Information on the following diseases can be found in the Related Disorders section of this report:

• Polyarteritis Nodosa
• Takayasu Arteritis
• Giant Cell Arteritis
• Lupus
• Anticardiolipin (Antibody) Syndrome
• Stroke
• Essential Thrombocytopenia
• .

The specific symptoms associated with antiphospholipid syndrome are related to the site where the blood clots occur. Blood clots can form in any blood vessel of the body. These clots are twice as likely to form in veins-- the vessels that carry blood to the heart as in arteries-- vessels that carry blood away from the heart. It may affect any organ of the body but the lower limbs, lungs and brain are the most frequently affected sites in the body. APS is also known to cause significant complications during pregnancy.

The severity of APS varies, ranging from minor blood clots that cause few problems to an extremely rare form (catastrophic APS) in which multiple clots form throughout the body. However, in most cases, blood clots will only develop at one site.

When blood clots affect the flow of blood to the brain a variety of issues can development including serious complications such as stroke or stroke-like episodes that are medically known as transient ischemic attacks. In addition, affected individuals may develop migraine headaches, mood alterations, vision problems and cognitive dysfunction such as memory loss or difficulty concentrating. Less frequently, seizures or unusual shaking or involuntary muscle movements may also occur.

Some individuals may develop symptoms that resemble multiple sclerosis including numbness or a sensation of pins and needles, visions abnormalities such as double vision, and difficulty walking.

Blood clots in large, deep veins are commonly referred to as deep vein thrombosis (DVT). The most common site of DVT is the leg, which can become painful and swollen. In some cases, a piece of the blood clot may break off and travel in the bloodstream, on other sites such as lung or the brain.

Skin rash and other skin diseases may occur in people with APS. These include blotchy reddish patches of discolored skin, a condition known as livedo reticularis. In some cases, sores (ulcers) may form on the legs. Lack of blood flow to the extremities can cause loss of living tissue (necrotic gangrene), especially in the fingers or toes.

Additional abnormalities that may occur in individuals with APS include clot like deposits on the valves of the heart (valvular heart disease), which can permanently damage the valves affected individuals may also experience chest pain (angina) and the possibility of a heart at an early age.

Some individuals may also develop low levels of blood platelets, which is also know as thrombocytopenia. Thrombocytopenia associated with antiphospholipid antibodies is usually mild and only rarely causes easy or excessive bruising and prolong bleeding episodes. Affected individuals are also at risk for autoimmune hemolytic anemia, a condition characterized by the premature destruction of red blood cells by the immune system.

In women, APS can cause complications during pregnancy including repeated miscarriages, fetal growth delays (intrauterine growth retardation), and preeclampsia. Preeclampsia is a condition characterized by high blood pressure, swelling and protein in the urine. Symptoms associated with preeclampsia vary greatly, but may include headaches, changes in vision, abdominal pain, nausea and vomiting.

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME (CAPS)
Catastrophic antiphospholipid syndrome is an extremely rare variant of APS in which multiple blood clots affect various organ systems of the body potentially causing life-threatening multiorgan failure. The specific presentation, progression and organs involved vary from case to case. CAPS may develop in a person with primary or secondary APS or in individuals without a previous diagnosis of APS. In some cases, infection, trauma, or surgery appears to trigger the condition.

Antiphospholipid syndrome is an autoimmune disorder of unknown cause. Autoimmune disorders are caused when the body's natural defenses (antibodies, lymphocytes, etc.) against foreign organisms suddenly begin to attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of APS. In rare cases, APS has run in families suggesting that a genetic predisposition to developing the disorder may exist.

The antibodies that are present in APS are known as antiphospholipid antibodies. There are several different types of antiphospholipid antibodies. In APS, two types are most prevalent: lupus anticoagulant and anticardiolipin antibodies. These antibodies were originally thought to attack phospholipids, fatty molecules that are a normal part of cell membranes found throughout the body. However, researchers now know that these antibodies mostly target certain blood proteins that bind to phospholipids. The two most common proteins affected are beta-2-glycoprotein I and prothrombin. The exact mechanism by which these antiphospholipid antibodies eventually lead to the development of blood clots is not known.

APS may occur in patients with another autoimmune disorder, most commonly lupus . These cases are referred to as secondary APS.

Antiphospholipid syndrome affects males and females in equal numbers. It can affect people of all ages and ethnic backgrounds. The median age at presentation is 50, although the syndrome can develop in the teen-age years or in children. The incidence or prevalence of APS in the general population is unknown.

Some estimates suggest that 1 in 5 cases of recurrent miscarriages or deep vein thromboses are actually due to APS. As many as one-third the cases of stroke in people under 50 years of age may be due to APS. Approximately 30-40 percent of individuals with lupus have APS as well.

Symptoms of the following disorders can be similar to those of antiphospholipid syndrome. Comparisons may be useful for a differential diagnosis.

Several rare genetic disorders are characterized by the formation of blood clots (thromboses). These disorders may be collectively referred as the thrombophilias and include protein C deficiency, protein S deficiency, antithrombin III deficiency, and factor V Leiden thrombophilia. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)

Some individuals with APS may be misdiagnosed as having multiple sclerosis (MS) because of the development of similar neurological symptoms. Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) that may be progressive, relapsing and remitting, or stable. The pathology of MS consists of small lesions called plaques that may form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nervous system signals and thus result in a variety of symptoms including eye abnormalities, impairment of speech, and numbness or tingling sensation in the limbs and difficulty walking. The exact cause of multiple sclerosis is unknown. (For more information on this disorder choose "Multiple Sclerosis" as your search term in the Rare Disease Database.)

