About Antiphospholipid Syndrome

Antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome and sometimes Hughes syndrome, is a disorder characterized by elevated levels of multiple different antibodies (proteins produced by the body to fight off foreign substances) that are associated with both arterial and venous thrombosis (clots in the arteries and veins).

There are two primary classes of antiphospholipid (aPL) antibodies, the antibodies associated with APS. These are called anticardiolipin antibodies and the lupus anticoagulant, and are directed against specific molecules. These aPL antibodies appear to be mainly directed against two particular molecules: beta-2-glycoprotein I (ß2GPI, a normal protein found in the blood whose function is unknown) and another molecule known as prothrombin (a normal blood protein that binds to phospholipids and plays a very important role in blood clotting).

These aPL antibodies were first noted in a group of people who had positive tests for syphilis without signs of infection. It was then noticed that some individuals who continued to have false-positive tests for syphilis went on to develop systemic lupus erythematosus (SLE) and other similar conditions. Later studies found a protein called the lupus anticoagulant in a number of individuals with SLE. A case report in 1956 described an individual with recurrent pregnancy loss, thrombophlebitis (inflammation of a vein related to a blood clot) and lupus anticoagulant. The work of Dr. Graham Hughes and his colleagues in the 1980s provided further understanding of APS, including the introduction of testing for anticardiolipin antibodies.

Up until the 1980s, it was thought that aPL antibodies were directed against a type of molecule known as anionoic phospholipids. However, in the early 1990s, several different groups discovered that this was not the case. Anticardiolipin antibodies were found to act against ß2GPI, while the lupus anticoagulant was first found to act against ß2GPI and, more recently, prothrombin.

There are two main classifications of APS. If the individual has no known underlying autoimmune disorder, the person is said to have primary APS. If the individual has SLE or another underlying autoimmune disorder, the person is said to have secondary APS. Although APS is divided into these two categories, research indicates that there is little essential difference between them.

APS usually shows up for the first time as vascular thrombosis (a blood clot in an artery or vein) or embolism (the blockage of a blood vessel caused by a clot that has moved in the blood stream from the site where it formed to a different place in the body) or as recurrent pregnancy loss. Thrombocytopenia (a low platelet count), certain skin problems, neurological signs, heart valve disease and certain autoimmune diseases have also been noted in association with APS. Pulmonary hypertension (high blood pressure in the arteries that supply the lungs) and sensorineural hearing loss (hearing loss caused by damage to the inner ear or to the nerve pathways from the inner ear) have been noted in some individuals with APS as well.

Conditions associated with APS include:

• Systemic Vascular Thrombosis
  While the deep veins of the legs are the most frequent sites of thrombosis, thromboembolism can involve virtually any vein or artery. Deep vein thrombosis tends to be the most common finding, occurring in half of affected individuals; other sites of venous thrombotic events include the veins of the lungs (due to pulmonary embolism, a clot that typically has dislodged from a vein below the pulmonary veins and lodged in a pulmonary vein), thoracic veins (veins in or above the chest that carry blood to the heart including the superior vena cava, subclavian vein, or jugular vein), and abdominal or pelvic veins.
  
  A risk of recurrent thrombi is associated with APS as well. Most studies suggest that individuals who have a recurrent episode will have it in a similar blood vessel type. For example, individuals who have a stroke initially will most often have a stroke if they have a recurrence. Nonetheless, individuals are reported who have had different types of thrombotic events.

• Pregnancy Loss and Other Complications
  APS is associated with miscarriages as well as other complications of pregnancy. Most studies have estimated the prevalence of aPL antibodies among pregnant women at 5 percent or less; most of these women do not have any signs or symptoms of APS. Around 10-20 percent of women with multiple pregnancy losses are thought to have APS.
  
  Women with APS often have a history of recurrent (usually defined as three or more) pregnancy losses. Pregnancies occurring in women with APS are at significantly increased risk of miscarriage, prematurity, slower than expected growth of the fetus, and preeclampsia (high blood pressure during pregnancy). Pregnant women with APS are also more prone to develop deep vein thrombosis during pregnancy or puerperium (the period between childbirth and the return of the uterus to its normal size).

• Thrombocytopenia
  An association with immune thrombocytopenia (low platelets) has also been established. This occurs to varying degrees in as many as 50 percent of individuals with APS. Because platelets help the blood to clot, thrombocytopenia can sometimes cause a bleeding disorder in an otherwise healthy person. However, in APS, thrombocytopenia is usually moderate and is rarely significant enough to cause bleeding complications or to affect anticoagulant (anti-clotting) therapy.

• Skin Disorders
  Certain skin conditions have also been observed in APS. These include livedo reticularis (mottled discoloration of the skin), ulcers (sores) on the skin, usually on the legs, and sometimes skin necrosis (a condition in which the skin tissue dies).

