Chapter 82: Antibody-Mediated Coagulation Factor Deficiencies

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 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 recommended at 12-hour intervals, which may be increased to doses of 100 U/kg. Treatment should be continued until clear signs of clinical improvement appear, such as relief of pain, reduction of swelling, or mobilization of the joint.

— For mucous membrane bleeding, 50 U/kg is recommended at 6-hour intervals under careful monitoring. If hemorrhage does not stop, the dose may be increased to 100 U/kg at 6-hour intervals.

— For severe soft-tissue bleeding, such as retroperitoneal bleeding, 100 U/kg at 12-hour intervals is recommended.

— Central nervous system bleeding has been effectively treated with doses of 100 U/kg at 6- to 12-hour intervals. One should not exceed a daily dose of FEIBA of 200 U/kg.

The response to bypassing agents is variable and does not correlate with the inhibitor titer. A major concern with the use of rFVIIa and activated coagulation factor concentrates is that there is no laboratory method available for predicting response to therapy or monitoring patients on therapy.

The major serious adverse event associated with bypassing agents is thrombosis. However, this risk is considered low when used for approved indications at the recommended doses.

A commercial plasma-derived porcine factor VIII concentrate was useful in the treatment of factor VIII inhibitor patients for approximately 20 years but was discontinued in 2004 because of viral contamination of the product. Porcine factor VIII has the advantage of potentially being guided by laboratory monitoring of recovery of factor VIII activity in plasma. However, the development of antiporcine factor VIII antibodies often precluded its long-term use.

Although acquired inhibitors may remit spontaneously, initiation of immunosuppressive therapy at the time of diagnosis to eradicate the inhibitor is recommended because of the serious course of this condition. A variety of immunosuppressive agents have been used, including cyclophosphamide, azathioprine, cyclosporine A, intravenous immunoglobulin, and rituximab. Plasmapheresis and immunoadsorption of the inhibitory antibody have been used. Finally, immune tolerance induction using human factor VIII has been used successfully.

Antibodies inhibiting thrombin and factor V frequently coexist in immune responses to commercial products that contain thrombin (eg, adhesive tissue glue). Thrombin products have been used widely in surgical and endoscopic procedures.

Thrombin is used either alone or as a component of fibrin sealants, which consist of fibrinogen and thrombin preparations that are mixed together at the wound site to form a topical fibrin clot. Both types of products are heavily contaminated with other plasma proteins, including factor V and prothrombin. Almost all patients exposed to bovine proteins develop a detectable immune response. In half of these patients, antibovine antibodies cross-react with human thrombin, factor V, or prothrombin.

Usually, these antibodies cause no clinical problems. However, mild to life-threatening hemorrhage can occur, especially if the titer of antihuman factor V antibodies is high. The risk of bleeding is higher in patients who receive bovine thrombin products more than once because of the development of a secondary immune response.

β-lactam antibiotics also have been associated with anti–factor V autoantibodies and may partly explain the increased incidence with surgery. Anti–factor V autoantibodies have been identified rarely in patients with autoimmune diseases, solid tumors, and monoclonal gammopathies. In approximately 20% of cases of factor V autoantibody formation, no underlying disease was identified.

Patients with inhibitory antibodies to factor V have prolonged PT and aPTT, low factor V levels and a normal thrombin time. The diagnosis of a factor V inhibitor is based on the specific loss of factor V coagulant activity when patient and normal plasma are mixed in a coagulation assay.

In case of bleeding, patients may be treated with (high dose) fresh frozen plasma or with a bypassing agent, such as recombinant factor VIIa.

Antiprothrombin antibodies are most commonly associated with the antiphospholipid syndrome (see Chap. 84). The antiphospholipid syndrome is caused by lupus anticoagulants, which are defined as antibodies that produce phospholipid-dependent prolongation of in vitro coagulation assays.

However, most patients with lupus anticoagulants have demonstrable antiprothrombin antibodies or a hypoprothrombinemia but no bleeding diathesis.

Clinically significant antibodies to coagulation factors other than factor VIII, factor V, and prothrombin that produce acquired bleeding disorders are rare. In contrast to acquired hemophilia A, acquired hemophilia B is extremely rare.

An acquired inhibitor to protein C associated with a fatal thrombotic disorder has been reported, but evidently is rare.

In contrast, there is a relatively high prevalence of pathogenic anti–protein S antibodies. Inhibitory antibodies to protein S were detected in 5 of 15 patients with acquired protein S deficiency. Anti–protein S antibodies appear to be a risk factor for venous thrombosis and can be manifested in vitro as activated protein C resistance.