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Antiphospholipid antibodies

Substances in the blood, called phospholipids, are required for blood to clot. In some people, the body mistakenly identifies phospholipids, or proteins bound to the phospholipids, as foreign substances, and makes antibodies against them. This process can be viewed as a confusion of the immune system, called an autoimmune process. These antibodies are called antiphospholipid antibodies (APLAs; sometimes also abbreviated to ‘aPL’). In some people, these antibodies do not cause any problems, but in others their presence can lead to blood clots and/or pregnancy loss (miscarriage). A person is referred to as having antiphospholipid syndrome (APS) if she or he has had a blood clot or pregnancy loss and a test for APLAs has been positive more than once, measured at least 12 weeks apart (Table 1).Table 1. Revised Sapporo criteria for diagnosing antiphospholipid syndrome (APS).1

Presence of one clinical event AND at least one repeatedly positive lab test
Clinical eventsLab testsa
Blood clot (= thrombosis):
• Venous
 ○ Deep vein thrombosis (DVT) = clot in leg or arm
 ○ Pulmonary embolism (PE) = clot in lung
 ○ Other (in eye = retinal vein thrombosis; around brain = sinus vein thrombosis; in abdomen = mesenteric, portal, or hepatic vein thrombosis)
• Arterial
 ○ Stroke
 ○ Heart attack
 ○ Leg or arm arterial clot (= ischemia or gangrene)
 ○ Other (in eye = retinal artery thrombosis; in abdomen = mesenteric artery thrombosis)
• Lupus anticoagulant in the plasma confirmed with clotting tests that depend on phospholipids
• Anticardiolipin of IgG or IgM isotype, present in medium or higher titer (>40 GPL units or MPL units, or >99th percentile)
• Anti-β2-glycoprotein-I of IgG or IgM isotype (in titer >99th percentile)
• Pregnancy loss defined as one of the followingb
 ○ Three or more losses before the 10th week of pregnancy
 ○ One or more losses at or after the 10th week of pregnancy
 ○ One or more premature deliveries at or before the 34th week of pregnancy because of eclampsia, preeclampsia, or placental insufficiency

a1 Tested twice, at least 12 weeks apart.

b Other possible causes of pregnancy loss or premature delivery should be excluded, such as maternal anatomic causes, hormonal issues, and/or chromosomal abnormalities.

IgG, immunoglobulin G; IgM, immunoglobulin M; GPL, IgG antiphospholipid units; MPL, IgM antiphospholipid units.

Tests for many types of APLAs exist (Table 2), but the most important ones are the anticardiolipin antibodiesanti-β2-glycoprotein-I antibodies, and the lupus anticoagulant tests. The presence of these antibodies may lead to an increased risk of blot clots and/or pregnancy loss. The significance of the other APLAs listed in Table 2 is unclear. They are, therefore, not part of the international consensus diagnostic criteria (called the revised Sapporo criteria – revised in 2006, also referred to as Sydney criteria)1 for APS (Table 1). It is unclear what these other antibodies mean for the patient and testing is, therefore, not recommended.Table 2. Antiphospholipid antibody (APLA) subgroups.

Detected by clotting test (= functional test)Lupus anticoagulant
Detected by tests that measure the level of antibody (IgG, IgM, or IgA) in the bloodAnticardiolipin

IgG, immunoglobulin G; IgM, immunoglobulin M; IgA, immunoglobulin A.

Slightly elevated anticardiolipin antibodies and anti-β2-glycoprotein-I antibodies are probably clinically not relevant; they are sometimes referred to as borderline elevations. Levels need to be at least moderately elevated to be a clearer risk factor for blood clots and pregnancy loss (Table 1).

What are the tests for APLAs?

APLAs can be detected in two ways. One way is to directly measure the amount of the antibody present (i.e. anticardiolipin, anti-β2-glycoprotein-I antibodies). The immune system makes three different forms of these kinds of antibodies, which are referred to as immunoglobulins. The three different immunoglobulins are: immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA). Therefore, three different tests can be performed for each phospholipid. However, only antibodies in the form of IgG and IgM are currently thought to be relevant for the diagnosis of APS. APLA tests are poorly standardized, which causes problems when interpreting the results or comparing results from one coagulation laboratory to another.