• Stroke and Other Neurological Disorders
  Stroke is associated with APS, as are some other neurological conditions. In addition to cerebrovascular thrombosis (a blood clot that forms in a blood vessel of the brain), embolic stroke (stroke caused by a blood clot that travels from a different location to a blood vessel in the brain) can also occur. Multiple strokes can sometimes lead to a condition called multi-infarct dementia.
  
  Other neurological problems have been have been reported in people with aPL antibodies, although they are not as strongly associated with APS as stroke. These include seizures, chorea (a movement disorder), migraines, Guillain-Barré syndrome, diabetic peripheral neuropathy, transverse myelitis (a disorder caused by inflammation across both sides of one level, or segment, of the spinal cord), and conditions similar to multiple sclerosis. Evidence for an association with cognitive dysfunction is growing.

• Heart Valve Disease
  A type of heart valve disease called Libman-Sacks endocarditis is sometimes seen in individuals with aPL antibodies. In this condition, growths on the heart valve can break off and travel through the blood stream, causing embolic events.

• Lupus and Other Autoimmune Disorders
  APS is classified within the category of autoimmune disorders (conditions caused by an immune response against the body's own tissues). Individuals with aPL antibodies sometimes have an additional autoimmune disorder, most commonly systemic lupus erythematosus (SLE). About 30-40 percent of individuals with SLE have elevated aPL antibodies. APS has also been associated with a number of other autoimmune disorders, including myasthenia gravis, Graves' disease, autoimmune hemolytic anemia, and Evan's syndrome.

A diagnosis of APS is made based on both clinical and laboratory findings. APS is diagnosed if an individual experiences one or more episodes of thrombosis or pregnancy loss and if aPL antibodies are detected through laboratory testing of the individual's blood.

There are two main types of antiphospholipid antibody tests - immunological tests, like the anticardiolipin ELISA (enzyme-linked immunoassay), and coagulation-based tests for the lupus anticoagulant. ELISAs are immunologically-based tests, or immunoassays, in which an antigen-antibody reaction is used to detect the antibodies. In contrast, lupus anticoagulant tests detect antibodies based on their ability to slow down phospholipid-dependent clotting reactions. Most individuals with APS have antibodies that can be detected in both tests; however, a significant percentage of patients are positive in one test but not the other. Therefore, to diagnose APS, it is standard practice for both tests to be performed. The tests are then repeated six to eight weeks later to confirm the presence of aPL antibodies.

There are no hard and fast statistics about the number of people with aPL antibodies or APS. What we know is based on estimates from different studies over time. Research suggests that aPL antibodies may be found in around 1 to 5 percent of the healthy general population. Primary APS accounts for over 50% of cases. In individuals with SLE, approximately 30 percent have aPL antibodies, and around 30-50 percent of these individuals have symptoms and signs of APS. It is more difficult to measure the number of people with primary APS, but studies indicate that between 5-30 percent of individuals with thrombosis and no history of SLE have aPL antibodies. Additional studies suggest that aPL antibodies may play a role in approximately one-third of strokes in individuals under the age of 50.

A female predominance has been noted, especially for secondary APS. This parallels the association of APS with SLE and other connective-tissue diseases, which also have a female predominance.

If thrombosis occurs in an individual with APS, this usually happens between the ages of 35-45 years. After age 60, signs and symptoms of are APS rarely seen for the first time.

Although APS has been reported to occur in multiple members of the same family, no clear inheritance pattern has been identified and no gene has been found to be the sole cause of this condition. One report in 1999 studied families with more than one affected member, examined possible modes of inheritance, and examined links with certain genes. In seven families, 30 out of 101 family members met diagnostic criteria for the syndrome. The data were fitted best by either a dominant (one copy of the altered gene inherited from one parent causes the condition) or codominant (features related to the condition from both parents are observed) model.

Treatment for APS must be individualized according to the person's current health status and the types of problems that person has experienced due to their APS. In general, for a person who has aPL antibodies and has had a thrombotic event, a short-term course of heparin (an anticoagulant, which is a type of medication used to prevent blood clots from forming or getting bigger) is followed by long-term - sometimes life-long - treatment with warfarin (another type of anticoagulant).

In women with moderate to high levels of aPL antibodies and a history of pregnancy loss who wish to get pregnant again, treatment is again individualized. After consulting with and obstetrician and rheumatologist and/or hematologist, women generally begin treatment with heparin and low-dose aspirin.

For those individuals who have been found to have aPL antibodies but have not had any signs or symptoms of APS, low-dose aspirin is generally recommended by their doctors.

If you or someone you know has been diagnosed with APS, we recommend talking with a health care provider to determine a personalized course of management.

Additional Resources for APS

• APS Foundation of America, Inc.

• National Blood Clot Alliance

• American Autoimmune Related Diseases Association, Inc.

• NINDS Antiphospholipid Syndrome Information Page

• Antiphospholipid syndrome