Vicki A. Ramsey-Williams, MD, PhD

Gretchen E. Tietjen, MD

DESCRIPTION

Antiphospholipid syndrome (APS) is an autoimmune condition associated with thrombotic events, thrombocytopenia, and recurrent fetal loss in the presence of circulating antiphospholipid antibodies (aPLs). APS can be primary or secondary to connective tissue disorders such as systemic lupus erythematosus (SLE), infectious diseases, or neoplastic disorders. Neurological manifestations of APS are variable and are most often due to recurrent cerebral ischemia (1).

EPIDEMIOLOGY

Incidence

The incidence of APS increases with age and chronic disease.

Prevalence

The prevalence of aPLs in the population is 2–5%, with the majority of subjects being asymptomatic.

RISK FACTORS

• SLE
• Race
  • While APS is less common in African-Americans, IgA and IgM anticardiolipin antibody (aCL) isotypes appear to be more prevalent in this subgroup.
• Age
  • Although the syndrome is more common in younger patients, 27% of patients with APS are over 60. It is estimated that 20–30% of young adults with thromboembolic events have positive aCLs and/or lupus anticoagulant (LA), and 7–10% of total patients with stroke are aPL positive if all ages are considered. Clinical manifestations of APS occur at a mean age of 31 years.
• Sex
  • The female-to-male ratio varies from 1.5–2:1 in primary APS up to 9:1 in patients with APS associated with SLE.

Pregnancy Considerations

aPLs can cause early and late spontaneous abortion. Pregnant women with APS are at increased risk of pre-eclampsia and placental insufficiency.

Genetics

• Familial aPLs positivity has been linked to HLAs DR7, DR4, DQw7, and DRw53. Familial coexistence has been linked to factor V Leiden mutation.
• An HLA-DQB1 sequence, called TRAELDT, may represent an autoantibody predisposing ‘candidate epitope’ in patients with connective tissue disorders.

ETIOLOGY

• APS is linked to the presence of aPLs—acquired antibodies against anionic phospholipid containing moieties in cell membranes. LA and aCL, especially the IgG isotype, were identified as risk factors for ischemic strokes. Although the mechanism of thrombosis is uncertain, it is believed that aPLs promote platelet aggregation and disruption of coagulation cascade with subsequent inhibition of the production of prostaglandin E₂—a potent vasodilator.
• The binding of aCL phospholipid is dependent on the presence of a β₂-glycoprotein (β₂-GPI), a plasma protein with high affinity to anionic phospholipids, creating an immunologic reaction that may lead to thrombosis.
• APL can interfere with protein C activity and decrease protein S levels, leading to inhibition of plasminogen activator protein.

COMMONLY ASSOCIATED CONDITIONS

• Frequent (>20% of cases) (1)[C]
  • Venous thromboembolism
  • Thrombocytopenia
  • Miscarriage or fetal loss
  • Stroke or transient ischemic attack
  • Migraine
  • Livedo reticularis
• Less common (10–20% of cases)
  • Heart valve disease
  • Pre-eclampsia or eclampsia
  • Premature birth
  • Hemolytic anemia
  • Coronary artery disease
• Unusual (<10% of cases)
  • Epilepsy
  • Vascular dementia
  • Chorea
  • Retinal artery or vein thrombosis
  • Amaurosis fugax
  • Pulmonary hypertension
  • Leg ulcers
  • Digital gangrene
  • Osteonecrosis
  • APS nephropathy
  • Mesenteric ischemia
• Rare (<1% of cases)
  • Adrenal hemorrhage
  • Transverse myelitis
  • Budd–Chiari syndrome

[Outline]

• Information
• Description
• Epidemiology
  • Incidence
  • Prevalence
• Risk Factors
  • Pregnancy Considerations
  • Genetics
• Etiology
• Commonly Associated Conditions

DIAGNOSTIC TESTS AND INTERPRETATION

Primary APS occurs without an identifiable cause and is characterized by the diagnostic criteria below. Secondary APS occurs in the setting of an autoimmune disorder, most commonly SLE.

