Antiphospholipid Syndrome 

  • Author: Elise Belilos, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 19, 2012
 

Background

Antiphospholipid syndrome (APS) is a disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, predominantly beta-2 glycoprotein I (apolipoprotein H); or evidence of a circulating anticoagulant.

Multiple terms for APS exist. Unfortunately, some synonyms can be confusing. Lupus anticoagulant (LA) syndrome, for example, is misleading because patients with APS may not necessarily have systemic lupus erythematosus (SLE) and LA is associated with thrombotic rather than hemorrhagic complications. In an attempt to avoid further confusion, APS is currently the preferred term for the clinical syndrome (as described below).

Some patients with APS have no evidence of any definable associated disease, while, in other patients, APS occurs in association with SLE or another rheumatic or autoimmune disorder. Traditionally, these have been referred to as primary or secondary APS, respectively. Currently, however, the preferred terminology is APS with or without associated rheumatic disease. Although antiphospholipid (aPL) antibodies are clinically linked to APS, whether they are involved in the pathogenesis or are an epiphenomenon is unclear. (Up to 5% of healthy individuals are known to have aPL antibodies.)

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Pathophysiology

In APS, the homeostatic regulation of blood coagulation is altered; however, the mechanisms of thrombosis are not yet defined. One hypothesis postulates a defect in cellular apoptosis, which exposes membrane phospholipids to the binding of various plasma proteins, such as beta-2 glycoprotein I. Once bound, a phospholipid-protein complex is formed and a neoepitope is uncovered, which subsequently becomes the target of autoantibodies. Recent evidence suggests that oxidized beta-2 glycoprotein I is able to bind to and activate dendritic cells in a manner similar to activation triggered by Toll-like receptor 4 (TLR-4), which could amplify the production of autoantibodies.[1, 2]

Other proposed mechanisms for the hypercoagulable effect of aPL antibodies, which may or may not depend on beta-2 glycoprotein I, include the following:

  • Production of antibodies against coagulation factors, including prothrombin, protein C, protein S, and annexins
  • Activation of platelets to enhance endothelial adherence
  • Activation of vascular endothelium, which, in turn, facilitates the binding of platelets and monocytes
  • Reaction of antibodies to oxidized low-density lipoprotein, thus predisposing to atherosclerosis and myocardial infarction (MI)

Complement activation has been increasingly recognized as a possible significant role in the pathogenesis of APS. Emerging evidence from murine models suggests that APL-mediated complement activation may be a primary event in pregnancy loss.[3]

Clinically, the series of events that leads to hypercoagulability and recurrent thrombosis can affect virtually any organ system, including the following:

  • Peripheral venous system (deep venous thrombosis [DVT])
  • Central nervous system (cerebrovascular accident [CVA], sinus thrombosis)
  • Hematologic (thrombocytopenia, hemolytic anemia)
  • Obstetric (pregnancy loss, eclampsia)
  • Pulmonary (pulmonary embolism [PE], pulmonary hypertension)
  • Dermatologic (livedo reticularis, purpura, infarcts/ulceration)
  • Cardiac (Libman-Sacks valvulopathy, MI)
  • Ocular (amaurosis, retinal thrombosis)
  • Adrenal (infarction/hemorrhage)
  • Musculoskeletal (avascular necrosis of bone)
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Epidemiology

Frequency

United States

The actual frequency of APS in the general population is unknown. One to 5% of healthy individuals have aPL antibodies. aCL antibodies tend to be found more frequently in elderly persons; thus, positive titer results should be interpreted with caution in this population. aPL antibodies are found in approximately 30-40% of patients with SLE, but only about 10% have APS.[4] Approximately half of APS cases are not associated with another rheumatic disease. In a study of 100 patients with confirmed venous thrombosis and no history of SLE, aCL antibodies were found in 24% and LA in 4%.

International

International frequency is probably similar to US frequency.

Mortality/Morbidity

  • APS may contribute to an increased frequency of CVAs or MIs, especially in younger individuals. CVAs may develop secondary to in situ thrombosis or embolization that originates from the valvular lesions of Libman-Sacks (sterile) endocarditis, which may be seen in patients with APS. Cardiac valvular disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary hypertension.
  • Catastrophic APS (CAPS) is a rare, serious, and often fatal manifestation (mortality rate of approximately 50%) characterized by multiorgan infarctions over a period of days to weeks.
  • Late spontaneous fetal loss (second or third trimester) is common; however, it can occur at any time during pregnancy. Recurrent early fetal loss (< 10 weeks’ gestation) is also possible.

Race

  • No defined racial predominance for primary APS has been documented, although SLE is more common in African American and Hispanic populations.

Sex

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

Age

  • APS is more common in young to middle-aged adults; however, it also manifests in children and elderly people. Disease onset has been reported in children as young as 8 months. In an international registry of pediatric APS cases, patients without associated rheumatic disease were younger and had a higher frequency of arterial thrombotic events, whereas patients with associated rheumatic disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.[5]
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Contributor Information and Disclosures
Author

Elise Belilos, MD  Section Head of Rheumatology, Division of Rheumatology, Allergy and Immunology, Winthrop-University Hospital; Assistant Professor of Clinical Medicine, Department of Internal Medicine, State University of New York at Stony Brook

Elise Belilos, MD is a member of the following medical societies: American College of Rheumatology and Arthritis Foundation

Disclosure: Nothing to disclose.

Coauthor(s)

Steven Carsons, MD  Chief, Division of Rheumatology, Allergy, and Immunology, Professor of Medicine, Department of Internal Medicine, Winthrop University Hospital, State University of New York at Stony Brook

Steven Carsons, MD is a member of the following medical societies: American College of Rheumatology, New York Academy of Sciences, and Society for Experimental Biology and Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Carlos J Lozada, MD  Director of Rheumatology Fellowship Program, Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Pfizer Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD  Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

The authors gratefully acknowledge the contributions of Amiel Tokayer, MD.

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Antiphospholipid syndrome. Livedo reticularis.
Antiphospholipid syndrome. Arterial thrombosis resulting in ischemia and necrosis of the foot.
 
 
 
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