eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Antiphospholipid Antibody Syndrome

Author: Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Contributor Information and Disclosures

Updated: Aug 23, 2007

Introduction

Background

Antiphospholipid (aPL) antibodies have been found in association with clinical symptoms such as deep venous thrombosis, arterial occlusive events (eg, stroke, myocardial infarction), and recurrent fetal loss. They are also associated with vasospastic phenomena such as migraine headache, Raynaud phenomenon, and transient ischemic attack (TIA).

The terminology associated with aPL antibodies has been fraught with misnomers. Conley and Hartmann observed a prolongation in the prothrombin time (PT) in a series of patients with systemic lupus erythematosus (SLE), which was later termed the "lupus anticoagulant" (LAC). This term is misleading for the following reasons:

  • The LAC phenomenon can be caused by any number of antibodies to the phospholipid template of the coagulation cascade. 
  • These antibodies are frequently found outside the clinical spectrum of SLE.
  • Although these antibodies are responsible for a prolongation of the activated partial thromboplastin time (aPTT) in vitro, they are associated with a hypercoagulable state in vivo.
In the early 1980s, Harris identified anticardiolipin antibodies in a subset of these patients. Since that time, antibodies to phospholipids alone have been determined to be associated with infectious causes more often. In contrast, antibodies to combinations of phospholipids and serum proteins (eg, b 2-glycoprotein I [b 2-GPI] or prothrombin) are more likely associated with the vasculopathic events of antiphospholipid syndrome (APS).

aPL antibodies associated with vaso-occlusive events without any underlying disease process is termed the primary antiphospholipid syndrome (PAPS). The presence of aPL antibodies and a vaso-occlusive event superimposed on an underlying disease, such as SLE or malignancy, is a secondary antiphospholipid syndrome.

Preliminary classification criteria for "definite" APS were proposed in a report from the Eighth International Symposium on Antiphospholipid Antibodies and were published in Arthritis and Rheumatism.1

The purpose of the report was to define the essential features of APS in order to facilitate studies of treatment and causation. This definition was intended to encompass the clinical and laboratory features most closely associated with aPL in prospective studies based on the strongest experimental evidence. The hope was to use the "cleanest" patient populations for basic research and clinical treatment studies. These criteria were not meant to supplant the physician's clinical judgment in making the diagnosis in any particular patient. Although features such as migraine headache, peripheral vasospasm, and thrombocytopenia were excluded from the published criteria, they were argued to be valid and useful clinical parameters in arriving at the diagnosis of APS in the clinical setting at the Ninth International Symposium on Antiphospholipid Antibodies.

In a consensus conference held at the 11th International Symposium on Antiphospholipid Antibodies, existing evidence on clinical and laboratory features of APS was appraised and amendments to the Sapporo criteria were proposed. The criteria were reiterated to be used for clinical research to define homogenous populations for studies. Therefore, in order to address the needs of clinicians and to expand the data for future research, the discussion included definitions on features of APS that were not included in the updated criteria for use clinically and in research. These were published as the "International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome (APS)" in J Thrombosis Haemost.2

Updated Clinical Criteria

  • Vascular thrombosis - One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ confirmed by imaging studies, Doppler studies, or histopathology (without significant vessel wall inflammation) 
  • Pregnancy morbidity (normal morphology on ultrasonography or direct examination findings)
    • One or more unexplained fetal deaths at more than 10 weeks’ gestation
    • One or more premature births at less than 34 weeks’ gestation due to severe preeclampsia, eclampsia, or placental insufficiency 
    • Three or more unexplained consecutive spontaneous abortions at less than 10 weeks’ gestation, excluding maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes

In research studies of patient populations that contain more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify subjects according to the 3 groups above.

Updated Laboratory Criteria

  • Anticardiolipin (aCL) antibody of the immunoglobulin G (IgG)/immunoglobulin M (IgM) isotype in medium/high titer (>40 IgG phospholipid units [GPL], >40 IgM phospholipid units [MPL], or >99th percentile) on 2 or more occasions at least 12 weeks apart (measured by a b 2-GPI–dependent enzyme-linked immunosorbent assay [ELISA]). 
  • Lupus anticoagulant on 2 or more occasions at least 12 weeks apart, according to the guidelines set forth by the International Society of Thrombosis and Hemostasis.
    • Prolonged phospholipid-dependent coagulation (eg, aPTT, Kaolin clotting time [KCT], dilute Russell viper venom test, dilute PT)
    • Failure to correct the prolonged coagulation time by a mix with platelet poor plasma (PPP)
    • Shortening or correction of the prolonged coagulation time with excess phospholipid
    • Exclusion of other coagulopathies (eg, factor VIII inhibitor, heparin)

