Chapter 82: Antibody-Mediated Coagulation Factor Deficiencies

INTRODUCTION

• 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) but also any other coagulation factor may be inhibited by an autoantibody.

ACQUIRED HEMOPHILIA A

• Acquired hemophilia A can either be idiopathic or associated with other autoimmune disorders, malignancy, the postpartum period, and the use of drugs (such as penicillin and sulfonamides).

• The incidence of autoantibodies to factor VIII is 0.2 to 1 per 1 million persons per year.

• Acquired hemophilia A patients usually present with spontaneous bleeding, which often is severe and life- or limb-threatening. These patients are more likely to have a more severe bleeding diathesis than patients with hemophilia A and an inhibitor.

• Common bleeding sites are soft tissues, skin, and mucous membranes. In contrast to patients with congenital hemophilia A, hemarthroses, intramuscular, and central nervous system bleeding are rare.

• Patients with acquired hemophilia A have a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT). The presence of a prolonged aPTT in a 1:1 mixture between patient and normal plasma establishes the diagnosis of a circulating anticoagulant. Specific assays for factor VIII activity and/or antigen will confirm the diagnosis.

• Once the identity of an inhibitor has been established, its titer is determined using the Bethesda assay. The inhibitor titer is defined as the dilution of patient plasma that produces 50% inhibition of the factor VIII activity and is expressed as Bethesda units per mL (BU/mL). Inhibitors are classified as low titer or high titer when the titers are less than 5 BU/mL or greater than 5 BU/mL, respectively.

• Acquired factor VIII inhibitors sometimes resolve spontaneously. However, it is not possible to predict in which subset of patients this will occur, and so treatment will be required when bleeding complications ensue.

• Patients with a factor VIII inhibitor titer of less than 5 BU/mL often are treated successfully with sufficient doses of recombinant or plasma-derived factor VIII concentrates to neutralize the inhibitor. Patients with titers between 5 and 10 BU/mL also may respond to factor VIII concentrates, whereas those with titers greater than 10 BU/mL generally do not respond.

• Factor VIII bypassing agents, which drive the coagulation mechanism through the extrinsic pathway, are the mainstays of management of patients with a high titer of an inhibitor. Two agents, recombinant activated factor VII and plasma-derived factor eight-inhibitor bypassing agent (FEIBA; also called activated prothrombin complex concentrate) are approved by the US Food and Drug Administration for treatment of acquired hemophilia A.

• The recommended dose range of rFVIIa for the treatment of patients with hemorrhage due to acquired hemophilia is 70 to 90 μg/kg repeated every 2 to 3 hours until hemostasis is achieved. The minimum effective dose in acquired hemophilia has not been determined.

• Recommended doses of FEIBA depend on the type of bleeding.

  — In joint hemorrhage, 50 U/kg is ...