Chapter 476 Acquired Inhibitors of Coagulation
Acquired circulating anticoagulants (inhibitors) are antibodies that react or cross react with clotting factors or components used in coagulation screening tests (phospholipids), thereby prolonging screening tests, such as prothrombin time and partial thromboplastin time. Some of these anticoagulants are autoantibodies that react with phospholipid and thereby interfere with clotting in vitro but not in vivo. The most common form of these antiphospholipid antibodies has been referred to as the lupus anticoagulant (Chapter 473). This anticoagulant is found in patients with systemic lupus erythematosus (Chapter 152), in those with other collagen-vascular diseases, and in association with HIV. In otherwise healthy children, spontaneous lupus-like inhibitors have developed transiently after incidental viral infection. These transient inhibitors are usually not associated with either bleeding or thrombosis.
Although the classic lupus anticoagulant is more often associated with a predisposition to thrombosis than with bleeding symptoms, bleeding symptoms in a patient with the lupus anticoagulant may be caused by thrombocytopenia, as a manifestation of the antiphospholipid syndrome or of lupus itself, or rarely, by a coexistent specific autoantibody against prothrombin (factor II). This antiprothrombin antibody does not inactivate prothrombin, but causes accelerated clearance of the protein, resulting in low levels of prothrombin.
Rarely, antibodies may arise spontaneously against a specific clotting factor, such as factor VIII or von Willebrand factor, similar to those seen more frequently in elderly patients. These patients are prone to excessive hemorrhage and may require specific treatment. In patients with a hereditary deficiency of a clotting factor (factor VIII or factor IX), antibodies may develop after exposure to transfused factor concentrates. These hemophilic inhibitory antibodies are discussed in Chapter 470.1.
Inhibitors against specific coagulation factors usually affect factors VIII, IX, and XI, or rarely, prothrombin. Depending on the target of the antibody, prothrombin time, partial thromboplastin time, or both may be prolonged. The mechanism by which the inhibitory antibody functions determines whether mixing patient plasma with normal plasma will normalize (correct) the clotting time. Patient plasma containing antibodies directed against the active site of the clotting factor (factor VIII or factor IX) will not correct on 1 : 1 mixing with normal plasma, whereas antibodies that lead to increased clearance of the factor (prothrombin) will correct on 1 : 1 mixing. Specific factor assays are used to determine which factor is involved.
Management of the patient with an inhibitor against factor VIII or IX is the same as for the patient with hemophilia who has an alloantibody against factor VIII or factor IX. Infusions of recombinant factor VIIa or activated prothrombin complex concentrate may be needed to control significant bleeding. Acute bleeding due to an antiprothrombin antibody can often be treated with a plasma infusion and may benefit from a short course of corticosteroid therapy.
Asymptomatic spontaneous inhibitors that arise after a viral infection tend to disappear within a few wk to mo. Inhibitors seen with an underlying disease, such as systemic lupus erythematosus, often disappear when the primary disease is effectively treated.
Hunt BJ. Pediatric antiphospholipid antibodies and antiphospholipid syndrome. Semin Thromb Hemost. 2008;34:274-281.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763.
Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia. 2002;8:28-32.
Pipe SW, Goldenberg NA. Acquired hemostatic defects. In: Orkin SH, Nathan DG, Ginsberg D, et al, editors. Nathan and Oski’s hematology of infancy and childhood. ed 7. Philadelphia: Saunders Elsevier; 2009:1591-1622.
Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood. 2004;104:3858-3864.