Investigators are strongly advised to classify patients with APS into one of the following categories:

  • Patients with more than 1 laboratory criteria (any combination)
  • Patients with LAC present alone
  • Patients with aCL antibody present alone
  • Patients with anti-b 2-glycoprotein-I antibody present alone

A patient must meet at least one clinical and one laboratory criterion for a diagnosis of APS. Classification of APS should be avoided if less than 12 weeks or more than 5 years separate a positive aPL test and the clinical manifestation.

Patients with APS participating in research studies should be further grouped according to the presence or absence of additional risk factors for thrombosis. Patients should not be excluded from APS trials because of coexistent inherited or acquired factors for thrombosis.

Patients with APS participating in research studies who fulfill the revised classification criteria should be classified separately from patients with “features associated with APS” or with “noncriteria features of APS.” These features, which were discussed by the consensus panel but not included in the revised criteria, include the following:

  • Heart valve disease
  • Livedo reticularis
  • Thrombocytopenia
  • Nephropathy
  • Neurological manifestations
  • Immunoglobulin A (IgA) aCL
  • IgA anti-b 2GPI
  • Antiphosphatidylserine antibodies
  • Antiphosphatidylethanolamine antibodies
  • Antibodies against prothrombin alone
  • Antibodies to the phosphatidylserine-prothrombin complex

Pathophysiology

The mechanism or mechanisms by which the antiphospholipid antibodies interact with the coagulation cascade to produce clinical events are largely speculative and have not been clearly elucidated. The presence of preexisting or coincident vascular (endothelial) damage along with the identification of an aPL antibody as requisites for the emergence of a thrombotic complication has been coined the "2-hit" hypothesis.
  • Possible mechanisms by which aPL may induce thrombotic events include the following:
    • aPL may combine with platelet membrane phospholipids, resulting in increased platelet adhesion and aggregation.
    • aPL may combine with the endothelial cell membrane phospholipids along with b 2-GPI and induce endothelial cell damage, impaired prostacyclin production, increased platelet adhesion, and aggregation. 
    • Endothelial cell damage may also result in decreased production of endothelium-derived relaxing factor and, thus, increased vasospasm and ischemia.
    • In secondary APS, vascular endothelial cell damage has already occurred, enhancing the vascular spasm/occlusion, ischemia/infarction, and reperfusion injury.
    • b 2-GPI may be bound up by aPL and (1) prevented from covering up exposed procoagulant inner membrane leaflet phospholipids or (2) blocked from inhibiting platelet prothrombinase activity.
    • b 2-GPI and oxidized low-density lipoprotein (LDL) complexes may be bound up by aPL, cleared by macrophages, and, thus, promote accelerated development of atherosclerosis in autoimmune patients.
    • aPL may interfere with the interaction of coagulation protein C and coagulation protein S and, thus, affect the formation of the APC coagulation control complex (activated protein C, protein S, and factor V).
  • Possible mechanisms by which aPL might be generated include the following:
    • Autoimmunity may be a factor; a break in tolerance may lead to an "escaped clone."
    • Closely related to the previously mentioned mechanism is the concept that aPL antibodies are a response to inner membrane leaflet antigens (ie, phosphoserine) that are exposed in apoptotic blebs on cells not eliminated from the circulation because of an overloaded or defective clearance system.
    • aPLs may also be cross-reactive antibodies induced by exogenous antigens from infectious organisms (eg, viral or bacterial).

Frequency

United States

aPL antibodies are reportedly present in 1-15% of the general population (higher in elderly persons). These antibodies are believed to be present in as many as 70% of patients with SLE; however, the frequency rate of APS (ie, aPL antibodies plus a clinical event) is far lower. In patients with SLE, a history of thrombosis was reported in 61% of those with positive test results for LAC, in 52% of those who had positive anticardiolipin antibodies, and 24% of those who had no aPL antibodies.

International

No major differences have been noted between frequency rates in the United States and frequency rates worldwide. A large multicenter European SLE registry suggests that 3-7% of patients with SLE and aPL are at risk for new-onset thrombosis.

