Antiphospholipid Antibodies

Antiphospholipid antibodies are antibodies directed against phosphorus-fat components of your cell membranes called phospholipids, certain blood proteins that bind with phospholipids, and the complexes formed when proteins and phospholipids bind. Approximately 50% of people with lupus possesses these antibodies, and over a twenty-year period of time, one half of lupus patients with one of these antibodies—the lupus anticoagulant—will experience a blood clot. People without lupus can also have antiphospholipid antibodies.

The most commonly discussed antiphospholipid antibodies are the lupus anticoagulant (LA) and anticardiolipin antibody (aCL). These two antibodies are often found together, but can also be detected alone in an individual. Other antiphospholipid antibodies include anti-beta 2 glycoprotein 1 (anti-ß2 GPI), anti-prothrombin, and the “false-positive” test for syphilis. Like other antibodies involved in lupus that are directed against self (auto-antibodies), antiphospholipid antibodies can come and go or increase and decrease.

The presence of an antiphospholipid antibody such as the lupus anticoagulant and anticardiolipin antibody in an individual is associated with a predisposition for blood clots. Blood clots can form anywhere in the body and can lead to stroke, gangrene, heart attack, and other serious complications. In people with lupus, the risk of clotting does not necessarily correlate with disease activity, so the presence of these antibodies can cause problems even when a person’s lupus is in control. Complications of antiphospolipid antibodies in lupus include fetal loss and/or miscarriages, blood clots of the veins or arteries (thromboses), low platelet counts (autoimmune thrombocytopenia), strokes, transient ischemic attacks (stroke warnings), Libman-Sacks endocarditis (formation of a clot on a specific heart valve), pulmonary emboli, and pulmonary hypertension.

Many people with antiphospholipid antibodies have a purple or reddish lacy pattern just under their skin known as livedo. This pattern is especially apparent on the extremities (i.e., the arms and legs). It is important to realize, however, that having livedo does not necessarily mean one has antiphospholipid antibodies; rather, doctors acknowledge a correlation between the two conditions. Livedo can be associated with other diseases of the blood vessels, but in fact, many perfectly healthy women also experience the condition.

Antiphospholipid Antibody Syndrome (APS)

Individuals who experience complications from antiphospholipid antibodies are diagnosed with Antiphospholipid Antibody Syndrome (APS). This condition can occur both in people with lupus and those without lupus. Fifty percent of people with lupus have APS. The presence of one or more clinical episodes of thromboses (blood clots) and/or complications during pregnancy, such as miscarriage or premature birth, in conjunction with a significant level of anticardiolipin antibodies, antiphospholipid antibodies, and/or anti-ß2 GPI anti- antibodies usually indicates the presence of APS. When APS is the sole diagnosis, and no other connective tissue diseases are present, APS is often said to be the primary diagnosis; when APS is present in association with lupus or another connective tissue disease, APS is said to be “secondary.” This classification is controversial, however, because some people with primary APS (about 8%) later develop lupus, suggesting a connection between the two conditions.

Types of Antiphospholipid Antibodies

False-Positive Test for Syphilis

In the 1940s, when it was common for people to have premarital exams, doctors realized that some women with lupus tested positive for syphilis. Further studies indicated that 1 in 5 people with lupus had a false-positive syphilis test. The syphilis test of those days—the Wasserman test—was dependant on an antibody found in syphilis patients called reagin. The substance to which this antibody reacts is cardiolipin, so the individuals with a false-positive syphilis test actually had a form of anticardiolipin antibodies. The false-positive syphilis test was the first recognized test for antiphospholipid antibodies, but it is now known that people can have antiphospholipid antibodies without having a false-positive syphilis test and vice versa. The false-positive test is not associated with an increased risk of blood clots in all medical studies performed in the past, but certain studies, including the Johns Hopkins Lupus Cohort, suggest that there is a connection.

The false-positive syphilis test was one of the first three recognized indications of antiphospholipid antibodies. The other two were the lupus anticoagulant and anticardiolipin antibody.

Lupus Anticoagulant

In the late 1940s, it was found that an antibody present in some lupus patients prolonged a clotting test dependent on phospholipids. For this reason, it was thought that this antibody increased the tendency to bleed, and thus it was deemed the lupus anticoagulant. However, this name is now recognized as a misnomer for two reasons. First, the term “anticoagulant” is a false label, since lupus anticoagulant actually increases the ability of the blood to clot. Second, the term “lupus” in the name of the antibody is misleading, since more than half of all people who possess this antibody do not have lupus.

Tests called coagulation tests are used to detect the lupus anticoagulant (LA). Remember that even though the lupus anticoagulant causes the blood to clot more easily in vivo (i.e., in a person’s body), they actually cause prolonged clotting times in vitro (i.e., in a test tube). Therefore, if it takes more time than normal for the blood to clot, the lupus anticoagulant is usually suspected. The activated partial thromboplastin time (aPTT) is often used to test for LA. If this test is normal, more sensitive coagulation tests are performed, including the modified Russell viper venom time (RVVT), platelet neutralization procedure (PNP), and kaolin clotting time (KCT). Normally, two of these tests (the apt and the RVVT) are performed to detect whether lupus anticoagulant is present.

Anticardiolipin Antibody

Even though the false-positive syphilis test and the lupus anticoagulant were identified in the 1940s, the link between these entities was not investigated until the 1980s, when a researcher at the Graham Hughes laboratory in Britain named Nigel Harris began looking at antibodies to the phospholipid antigens. Harris realized that cardiolipin was a major element of the false-positive syphilis test, and he developed a more specific test for the antibody. He also determined that the presence of these anticardiolipin antibodies was associated with recurrent thromboses (blood clots) and pregnancy losses. Others in Hughes’ laboratory began to publish studies showing the link between anticardiolipin antibodies and stroke, deep vein thrombosis (DVT), recurrent pregnancy loss, livedo, seizures, and other conditions. In fact, what we now know as antiphospholipid syndrome was known as the anticardiolipin syndrome even though other antiphospholipids, namely the lupus anticoagulant, were known to produce similar effects.

There are different classes (isotypes) of anticardiolipin antibody, namely IgG, IgM, and IgA. IgG is the anticardiolipin antibody type most associated with complications. An enzyme-linked immunosorbent assay (ELISA) is used to test for anticardiolipin antibodies. One can test for all isotypes at once, or they can be detected separately. High levels of the IgM isotype are associated with autoimmune hemolytic anemia, a condition in which an individual’s immune system attacks their red blood cells.

Anti-beta2 glycoprotein 1

Beta2 glycoprotein 1 is the protein in the body to which anticardiolipin antibodies bind, and it is also possible to measure antibodies to beta2 glycoprotein 1. An individual can be positive for anticardiolipin antibodies and negative for anti-ß2 GPI and vice versa, and detection of anti-ß2 GPI is not yet part of routine testing done for patients with an increased likelihood of blood clots.


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