Lab

Initial Lab Tests

• APS is present if at least one of the following clinical and one lab criteria are met (2)[C]:
  • Clinical criteria:
    • Vascular thrombosis, arterial or venous.
    • Obstetric morbidity including (a) fetal death at or beyond 10 weeks’ gestation, (b) premature birth before 34 weeks’ gestation due to eclampsia or placental insufficiency, or (c) 3 or more consecutive spontaneous abortions before 10 weeks’ gestation.
  • Laboratory criteria:
    • LA+ in plasma ≥2 occasions at least 12 weeks apart.
    • ACL IgG and/or IgM+ in serum or plasma at medium or high titer ≥2 occasions at least 12 weeks apart.
    • Anti-B₂ glycoprotein IgG and/or IgM+ in serum or plasma with titer >99 percentile ≥2 occasions at least 12 weeks apart.
• Hematologic abnormalities that may be associated with APS include:
  • Thrombocytopenia (26–31%)
  • Prolonged aPTT (50%)
  • Positive Coombs’ test
  • False-positive rapid plasma reagin or venereal disease research laboratory
  • Neutropenia
  • Lymphopenia
  • Decreased C₄ levels

Follow-Up & Special Considerations

• Persistently positive antibody titers after 12 weeks is required for diagnosis.
• Phenothiazines may induce aPLs.

Imaging

Initial Approach

• CT and MRI findings are nonspecific. At least 50% of patients with APS will show a single lesion on CT, and about half this number will have multiple infarcts. Less common findings include white matter abnormalities, cortical atrophy, and venous sinus thrombosis.
• Conventional cerebral angiography, CT angiography, or magnetic resonance angiograph may show evidence of intracranial stenosis in 40% of patients, half of which are in the middle cerebral artery branches. Only 22% of patients may show extracranial lesions. Dural sinus thrombosis is a common finding. Rarely, the angiogram picture may be suggestive of vasculitis.

DIFFERENTIAL DIAGNOSIS

APS should be considered in patients with cryptogenic stroke. Other causes of unexplained arterial or venous thrombosis should be excluded:

• Protein C or S deficiency
• Homocystinuria
• Antithrombin III deficiency
• CNS vasculitis
• Coagulation factors disorders
• Factor V Leiden mutation
• Sickle cell disease
• Underlying malignancy with hypercoagulability
• Conditions associated with transient elevation of aPLs, such as AIDS, neuroleptic agents (in particular phenothiazines), recombinant tissue plasminogen activator (rt-PA), aging (50% of patients over 80 are aPLs positive), and insulin-dependent diabetes mellitus
• aPLs positivity in patients with multiple sclerosis without APS ranges from 8 to 33%

[Outline]

• Diagnostic Tests and Interpretation
  • Lab
    • Initial Lab Tests
    • Follow-Up & Special Considerations
  • Imaging
    • Initial Approach
• Differential Diagnosis

• Asymptomatic patients with aPLs do not benefit from low-dose aspirin for prophylaxis of thrombosis, but may develop vascular events if additional thrombosis risk factors are present (3)[C].
• Secondary prophylaxis: Antiplatelet agents or anticoagulants depending on patient risks.

MEDICATION

First Line

• Antiplatelet agents
  • Aspirin: Aspirin reduces the risk of stroke recurrence by inhibiting platelet aggregation through inhibition of endothelial prostacyclin synthesis. Aspirin can be used in variable doses of 81 to 1,300 mg in patients with a single thromboembolic event and positive aCLs (4,5)[A].
  • Other antiplatelet agents: Ticlopidine, clopidogrel, and dipyridamole have not been studied in the aCL-positive subgroup of stroke patients (5)[C].
• Anticoagulants
  • Warfarin is an effective therapy for recurrent thromboembolic events, with an international normalized ratio aim of 2–3 (5)[B]. Abrupt discontinuation of warfarin may increase the probability of recurrent thrombosis. A combination of aspirin and warfarin has been used for patients with recurrent events on warfarin alone (4)[B].
  • Heparin: High doses of unfractionated heparin or low molecular weight heparin appear to be efficacious in protecting against recurrent thrombosis.
• Thrombolytics
• Alteplase rt-PA has been successfully used in patients with APS and can be used in selective patients with acute stroke.
• Contraindications: Known hypersensitivity reactions for any of the above drugs. Warfarin is contraindicated in those with active or potential sources of bleeding or frequent falls.