Mortality/Morbidity

Mortality and morbidity are related to clinical manifestations. An increased incidence of the following is seen in young individuals:

  • Cerebrovascular accident (CVA), stroke 
  • Myocardial infarction (MI)
  • Endocarditis (may lead to valvular replacement) 
  • Pulmonary emboli (may lead to pulmonary hypertension) 
  • Deep vein thrombosis (DVT)
  • Fetal loss from second trimester to the perinatal period, including intrauterine growth retardation (IUGR), prematurity, and symptoms of toxemia
  • Catastrophic APS (Multisystem failure secondary to thrombosis, infarction, or both may lead to death in 50% of cases.)

Race

Overall, no specific race predilection has been observed.

  • The frequency rate of PAPS is skewed by race predilection of risk factors for thrombosis and atherosclerotic disease.
  • The frequency of secondary APS is skewed by race predilection for autoimmune diseases.

Sex

  • In secondary APS, the frequency rate is skewed by the female predominance in autoimmune diseases (eg, SLE) in general.
  • In PAPS, the frequency rate is skewed by the inclusion of pregnancy-related events in the classification schema.
  • In both APS and PAPS, the frequency rate related to sex is equalized in young patients, especially prior to the onset of puberty.

Age

  • APS has been described in patients of all ages. The prenatal, perinatal, and neonatal periods can be affected.

Clinical

History

Vasospastic or vaso-occlusive events can occur in any organ system; thus, a thorough history should be taken, and an organ-specific review of systems should be performed. A broad spectrum of involvement ranging from rapidly progressive to clinically silent and indolent may be present.

  • Head, ears, eyes, nose, and throat
    • Blurred or double vision
    • Visual disturbance ("wavy lines,” “flashing lights")
    • Visual loss (field cuts, total vision loss)
  • Cardiorespiratory
    • Chest pain
    • Radiating arm pain
    • Shortness of breath
  • Gastrointestinal
    • Abdominal pain
    • Abdominal distension (bloating)
    • "Abdominal migraine"
    • Emesis
  • Peripheral vascular
    • Leg pain
    • Leg swelling
    • Claudication
    • Digital ulcerations
    • Leg ulcerations
    • Cold-induced finger pain, toe pain, or both
  • Musculoskeletal
    • Bone pain
    • Joint pain
  • Cutaneous
    • Purpuric rashes, petechial rashes, or both
    • Persistent or transient lacy rashes of livedo reticularis
    • Dusky fingers, dusky toes, or both
    • Blanching of fingers, blanching of toes, or both
  • Neurologic and psychiatric
    • Syncope
    • Seizures
    • Headache (migraine)
    • Paresthesias
    • Paralysis
    • Ascending weakness
    • Tremors
    • Abnormal movements
    • Memory loss
    • Problems with concentrating, reading comprehension, calculations (change in school performance)
  • Endocrine - Weakness, fatigue, arthralgia, abdominal pain (Addisonian features)
  • Genitourinary/renal
    • Hematuria
    • Peripheral edema
  • Pregnancy-related history - Not expected to be of frequent concern in the field of pediatrics but may be significant in teenagers
  • Family history
    • A strong family history is more pertinent to most pediatric patients and may assist in identifying patients at risk.
    • Family history may include the following:
      • Frequent miscarriage, premature birth, IUGR, oligohydramnios, chorea gravidarum, placental infarction, preeclampsia, toxemia of pregnancy, or neonatal thromboembolism
      • MI or stroke in persons younger than 50 years 
      • DVT, phlebitis, or pulmonary embolus 
      • Strong family history of migraine, Raynaud phenomenon, or TIAs
  • Medication history - Use of oral contraceptives at the time of a clinical event

Physical

Physical findings are specific to the affected organ and can involve any organ system. Catastrophic antiphospholipid syndrome (APS) is a multisystem failure secondary to thrombosis, infarction, or both and has a picture of microangiopathy on histology.

