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May, 2001

The Lupus Anticoagulant - An Update

Franklin A. Bontempo, M.D.
Medical Director, Coagulation Laboratory

                                                                                                           

INTRODUCTION

Lupus anticoagulants (LA) are a heterogeneous group of antibodies that cause a variety of clinical and laboratory effects.  They affect 2-4% of the U.S. population, making familiarity with them a necessity for the clinician.  Many LA are discovered accidentally such as when a prolonged activated partial thromboplastin time (APTT) is found during a pre-operative evaluation.  Often, there are no clinical consequences other than the need to explain the reason for the long APTT.  A minority of patients with LA have a hypercoagulable state manifested by recurrent thromboses, multiple spontaneous miscarriages, migraine headaches, or stroke.  Very rarely, patients may have bleeding.

Definition

 LA have traditionally been classified as anti-phospholipid antibodies, but a more correct view is that they are antibodies directed against plasma proteins, which also bind to phospholipid surfaces.  They are usually IgG, IgM, or mixtures of both, and frequently interfere with standard phospholipid-dependent coagulation tests.  Importantly, the clotting test abnormalities caused by LA are in vitro phenomena; the antiphospholipid antibodies of the LA react with the phospholipid preparations used to initiate clotting reactions.  In vivo clotting factor activities are not diminished and, except in extremely rare cases where there are specific antibodies directed against clotting factor II, there is no danger of a bleeding diathesis.  It should also be recognized that most patients with LA do not have lupus erythematosus or other systemic autoimmune disorders.     

Etiology

  The exact etiology of LA is unclear.  These antibodies are commonly found in asymptomatic elderly individuals.  Among patients with autoimmune disorders, those with SLE have the highest incidence (20-45%).  Patients with HIV infection also have a high incidence of LA at some time in their course.  A number of drugs, most notably, procainamide, hydralazine, isoniazid, dilantin, phenothiazines, quinidine, and ACE inhibitors are known to induce LA.  The majority of patients with drug-induced LA however, have no systemic autoimmune disease or any other underlying disorder and have no clinical manifestations.   

Lupus anticoagulants and thrombosiS

Although only a minority of patients with LA present with recurrent episodes of thrombosis, LA are one of the most common acquired predisposing causes of thrombosis; they are associated with cerebral, deep venous, or renal vein thromboses, as well pulmonary emboli or arterial occlusions, particularly stroke.  Depending upon the population studied, the incidence of thrombotic complications in patients with LA ranges from 5-20%.  Reports indicate that LA are found in 8-14% of patients with deep venous thrombosis and approximately 1/3 of patients with stroke <50 years of age.  There is also evidence that the type of recurrent thrombotic event, venous or arterial, tends to be persistent over time in the same patient.    

Lupus anticoagulants and Pregnancy

 LA have clearly been associated with an increased risk of fetal loss due to pre-eclampsia, placental abruption, intrauterine growth retardation, and stillbirth.  Some evidence suggests that this may be due to antibodies against the placental anticoagulant protein, annexin  V.  Placental infarction has been suggested as the cause of the failure to carry to term but pathological analysis has not definitely supported this contention.

Lupus anticoagulants and thrombocytopenia

An immune type thrombocytopenia has been observed in a small percentage of patients with LA; this may be due to reactions between antibodies and platelet membrane-associated phospholipids.

 

Laboratory Diagnosis

No single test is definitive for a lupus anticoagulant.  As a result, a variety of tests and testing algorithms are used in an attempt to establish the diagnosis.  The typical screening test is a prolongation of the standard APTT that fails to correct when the patient's plasma is mixed with normal plasma.  This suggests an inhibitor since normal plasma usually corrects any factor deficiency.  However, this screening alone is inadequate to establish the presence of a LA because many affected patients, especially pregnant women, have normal APTT's.   Conversely, occasional patients with a prolonged APTT that does not correct may have specific antibodies against individual clotting factors.  Thus, additional tests are needed both to establish and exclude the presence of a lupus anticoagulant.

 

Other tests that aid in the recognition and confirmation of lupus anticoagulants include tests for anticardiolipin and antiphosphatidylserine antibodies, the tissue thromboplastin inhibition index (TTI), the dilute Russell viper venom time (dRVV), the prothrombin time (PT), the hexagonal lipid neutralization test, and testing for -2 glycoprotein I.  Standard clotting factor assays may also be performed; they can differentiate LA from the more clinically dangerous specific antifactor antibodies such as anti-factor VIII antibody. 

All of the foregoing tests either directly measure antiphospholipid antibodies or manipulate the amount of active phospholipid available to initiate the clotting cascade. 

Management

When LA are found incidentally in asymptomatic patients, no therapy may be necessary.  In patients with drug-induced LA, discontinuing the agent will usually cause any abnormal clotting tests to revert to normal in 2-3 weeks. 

When thrombotic patients who need anticoagulation with heparin have long APTT's due to a lupus anticoagulant, monitoring the heparin can be accomplished by using the anti-factor Xa activity assay, which is usually used for the monitoring of low molecular weight heparin.  Although the PT is less affected by LA than the APTT, the chromogenic factor X assay may be used to determine the accuracy of the INR in patients with LA. 

Several studies of small groups of non-randomized patients suggest that a combination of aspirin and prednisone or heparin alone may result in successful term pregnancy in women with recurrent fetal loss.  However, no randomized study has established the usefulness of either regimen.

LA may influence the recommendation for the duration or intensity of anticoagulant therapy in patients with thrombotic events.  If a LA, present initially, persists after a standard course of anticoagulation in a patient with thrombosis, continued anticoagulation is usually recommended for at least three additional months when repeat testing for the LA is again performed.  If the LA disappears, anticoagulation may be discontinued; if it remains, indefinite anticoagulation is usually recommended because of a high recurrent thrombotic risk. 

Higher intensity INR ranges of 2.5 to 3.5 have been shown to be beneficial in patients with LA on oral anticoagulation, but the uses of the chromogenic factor X assay to determine any possible interference of the LA with the PT/INR may again provide more accurate dosing. 

Attempting to suppress any undefined underlying autoimmune process with prednisone in patients with LA to lower thrombotic risk has not been shown to be effective and is currently not recommended.

                                                                                                                                                                             

           Copyright 2001, The Institute For Transfusion Medicine

                                                                                                             


For questions or further information regarding The Lupus Anticoagulant - An Update, please contact Franklin A. Bontempo, M.D. at The Institute For Transfusion Medicine: 412-209-7304

Copies of previous Transfusion Medicine Update issues can be obtained from our web page: www.itxm.org.  To be placed on our mailing list for a hard copy, please contact Deborah Small by e-mail: dsmall@itxm.org or by phone: (412) 209-7320.