The second way to look for the presence of APLAs is to measure the effect the antibodies have on the clotting system in a test tube (lupus anticoagulant or lupus inhibitor tests). A variety of clotting tests are used for this purpose, most commonly the DRVVT-based test and the LA-PTT-based test. Lupus anticoagulants are detected by mixing the patient’s blood with phospholipids and measuring the time that it takes the blood to clot in the tube. The lupus anticoagulant test is one of the most error-prone tests performed in coagulation laboratories. A prudent approach to the report of an abnormal test may be to obtain copies of the test results and have them reviewed by a physician knowledgeable about APLAs.

A person can be diagnosed with APS with only one of the APLA tests positive, or two, or several, as indicated by the individual circles and the overlapping of the circles in Figure 1. Although anticardiolipin antibodies are more common than lupus anticoagulants, the presence of a lupus anticoagulant puts a person at a higher risk of having a clot than does the presence of anticardiolipin antibodies alone. In general, for a person who has anticardiolipin or anti-β2-glycoprotein-I antibodies, the higher the antibody level, the greater the risk of developing a blood clot. A person who is positive for all three tests (anticardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant) – ‘triple-positive’ – has the highest risk for blood clots and pregnancy loss.

Figure 1. Antiphospholipid antibody (APLA) tests and terminology.ACL, anticardiolipin; APS, antiphospholipid syndrome; β2-GP I, anti-β2-glycoprotein-I; LA, lupus anticoagulant; TP, ‘triple-positive’ APLA tests.

What is a lupus anticoagulant?

The term ‘lupus anticoagulant’ (also referred to as ‘lupus inhibitor’) was coined because these antibodies were originally discovered in people with systemic lupus erythematous (SLE or lupus), a specific type of autoimmune disease. However, subsequent studies have shown that at least 50% of people with lupus anticoagulants do not have SLE. The second part of the term, ‘anticoagulant’ (meaning blood thinner), has been used because these APLAs prolong the clotting time in the test tube. However, this term is a misnomer because it leads one to believe that people with lupus anticoagulants are at risk for bleeding when, in fact, they are at risk for clotting.

How does blood normally clot?

The body responds to small injuries in blood vessels by forming small blood clots to prevent bleeding. Blood clots form when proteins and platelets in the blood interact with one another and with the blood vessel wall at the site of an injury. Certain substances, such as phospholipids, must also be present in the blood for the clotting proteins to function properly. The body forms small blood clots in the blood vessels all the time, but a delicate balance prevents overwhelming clot formation. The body also breaks down the small clots that are formed so that they do not cause problems.

How do APLAs lead to blood clots?

We know that APLAs in a test tube cause blood to take longer to clot because the antibodies decrease the number of phospholipids available to help the clotting proteins. So why is it that APLAs within the body actually increase the tendency toward clotting? The mechanisms by which APLAs lead to blood clots are not well understood, but several different mechanisms have been proposed. APLAs may interact with the cells on the inner surface of blood vessels, making them more prone to form blood clots. They may interact with blood platelets, making them stickier and more likely to cause clots. And the APLAs may decrease the body’s natural ability to break up blood clots by interfering with natural clot-busting proteins.

Who develops APLAs?

APLAs can be found in a variety of settings and are associated with autoimmune disorders, certain medications, and medical illnesses (Figure 2). They are also present in some healthy people. In the general population, approximately 1–5% of people have positive APLAs, typically at low levels. About one-third of people with SLE (lupus) have APLAs. In people with spontaneous blood clots in the veins (deep vein thrombosis (DVT) or pulmonary embolism (PE)), up to 30% have elevated APLAs at the time of the blood clot.2 In people with stroke, up to 40% may have some level of positive APLAs at the time of the event.2 These levels can fluctuate over time and either disappear, stay the same, decrease or increase as time goes by. In many people, the antibody identified in their blood disappears (for unclear reasons) over the subsequent several weeks, and, thus, these people do not meet the criteria for APS (Table 1). The presence of APLAs does not necessarily mean that a person will go on to develop lupus or another autoimmune disorder – very often people do not.

