine thrombin products that are contaminated with factor V. Pathogenic autoantibodies also have been described that target thrombin, factor IX, factor XI, factor XIII, protein C, protein S, and the endothelial cell protein C receptor.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: aPTT, activated partial thromboplastin time; BU, Bethesda unit.

Antibodies directed against coagulation factors can develop as an acquired, autoimmune phenomenon or, as described in Chaps. 124 and 125, in response to replacement therapy in hereditary coagulation factor deficiencies. These “circulating anticoagulants” or “inhibitors” were recognized as early as 1906 as a cause of an acquired bleeding disorder.1,2 In 1966, factor VIII inhibitors were shown to be antibodies.3 The key feature that distinguishes antibody-mediated from other acquired coagulation factor deficiencies, such as impaired synthesis (e.g., as a consequence of vitamin K deficiency) or increased consumption (e.g., in disseminated intravascular coagulation), is the ability of the patient’s plasma to inhibit the coagulation of normal plasma.

Incidence and Associated Disorders

The clinical condition associated with acquired (spontaneous) factor VIII antibodies is called acquired hemophilia A. The incidence of autoantibodies to factor VIII is 0.2 to 1 per 1 million persons per year.4 This disorder is the most common spontaneous antibody-induced bleeding disorder involving a specific coagulation factor. The associated clinical condition is called acquired hemophilia A. Approximately 50 percent of acquired hemophilia A patients have an underlying condition, such as an autoimmune disorder (e.g., rheumatoid arthritis or systemic lupus erythematosus), malignancy, pregnancy, or a history consistent with a drug reaction.5 The remaining cases, referred to as idiopathic, commonly occur in older patients of either sex.

Mechanisms of Autoantibody Development

In addition to non-self-antigen, antigen products of infection and cellular damage of the host can promote an immune response.6 These inciting agents include microbial products and host proteins associated with inflammation, such as heat shock proteins.6 It was proposed that in the absence of these “danger” signals, autoimmunity can be avoided.7 Additionally, several other mechanisms exist that prevent an immune response ...

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