Lupus (systemic lupus erythematosus) is a chronic, inflammatory autoimmune disorder that can affect various organ systems. In autoimmune disorders, the body's own immune system mistakenly attacks healthy cells and tissues causing inflammation and malfunction of various organ systems. In lupus, the organ systems most often involved include the skin, kidneys, blood and joints. Many different symptoms are associated with lupus, and most affected individuals do not experience all of the symptoms. The initial symptoms may include arthritis, skin rashes, fatigue, fever, , pleurisy, and weight loss. In some cases, lupus may be a mild disorder affecting only a few organ systems. In other cases, it may result in serious complications. (For more information on this disorder, choose "Lupus" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of antiphospholipid syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings (at least one blood clot or clinical finding), and a variety of tests including simple blood tests.

Specialized blood tests called coagulation tests are used to measure blood clotting and can indicate the presence of lupus anticoagulant in the blood. An Enzyme-Linked Immunosorbent Assay (ELISA) test can detect the presence of anticardiolipin antibodies in the blood. Positive tests should be repeated because antiphospholipid antibodies can be present in short intervals (transiently) due to other reasons such as infection or drug use. Borderline negative tests may need to be repeated because individuals with APS have initially tested negative for the antiphospholipid antibodies.

Treatment
Individuals with APS who do not have symptoms may not require treatment. Some individuals may undergo preventative (prophylaxis) therapy to avoid blood clots from forming. For many individuals, daily treatment with aspirin (which thin the bloods and prevents blood clots) may be all that is needed.

Affected individuals are also encouraged to avoid risk factors that increase the risk of a blood clot forming. Such risks include smoking, the use of oral contraceptives, high blood pressure (hypertension), or diabetes. Individuals with repeated thrombotic events may require lifelong anticoagulant therapy.

Individuals with a history of thrombosis or a high-risk of developing thromboses may be treated with drugs that preventing clotting by thinning the blood. These drugs are often referred to as anticoagulants and may include heparin and warfarin (Coumadin).

During pregnancy, women at a high risk for pregnancy loss are treated with heparin, sometimes in combination with low dose aspirin.

In some cases, heart valve damage may be severe and require surgical replacement.

A national registry and tissue repository called the Antiphospholipid Syndrome Collaborative Registry (APSCORE) has been established by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Center on Minority Health and Health Disparities (NCMHD). Biomedical researchers at eight medical centers will collect and update clinical, demographic and laboratory information from patients and make it available to researchers and medical practitioners. For information, contact:

Robert A.S. Roubey, MD
Associate Professor of Medicine
Division of Rheumatology and Immunology, CB "7280
Thurston Building, Room 3330
University of North Carolina
Chapel Hill, NC 27599-7280
(919) 966-0572 (registry phone)
apscore@med.unc.edu

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

An antimalarial drug known as hydroxychloroquine (Plaquenil) is being studied for use in individuals with APS. This drug has proven effective in treating fatigue, skin rashes, and aches and pains in individuals with lupus. The drug also has a mild effect in preventing blood clotting.

Rituximab is a drug that targets certain white blood cells, called B cells. This drug has recently been approved for the treatment of rheumatoid arthritis and is being actively investing in lupus. Recently, a few case reports suggest that rituximab may be helpful in refractory cases of APS. No controlled trials have been performed.

A procedure known as plasmapheresis has been tried in some cases of APS. This procedure is a method for removing unwanted substances (such as antibodies) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness. More research is needed before plasmapheresis can be recommended for use as a potential therapy for individuals with APS.

TEXTBOOKS
Hogan WJ, Nichols WL. Antiphospholipid Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:2.

Lichtman MA, Beutler E, Kipps TJ, Selisohn U, et al. Eds. Williams Hematology. 7th ed. McGraw-Hill Companies. New York, NY; 2006:2009-29.

JOURNAL ARTICLES
Hanly JG. Antiphospholipid Syndrome: an overview. CMAJ. 2003;168:1675-82.

Derkson RHWM, de Groot PG. Clinical consequences of antiphospholipid antibodies. Neth J Med. 2004;62:273-8.

Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome. A systemic review. JAMA. 2006;295:1050-7.

Kamat AV, D'Cruz DP, Hunt BJ. Managing antiphospholipid syndrome in children. Haematologica. 2006;91:167-80.

Cervera R, Asherson RA, Acevedo ML, et al., Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients. Ann Rheum Dis. 2004;63:1312-7.

Misita CP, Moll S. Antiphospholipid antibodies. Circulation. 2005;112:e39-44.

FROM THE INTERNET
Tektonidou M. Antiphospholipid Syndrome. Orphanet encyclopedia, September 2003. Available at: http://www.orpha.net/data/patho/Pro/en/Antiphospholipid-FRenPro5517.pdf Accessed on: March 9, 2007.

Carsons S. Antiphospholipid Syndrome. Emedicine Journal, December 5, 2004. Available at: http://www.emedicine.com/med/topic2923.htm Accessed on: March 9, 2007.