Figure 2. Conditions associated with antiphospholipid antibodies.APLAs, antiphospholipid antibodies; APS, antiphospholipid syndrome.

What is primary antiphospholipid syndrome (APS)? What is secondary APS?

As noted above and in Table 1, the term ‘antiphospholipid syndrome’ (APS) is used if a patient has had a blood clot or pregnancy loss and a test for APLAs that has been positive more than once, measured at least 12 weeks apart (Table 1). APS is called ‘primary’ APS when it occurs without an associated autoimmune disorder. APS is called ‘secondary’ APS when it is associated with another condition or autoimmune disorder, such as SLE or rheumatoid arthritis. Of note, only a fraction of people with autoimmune disorders and APLAs will have blood clots and/or pregnancy losses.

Are APLAs inherited?

APLAs are typically not inherited from family members. Instead, they are acquired, meaning that the body simply starts making antibodies at some point, possibly in response to some sort of trigger or a disturbance of the immune system. The children of someone with APLAs are no more likely to develop APLAs than children of people without APLAs. A few families have been reported in which the tendency to form APLAs appears to be hereditary, but this is extremely rare. Nothing is known about the genetic mechanism.

What problems can APLAs cause?

APLAs can cause venous blood clots, arterial blood clots, and problems with pregnancy. APLAs can also be associated with other problems, including low platelets, anemia (low blood count), heart valve disease, skin rashes (livedo reticularis), joint pain, joint inflammation (arthritis), dry eyes, and dry mouth.

APLAs may cause blood clots in veins, usually either a DVT in the leg or a PE in the lung. Less common locations for venous clots include superficial veins (i.e. superficial thrombophlebitis), and veins in the arms, eyes, in or around the brain, and in or around the liver or intestines.

APLAs may also cause blood clots in arteries, including: the brain arteries (stroke), heart arteries (heart attack), or the arteries of the arm, leg, eye, kidney, or intestines. Suspicion for the presence of APLAs in a person with an arterial clot is higher if the person has no obvious risk factor for arterial disease (i.e. has no diabetes, high blood pressure, high cholesterol, or smoking) and is relatively young, such as less than 45–50 years old.

What are the risks of APLAs in pregnancy?

APLAs are present in approximately 10–20% of women with recurrent miscarriages. Women with APLAs have an increased risk of pregnancy loss in the first trimester and also after 10 weeks of pregnancy. APLAs are also associated with other pregnancy complications, including premature delivery, eclampsia, preeclampsia, and placental insufficiency (i.e. problems with the placenta).

A woman is considered to have had a clinical event that meets the revised Sapporo criteria for APS (Table 1) if she has had one of the following: (a) three or more spontaneous losses before the 10th week of pregnancy in the absence of maternal anatomic causes, hormonal issues, or chromosomal abnormalities; (b) one or more unexplained losses at or after the 10th week of pregnancy; or (c) one or more premature deliveries at or before the 34th week of pregnancy because of eclampsia, severe preeclampsia, or placental insufficiency. Other possible causes of pregnancy loss or premature delivery should be ruled out before testing for the presence of APLAs.

What is catastrophic APS?

Most patients with APLAs who develop blood clots will develop them as individual events and possibly have recurrent blood clots at a later time. However, a very small group of people with APLAs develop multiple blood clots in different organ systems throughout the body within a matter of days. This is called catastrophic APS, which is quite rare. Blood clots may occur at the same time in the kidney, the brain, the heart, the arms or legs, the lungs, and/or other organs, with resultant failure of multiple organs and a high risk of dying. The treatments are blood thinners, steroids, a procedure known as plasmapheresis (described below), and possibly medications to suppress the immune system.

Who should be tested for APLAs and when?

