Antiphospholipid Antibodies/Lupus Anticoagulant Dx

Last updated: November 3, 2014

Synonyms: APL or anticardiolipin (ACL) antibodies, LAC, biologic false-positive test for syphilis.

CPT Codes:  DRVVT (dilute Russell viper venom time) 85613; lupus anticoagulant (by hexagonal phospholipid neutralization test  85598 or platelet neutralization test 85597); anti-phospholipid (cardiolipin) assay  86147;  anti-beta-2 glycoprotein 1 assay  86146

Description: APLs are antibodies that bind to negatively charged phospholipids, including cardiolipin. LAC is a functional description of abnormalities in several hematologic tests often found in patients with APL antibodies. Patients may possess all or only one of these laboratory abnormalities in clinical association with APL syndrome.

Method: APL antibodies are detected by ELISA. Such tests may be used to detect antibodies not only to cardiolipin but also to phosphatidylcholine, phosphatidylserine and other negatively charged phospholipids. Although several antibody isotypes [e.g., immunoglobulin (Ig)G, IgA, IgM] can have ACL activity, high-titer IgG ACL most strongly correlates with the clinical APL syndrome. It has been demonstrated that most pathogenic ACL antibodies have binding activity only in the presence of another serum protein, Beta2-glycoprotein-I (β2GP-I). Antibodies that react with β2GP-I may be important to the thrombotic tendency in patients with APL syndrome because they are not seen among patients with non-pathogenic ACL (i.e., ACLs not associated with clinical APL syndrome). Moreover, some patients with clinical APL syndrome may have antibodies that bind β2GP-I (which are also detected by ELISA) and do not bind cardiolipin at all.

LAC refers to abnormalities in several hematologic laboratory clotting tests. The name is derived from observations that blood from some patients with SLE clotted more slowly than normal in vitro, suggesting an anticoagulant factor. This was a misnomer because not only did many of the patients not have lupus, but this laboratory finding was associated clinically with thrombosis rather than a bleeding tendency. To understand this phenomenon, recall that several in vitro clotting assays require the addition of negatively charged phospholipids to potentiate clot formation. APL antibodies bind to these phospholipids, interfering with their ability to promote clotting in the test tube. Thus, despite their association with thrombosis in patients, these antibodies demonstrate anticoagulant properties in the laboratory. Currently, several laboratory tests are widely performed that define the presence of an LAC. A prolonged partial thromboplastin time (PTT) with a normal prothrombin time is often the first suggestion of such an abnormality. If the PTT does not correct with a 1:1 dilution with normal serum (as expected with a deficiency of clotting factors), the presence of an inhibitor such as the LAC is suggested.

A variety of other dynamic clotting tests are available that are more phospholipid dependent than the PTT. Such tests are also used to confirm the presence of the LAC and include the dilute Russell viper venom time (DRVVT)  and kaolin clot time. Finally, correction of a prolonged PTT by the addition of excess phospholipid, as is done in the platelet neutralization test and the hexagonal phospholipid test, suggests the LAC.

Tests for RPR (rapid plasma reagin) and VDRL (venereal disease research laboratory) also identify ACL.

Increased Values: APL antibodies are uncommon in normal persons. Normal values on the ELISA for APL antibodies are defined with abnormal values being >5 standard deviations above the mean. This value is designated 10 PL units (these units are known as GPL for IgG antibodies, MPL for IgM, and APL for IgA). APL antibodies are elevated in most patients with APL syndrome. High-titer IgG APL antibodies are most strongly correlated with clinical syndromes. Uncommonly, patients with clinical APL syndrome may have abnormalities only on LAC testing or antibodies only to β2GP-I.

Elevated levels of APL antibodies are seen in patients with SLE. The reported prevalence of IgG or IgM APL antibodies varies from 17% to 60%, with most studies reporting >30%. The prevalence of APL is also elevated in patients with RA, being found in approximately 17% of patients (range, 4%–49%). In other autoimmune diseases, the prevalence of APL antibodies is not substantially above normal. APL antibodies may also be found in a variety of infectious diseases, including syphilis, tuberculosis, and human immunodeficiency virus and other viral infections. They may also be found in patients with cancers. In these nonautoimmune conditions, APL antibodies are rarely associated with APL syndrome (e.g., thrombotic events).

Abnormal LAC test results are not common in autoimmune diseases. They may be abnormal in patients with dysfibrinogenemia or with other types of clotting inhibitors.

Indications: APL antibodies may be sought in patients with symptoms suggesting APL syndrome, such as recurrent arterial or venous thromboses, fetal wastage and thrombocytopenia. Testing for LAC and a false-positive RPR may also help secure such a diagnosis.

Cost: LAC panel, $35–220; cardiolipin antibodies, $300–500.

Favaloro EJ1, Wong RC. Antiphospholipid antibody testing for the antiphospholipid syndrome: a comprehensive practical review including a synopsis of challenges and recent guidelines. Pathology. 2014 Oct;46(6):481-95. PMID: 25158812  
Merkel PA, Chang Y, Pierangeli SS, et al. The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med 1996;101:576–583. PMID: 9003103 

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