  • Peripheral vascular
    • Point tenderness to palpation of bone or joints (bone infarction)
    • Pain on range of motion of joints without arthritis (avascular necrosis)
    • Limb swelling (DVT)
    • Peripheral edema (DVT, renal vein thrombosis)
    • Decreased capillary refill (arterial thrombosis, vasospasm)
    • Decreased pulses (arterial thrombosis, vasospasm)
    • Decreased perfusion (arterial thrombosis, vasospasm)
    • Gangrene (arterial thrombosis, infarction)
  • Pulmonary - Respiratory distress, tachypnea (pulmonary embolism [PE], pulmonary hypertension)
  • Renal
    • Hypertension (renal artery thrombosis, intrarenal vascular lesions)
    • Hematuria (renal vein thrombosis)
    • Acute renal insufficiency (intrarenal vascular lesions) (see Media files 10-12)
  • Cardiac
    • Insufficiency murmur of aortic, mitral valve (endocarditis)
    • Chest pain, diaphoresis (MI)
  • Gastrointestinal
    • Right upper quadrant tenderness, hepatomegaly (Budd-Chiari syndrome, hepatic small vessel thrombosis, hepatic infarction) 
    • Abdominal tenderness (mesenteric artery thrombosis)
  • Endocrine - Muscle weakness, progressive stiffening of pelvic and thigh muscles with flexion contractures associated with adrenal insufficiency (adrenal infarction/hemorrhage)
  • Ocular  
    • Retinal artery occlusion
    • Retinal vein thrombosis
    • Skin manifestations
    • Livedo reticularis (see Media files 1-2)
    • Purpuric lesions (see Media file 14)
    • Superficial thrombophlebitis
    • Vasospasm (ie, Raynaud phenomenon) (see Media file 3)
    • Splinter hemorrhages (periungual, subungual) (see Media file 4)
    • Peripheral infarctions (digital pitting)
    • Skin ulcerations (eg, leg ulcers)
    • Petechiae (associated with thrombocytopenia) (see Media files 13-14)
    • Bruising (associated with thrombocytopenia)
  • Central or peripheral nervous system abnormalities
    • Stroke, CVA
    • TIA
    • Paresthesia, polyneuritis, or mononeuritis multiplex (vasovasorum ischemia/infarction)
    • Paralysis, hyperreflexia, weakness (transverse myelitis, Guillain-Barré syndrome)
    • Movement disorders - Choreiform tremors (cerebral, cerebellar, basal ganglia infarction)
    • Multiple sclerosis–like disorder
    • Learning disability
    • Short-term memory loss

Causes

The causes of APS are unknown (see Pathophysiology).

The association of thrombotic events with preexisting or coincident vascular perturbation is emphasized by the high incidence of APS in patients with the following conditions:

  • Vascular inflammation, vasculitis
    • Autoimmune disease (eg, SLE, cryoglobulinemia)
    • Infectious processes (eg, hepatitis, parvovirus, syphilis)
  • Malignancy (eg, carcinoma, leukemia)
  • Vascular trauma
    • Postsurgery (eg, cardiac)
    • Trauma (eg, accidental)
  • Drug-induced state (eg, procainamide, phenytoin, hydralazine, chlorpromazine)
  • Hemodialysis-associated condition (increased aPL antibodies over time on dialysis)
    • Cuprophane membrane exposure
    • Oxidative stress

More on Antiphospholipid Antibody Syndrome

Overview: Antiphospholipid Antibody Syndrome
Differential Diagnoses & Workup: Antiphospholipid Antibody Syndrome
Treatment & Medication: Antiphospholipid Antibody Syndrome
Follow-up: Antiphospholipid Antibody Syndrome
Multimedia: Antiphospholipid Antibody Syndrome
References
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Further Reading

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Keywords

anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome, antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon syndrome, Sneddon's syndrome, thrombosis, primary antiphospholipid syndrome, PAPS, secondary antiphospholipid syndrome, antiphospholipid, aPl, deep venous thrombosis, arterial occlusive events, migraine headache, Raynaud phenomenon, transient ischemic attack, TIA, systemic lupus erythematosus, SLE, lupus anticoagulant, LAC, migraine headache, peripheral vasospasm, thrombocytopenia, anticardiolipin antibody, aCL antibody, cerebrovascular accident, myocardial infarction, endocarditis, pulmonary emboli

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Contributor Information and Disclosures

Author

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David D Sherry, MD, Director, Clinical Rheumatology, Attending Physician, Pain Management, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania
David D Sherry, MD is a member of the following medical societies: American College of Rheumatology and American Pain Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Steven R Neish, MD, SM, Director of Pediatric Cardiology Fellowship Program, Associate Professor, Department of Pediatrics, Baylor College of Medicine
Steven R Neish, MD, SM is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and American Heart Association
Disclosure: Nothing to disclose.

 
 
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