People who have had one of the clinical events listed in the revised Sapporo criteria (Table 1) and who do not have other identifiable reasons for blood clots or pregnancy loss can be considered for APLA testing. If they are found to have APLAs, the test should be repeated at least 12 weeks later, and, if positive again, the patient can be categorized as having APS. If the second set of tests is negative (i.e., normal), the person does not have APS and consideration can be given to stopping blood thinners (depending on other circumstances that led to the blood clot). For most people, no additional testing for APLAs is needed if the second set of tests is negative. In general, if the APLA tests at the time of the clinical event (i.e. blood clot or pregnancy loss) are negative, there is no need to recheck for APLAs unless the person later has another clinical event.

How should patients with APLAs be treated if they have no symptoms?

Some people with APLAs will never develop blood clots or experience pregnancy loss. Few data are available regarding the risk of a blood clot or pregnancy loss in an individual with APLAs with no symptoms (‘asymptomatic’). The risk of blood clots in asymptomatic individuals with APLAs is about 1.8% per year compared to 0.1% per year in the general population.3 Patients with ‘triple-positive’ antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein-I) appear to be at highest risk for blood clots, with nearly 40% having a blood clot within 10 years (3.7% per year).4 Unfortunately, low-dose aspirin (81 mg) alone has not been helpful in reducing blood clots in these patients in clinical trials. Currently, blood thinners are not recommended for people with APLAs who have never had a blood clot or pregnancy loss.

Asymptomatic individuals with APLAs should take the following precautions: (a) inform healthcare providers that they have APLAs; (b) consider using short-term blood thinners to prevent a blood clot during situations that increase the risk of developing a clot (i.e. surgery, immobilization); (c) know the symptoms of DVT (swelling, pain, warmth, and/or redness in the leg) and PE (sudden chest pain or shortness of breath); (d) seek medical care immediately if symptoms of DVT or PE develop; and (e) modify their other risk factors for arterial and venous blood clots, including avoiding hormone therapy (such as oral contraceptives or post-menopausal hormone replacement therapy), not smoking, normalizing weight, and controlling blood pressure, cholesterol, and blood sugar.

What is the treatment for venous blood clots (DVT or PE) in patients with APLAs?

Treatment for blood clots in people with APLAs is similar to treatment in people without APLAs.5 Blood thinner medications are typically used and different types are available.


Heparin may be used when the clot is first diagnosed. It is also the treatment of choice in pregnant patients, and, in rare cases, may be preferred as a long-term blood thinner. Types of heparins include injections into the vein of unfractionated heparin or injections into the skin of low-molecular-weight heparin (such as enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®)). Sometimes the heparin-like drug called fondaparinux (Arixtra®) is used, also as a skin injection.


Many people on blood thinners take oral medications called coumarins (warfarin (Coumadin® or Jantoven®); phenprocoumon (Marcumar®, Falithrom®); acenocoumarol (Sinthrome®)). When these drugs are taken, the ‘thinness’ of the blood needs to be closely monitored via a blood test called the International Normalized Ratio (INR). Most people with APLAs and a history of a venous clot should maintain an INR between 2.0 and 3.0.6,7

Direct oral anticoagulants (DOACs)

The DOACs8 are increasingly replacing warfarin (apixaban (Eliquis®); dabigatran (Pradaxa®); edoxaban (Savaysa®); rivaroxaban (Xarelto®)). They are approved for the treatment of venous clots and do not require blood level monitoring. Although DOACs are used in patients with APS, clinical trials directly comparing their performance with warfarin are still ongoing. It is not known at this point whether they are more, equally, or less effective compared to warfarin in patients with APS. It is, therefore, an individualized decision between a physician and patient whether to use warfarin or a DOAC for the treatment of DVT or PE in patients with APS.

For how long should blood thinners be taken after a blood clot?

The risk of having another blood clot in people with APLAs is higher than in people without APLAs, particularly if the patient has a lupus anticoagulant or is ‘triple positive’. While on blood thinners, people with APLAs have a risk of 3–10% over 3 years of having another clot.6,7 If blood thinners are stopped, people with APS have a 10–20% risk per year of having another clot.4,9 For this reason, blood thinners are often continued long-term in people with APLAs who have had a venous clot.

What if the antibodies disappear after a blood clot?

