(See also Overview of Coagulation Disorders.)
Circulating anticoagulants should be suspected in patients with excessive bleeding combined with either a prolonged partial thromboplastin time (PTT) or prothrombin time (PT) that does not correct when the test is repeated with a 1:1 mixture of normal plasma and the patient’s plasma.
Auto-antibodies directed against protein/phospholipid complexes typically cause arterial and/or venous thrombosis (the antiphospholipid antibody syndrome [APS]). The precise pathophysiology of thrombosis in APS is unknown. Although the protein-phospholipid autoantibodies frequently bind beta2-glycoprotein-1, it is unclear how this interaction effects thrombosis. In a subset of patients, the autoantibodies bind to prothrombin-phospholipid complexes and induce hypoprothrombinemia and bleeding.
Isoantibodies to factor VIII develop in about 30% of patients with severe hemophilia A as a complication of repeated exposure to normal factor VIII molecules during replacement therapy. Factor VIII autoantibodies also arise occasionally in patients without hemophilia, eg, in postpartum women as a manifestation of an underlying systemic autoimmune disorder or of transiently disordered immune regulation; or in older patients without overt evidence of other underlying disorders. Patients with a factor VIII anticoagulant can develop life-threatening hemorrhage.
Similarly, patients with severe hemophilia B can develop isoantibodies to factor IX, although this is less common, occurring in only about 3%.
Plasma containing a factor VIII antibody has a prolonged PTT that does not correct when normal plasma or another source of factor VIII is added in a 1:1 mixture to the patient’s plasma. Testing is done immediately after mixture and again after incubation. Similar testing is done for factor IX antibody.
Therapy with cyclophosphamide, corticosteroids, or rituximab (monoclonal antibody to CD20 on lymphocytes) may suppress autoantibody production in patients without hemophilia (eg, in postpartum women). The autoantibodies may disappear spontaneously.
Treatment of acute hemorrhage in patients with hemophilia A or hemophilia B who have factor VIII or factor IX isoantibodies is currently by recombinant activated factor VII.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that binds to both factor IX and factor X, links them into a factor Xase-like active complex that obviates the need for factor VIII. Emicizumab can be used to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A with factor VIII inhibitors.
Fitusiran and concizumab are under investigation for the treatment of acquired anti-factor VIII or anti-factor IX antibodies (1, 2).
Also in clinical trials is a B-domain depleted form of recombinant porcine factor VIII (3) that has reduced cross-reactivity with anti-human antibody inhibitors of factor VIII.
1. Sehgal A, Barros S, Ivanciu L, et al: An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 21:492–497, 2015.
2. Chowdary P, Lethagen S, Friedrich U, et al: Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: A randomized first human dose trial. J Thromb Haemost 13:743–754, 2015.
3. Kempton CL, Abshire TC, Deveras RA, et al: Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII in subjects with hemophilia A. Haemophilia 18:798–804, 2012.
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