(See also Overview of Coagulation Disorders Overview of Coagulation Disorders Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary. The major causes of acquired... read more .)
Circulating anticoagulants should be suspected in patients with excessive bleeding Excessive Bleeding Unusual or excessive bleeding may be indicated by several different signs and symptoms. Patients may present with unexplained nosebleeds (epistaxis), excessive or prolonged menstrual blood flow... read more 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 Antiphospholipid Antibody Syndrome (APS) Antiphospholipid antibody syndrome is an autoimmune disorder in which patients have autoantibodies to phospholipid-bound proteins. Venous or arterial thrombi may occur. The pathophysiology is... read more [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.
Factor VIII and Factor IX Anticoagulants
Isoantibodies to factor VIII develop in about 30% of patients with severe hemophilia A Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more as a complication of repeated exposure to normal factor VIII molecules during replacement therapy Treatment Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more . 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 Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more 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.
Treatment
In patients without hemophilia, cyclophosphamide, corticosteroids, or rituximab
In patients with hemophilia, recombinant activated factor VII
Therapy with cyclophosphamide, corticosteroids, or rituximab (monoclonal antibody to CD20 on lymphocytes) may suppress autoantibody production in patients without hemophilia (eg, in postpartum women). In some patients, 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 Treatment Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more .
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 Treatment references Circulating anticoagulants are usually autoantibodies that neutralize specific clotting factors in vivo (eg, an autoantibody against factor VIII or factor V) or inhibit phospholipid-bound proteins... read more ).
Also in clinical trials is a B-domain depleted form of recombinant porcine factor VIII (3 Treatment references Circulating anticoagulants are usually autoantibodies that neutralize specific clotting factors in vivo (eg, an autoantibody against factor VIII or factor V) or inhibit phospholipid-bound proteins... read more ) that has reduced cross-reactivity with anti-human antibody inhibitors of factor VIII.
Treatment references
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.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
factor ix |
AlphaNine SD, ALPROLIX, Bebulin, Bebulin VH, BeneFIX, IDELVION, IXINITY, Mononine, Profilnine, Profilnine SD, Proplex T, REBINYN, RIXUBIS |
cyclophosphamide |
Cyclophosphamide, Cytoxan, Neosar |
rituximab |
RIABNI, Rituxan, RUXIENCE, truxima |
emicizumab |
Hemlibra |
factor x |
Coagadex |