It is not known whether people who have had an APLA-associated blood clot lose their risk for developing another blood clot if the APLAs disappear over time and whether their blood thinner can be discontinued if the APLAs disappear. In the person with APS (by repeatedly positive blood tests), the authors of this article take the approach of rechecking APLAs every 6–12 months. If APLAs are negative on two consecutive tests, then a discussion about the discontinuation of blood thinners can be held, depending on the other circumstances surrounding the previous blood clot. This decision must be individualized for each patient.

What is the treatment for arterial blood clots (heart attack or stroke) in patients with APLAs?

Arterial blood clots are typically treated with medications that make the platelets less sticky and reduce the risk of future clots in the arteries. Examples are aspirin, clopidogrel (Plavix®), and aspirin combined with dipyridamole (Aggrenox®). It is not known whether people with APS and arterial blood clots do better on long-term aspirin or warfarin, or a combination of both. Other risk factors for arterial clots should also be modified, such as controlling blood pressure and cholesterol, losing weight, and stopping smoking.

How should patients with a history of pregnancy loss or pregnancy complications and APLAs be treated during future pregnancy?

Women with APLAs who have had recurrent pregnancy loss meeting revised Sapporo criteria should be treated with preventative doses of a heparin preparation and low-dose aspirin (81 or 100 mg per day) starting when a subsequent pregnancy is confirmed. Treatment increases the percent of successful pregnancies to about 70%.10 For many women, the heparin therapy should be continued even after birth (for 6–12 weeks) since the risk of blood clots does not immediately go away after delivery. If a venous blood clot develops during pregnancy, full dose blood thinners should be used and continued for at least 3 months after pregnancy.

What about immunosuppressants or other therapies?

APLAs are produced by the immune system, so medications that interfere with the immune system are sometimes used to treat people with APLAs. Examples include cyclophosphamide (Cytoxan®), azathioprine (Imuran®), hydroxychloroquine (Plaquenil®), rituximab (Rituxan®), and steroids (e.g. prednisone). These medications may be more beneficial for people who have secondary APS, such as patients with SLE (lupus), but they may also be considered in patients who have recurrent blood clots in spite of being on blood thinners.

Hydroxychloroquine (Plaquenil®)

In addition to its immune effects, this oral medication has some blood-thinning properties and may be a useful additional therapy for patients who have recurrent blood clots despite adequate anticoagulation.

Immunoglobulin (IVIG)

IVIG is a preparation of proteins which is given as an infusion directly into the veins. The benefits of this treatment for people with APLAs have not been well proven.


For some people with APS that is difficult to manage or in cases of catastrophic APS, it may be necessary to remove the APLAs from the blood with a filtering machine. This process is called plasmapheresis or plasma exchange.

Ongoing research

Research regarding APLAs is ongoing. This research may reveal new insights into treatments for people with APLAs and blood clots. For this reason, people with APLAs, particularly those taking long-term anticoagulation, should have regular follow-up with a physician to discuss new data and future plans for medical therapy. Enrolling in clinical trials, when available, helps advance our scientific knowledge of APLAs and improves patient outcomes. A list of clinical trials currently planned or enrolling patients can be found at Ongoing and future clinical trials will help to optimize anticoagulation strategies and improve pregnancy outcomes.

Patient resources

In addition to the Vascular Disease Patient Information Page on venous thromboembolism,5 an informative brochure on DVT and PE for patients with and without APLAs is also available ( Clot Connect is an information program of the University of North Carolina Hemophilia and Thrombosis Center.

The National Blood Clot Alliance is a nationwide, non-profit patient advocacy group representing the interests of people with blood clots and clotting disorders, including people with APS. The NBCA’s mission is to address major treatment issues, such as preventing thrombosis and its complications and reducing death and illness related to thrombosis. The NBCA wants patients to get involved (


Antiphospholipid antibodies (APLAs) are proteins that may be present in the blood and may increase the risk of blood clots and pregnancy loss. Patients with a history of unexplained blood clots or recurrent pregnancy loss may be tested for the presence of APLAs in the blood. If testing for APLAs is positive, repeat testing 12 weeks or more after initial testing is required for the diagnosis of antiphospholipid syndrome (APS).


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