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INTRODUCTION

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SUMMARY

Clinically significant autoantibodies to coagulation factors deficiencies are uncommon, but can produce life-threatening bleeding and death. The most commonly targeted coagulation factor in autoimmunity is factor VIII. Acquired hemophilia A, which results from these antibodies, can either be idiopathic or associated with older age, other autoimmune disorders, malignancy, the postpartum period, and the use of drugs such as penicillin and sulfonamides. Bleeding in acquired hemophilia A is treated with factor VIII bypassing agents. The underlying autoimmune disorder frequently responds to immunosuppressive medication. Antiprothrombin antibodies usually are found in patients with lupus anticoagulant and are associated with bleeding. Antibodies of von Willebrand factor are found in patients with type 3 von Willebrand disease in response to infusion of plasma concentrates containing von Willebrand factor. 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.

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Acronyms and Abbreviations

APC, activated protein C; aPCC, activated prothrombin complex concentrate; aPTT, activated partial thromboplastin time; BU, Bethesda units; CTLA4, cytotoxic T-lymphocyte associated protein 4; DAMP, damage-associated molecular patters; EACH, European Acquired Hemophilia Registry; FEIBA, factor eight inhibitor bypasssing agent; PAPP, pathogen-asscoiated molecular patterns; rVIIa, recombinant activated factor VII.

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DEFINITION AND HISTORY

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Antibodies directed against coagulation factors can develop as an acquired, autoimmune phenomenon. These “circulating anticoagulants” or “inhibitors” were recognized as early as 1906 as a cause of an acquired bleeding disorder.1 The most common coagulation factor targeted in autoimmunity is factor VIII. The key feature that distinguishes antibody-mediated from other acquired coagulation factor deficiencies, such as impaired synthesis (e.g., a result 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. Inhibitors also can develop in response to replacement therapy in patients with congenital coagulation factor deficiencies as discussed in Chap. 123.

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ACQUIRED HEMOPHILIA A

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DEFINITIONS AND EPIDEMIOLOGY

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The incidence of autoantibodies to factor VIII, which is the most commonly targeted coagulation factor in autoimmunity, is 1.4 per million people per year.2,3,4 The associated clinical condition is called acquired hemophilia A. Approximately 40 to 50 percent of acquired hemophilia A patients have underlying conditions, including other autoimmune disorders (e.g., rheumatoid arthritis and systemic lupus erythematosus), malignancy, pregnancy, or a history consistent with a drug reaction.5 The remaining idiopathic cases most commonly occur in elderly patients of either sex with the median age at diagnosis being in the mid-70s.

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MECHANISMS OF ANTIBODY DEVELOPMENT

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Even though adaptive immunity provides a unique ability to recognize a nearly infinite range of antigenic ...

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