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Coagulation Disorders Caused by Circulating Anticoagulants

By

Michael B. Streiff

, MD, Johns Hopkins University School of Medicine

Reviewed/Revised Sep 2023
View PATIENT EDUCATION

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 in vitro (antiphospholipid antibodies). Occasionally, the latter type of autoantibody causes bleeding by binding in vivo to prothrombin-phospholipid complexes.

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.

Autoantibodies directed against protein/phospholipid complexes typically cause arterial and/or venous thrombosis (the antiphospholipid syndrome Antiphospholipid Syndrome (APS) Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... 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 triggers thrombosis. In a subset of patients, the autoantibodies bind to prothrombin-phospholipid complexes and induce hypoprothrombinemia and bleeding.

Factor VIII and Factor IX Inhibitors

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 (1 General 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 ). 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.

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.

General references

  • 1. Iorio A, Fischer K, Makris M. Large scale studies assessing anti-factor VIII antibody development in previously untreated haemophilia A: what has been learned, what to believe and how to learn more. Br J Haematol 2017;178(1):20-31. doi:10.1111/bjh.14610

  • 2. Puetz J, Soucie JM, Kempton CL, Monahan PE; Hemophilia Treatment Center Network (HTCN) Investigators. Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database. Haemophilia 2014;20(1):25-31. doi:10.1111/hae.12229

Treatment

  • In patients without hemophilia, cyclophosphamide, corticosteroids, or rituximab are used to eliminate inhibitors

  • In patients with hemophilia, immune tolerance induction with long-term high-dose factor replacement is used to eliminate inhibitors

In patients without hemophilia who develop factor inhibitors, therapy with cyclophosphamide, corticosteroids, or rituximab (monoclonal antibody to CD20 on lymphocytes) is used to suppress autoantibody production. In some patients, the autoantibodies may disappear spontaneously.

In patients with hemophilia A, factor VIII inhibitors are eliminated with immune tolerance induction using high-dose factor VIII replacement. Some protocols include immunosupression in patients with refractory disease.

Recombinant human factor VIIa is used to treat acute bleeding episodes in patients with hemophilia A or B with inhibitors or patients without hemophilia who develop factor VIII or IX autoantibodies. Activated prothrombin complex concentrates can also be used to treat bleeding in patients with factor VIII inhibitors with or without hemophilia A. Because activated prothrombin complex concentrates contain factor IX, they cannot be used for treating patients with factor IX inhibitors. (1 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 ).

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.

Also in clinical trials is a B-domain depleted form of recombinant porcine factor VIII (4 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

Drugs Mentioned In This Article

Drug Name Select Trade
Cyclophosphamide, Cytoxan, Neosar
RIABNI, Rituxan, RUXIENCE, truxima
NovoSeven, NovoSeven RT, SevenFACT
Hemlibra
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NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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