Second Line

• Plasma exchange
  • Plasma exchange may lower the level of circulating antibodies; repeated exchanges may be required to avoid a rapid rise in aPLs titers. May be helpful in catastrophic APS (CAPS).
• Steroids
  • There is no conclusive evidence that steroids are beneficial in aCL-positive stroke patients. Its use in pregnant women is associated with decreased incidence of fetal loss, especially in patients with SLE.
• Immunoglobulin therapy
  • The role of intravenous immunoglobulin in APS is not well understood but is thought to bind to endothelial receptors, prohibiting the interaction of aPLs with their targets. Immunoglobulin therapy may cause thrombosis especially in elderly patients or those with other risk factors for thrombosis.
• Immunosuppressive agents
  • Azathioprine, cyclophosphamide, and methotrexate, with or without corticosteroids, have been used in refractory APS, with decreased aCL titers and LA activity.

ADDITIONAL TREATMENT

General Measures

• Some studies suggest that combination therapy with anticoagulants and antiplatelet therapy has shown to be more effective in secondary prevention of stroke in APS patients (2)[C].
• Control of risk factors
  • Avoid smoking, excessive alcohol intake, and oral contraceptive pills.
  • Management of blood pressure.

COMPLEMENTARY AND ALTERNATIVE THERAPIES

• Fish oil derivatives may help in preventing recurrent miscarriage in APS women.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

Admission is required for the management of acute stroke or neuropsychiatric symptoms.

[Outline]

• Information
• Medication
  • First Line
  • Second Line
• Additional Treatment
  • General Measures
• Complementary And Alternative Therapies
• In-Patient Considerations
  • Initial Stabilization

Patient Monitoring

• Patients should be reevaluated for new neurological complaints. Those on warfarin require routine monitoring of coagulation parameters.

PATIENT EDUCATION

• Patients should be educated regarding symptoms and signs of stroke and to consult with their physician regarding treatment or monitoring during pregnancy.

PROGNOSIS

• The disease duration is thought to be longer in secondary APS. The rate of recurrence of stroke or transient ischemic attack in patients with APS is 35–50%.
• A long-term study of primary APS patients showed that 8% develop SLE, 5% developed lupus-like disease, and 1% developed myasthenia gravis.

[Outline]

• Patient Monitoring
• Patient Education
• Prognosis

• Castro-Marrero J, Balade E, Villardel-Tarres M. Genetic risk factors of thrombosis in the antiphospholipid syndrome. Br J Haematol 2009;147(3):289–296.

SEE-ALSO

• Hughes’ syndrome
• Asherson's syndrome

ICD9

• 289.81 Primary hypercoagulable state
• 434.91 Cerebral artery occlusion, unspecified with cerebral infarction
• 435.9 Unspecified transient cerebral ischemia

• APS is associated with arterial and venous thrombosis.
• APS may be treated with antithrombotics or anticoagulants.
• Treatment is important in order to avoid sequelae of the condition including stroke and fetal loss.

1. Ruiz-Irastorza G, Crowther M, Branch W, et al. Antiphospholipid syndrome. Lancet 2010;376(9751):1498–1509.
2. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.
3. Erkan D, Harrison M, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome. Arthritis Rheum 2007;56(7):2832–2891.
4. Okuma H, Kitagawa Y, Yasuda T, et al. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci 2009;7(1):15–18.
5. Sacco RL, Adams R, Albers G, et al. Guideline for prevention of stroke in patients with ischemic stroke or transient ischemic attack. A statement for healthcare professionals from the American Heart Association/America Stroke Association Council. Stroke 2006;37:577–617.