About the Condition

Description/definition:

The antiphospholipid syndrome (APS) is an acquired systemic autoimmune multisystem disorder characterized by arterial, venous, or small vessel thromboembolic events and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPLs), a heterogenous group of autoantibodies which are directed against phospholipid-binding proteins.

Classification of APS:

  • By presence of other clinical conditions:
    • Primary:
      • Occurs with no underlying systemic autoimmune disease.
      • Approximately half of patients with APS.
    • Secondary:
      • Occurs with concomitant systemic autoimmune disease.
      • Systemic lupus erythematosus (SLE) is the disease most commonly associated with APS:
        • SLE is present in approximately 35 percent of cases of APS.
        • Secondary APS present in approximately 20% and 30% of patients with SLE.
  • According to predominant clinical phenotype:
    • Thrombotic APS – characterized by venous, arterial, or microvascular thrombosis.
    • Obstetrical APS- characterized by fetal loss after the 10th week of gestation, recurrent early miscarriages, intrauterine growth restriction, or severe preeclampsia.
    • Catastrophic APS (CAPS) – a rare and life-threatening form of the disease, defined as intravascular thrombosis affecting ≥ 3 organs or systems and/or tissues simultaneously or within 1 week.

Prevalence

The estimated prevalence of APS is 1 in 2000 of the general population.

Among patients without autoimmune disease, the prevalence of antiphospholipid-antibody positivity is:

  • 6% among women with pregnancy complications
  • 10% among patients with venous thrombosis
  • 11% among patients with myocardial infarction
  • 17% among patients with stroke who are younger than 50 years of age

About 10% percent of healthy blood donors are positive for anticardiolipin antibodies, and 1% are positive for lupus anticoagulant. However, after 1 year, less than 1% are still positive for these tests.

Pathophysiology:

In the antiphospholipid syndrome (APS), the major target of antiphospholipid antibodies is β2-glycoprotein I (β2 GPI), a plasma protein that binds avidly to phospholipid surfaces, even more so when dimerized by binding to an anti-β2 GPI antibody.

A key initiating pathogenic process is the exposure of negatively charged endothelial surface phospholipid. Exogenous and circulating β2GP1 can bind to this phospholipid surface and change its conformation, exposing a cryptic Arg39-Arg43 epitope in domain I that is recognized by pathologic aPL.

The binding of antiphospholipid antibodies to β2 GPI on cellular surfaces up-regulates the expression of prothrombotic cellular adhesion molecules such as E-selectin and tissue factor. Furthermore, the binding of antiphospholipid antibody to β2 GPI suppresses the activity of the tissue factor pathway inhibitor

aPL are pathogenic, not just diagnostic for APS.

Clinical Presentation

Thrombotic antiphospholipid syndrome (APS):

  • Thromboses are the hallmark of APS.
  • APS is one of the few clinical conditions in which patients can present with both venous and arterial thrombosis.
  • The risk of both venous and arterial thrombosis and/or thromboembolism is increased in individuals with positive tests for lupus anticoagulant (LA) activity (odds ratio [OR] 11) or with medium or high levels of anticardiolipin antibodies (aCL; OR 1.6).
  • Venous thromboses are more common than arterial thromboses.
    • Patients with venous thromboembolism most commonly present with lower-extremity deep-vein thrombosis, pulmonary embolism, or both.
    • Stroke and transient ischemic attack are the most common arterial events in patients with APS.

Obstetrical APS:

  • Characterized by:
    • Fetal loss after the 10th week of gestation (losses before 10 weeks, especially if not recurrent, would more commonly be attributed to chromosomal defects.)
    • Recurrent early miscarriages
    • Intrauterine growth restriction
    • Severe preeclampsia

Other clinical presentations:

  • Livedo reticularis
  • Thrombocytopenia
    • Typically mild, with platelet count 50-150 x 109/L.
    • Severe thrombocytopenia (platelet count, is rare and should prompt the clinician to consider other causes of a low platelet count.
  • Transient ischemic attack
  • Valvular heart disease, including valve:
    • Vegetations
    • Thickening
  • Antiphospholipid antibody-related nephropathy:
    • Acute thrombotic microangiopathy (TMA)
    • Chronic vaso-occlusive lesions
  • Hemolytic anemia
  • Cognitive dysfunction
  • Pulmonary hypertension
  • Cutaneous ulcers
  • Adrenal insufficiency due to hemorrhagic infarction
  • Catastrophic antiphospholipid syndrome:
    • Multiorgan failure due to small-vessel thromboses; large venous or arterial thrombosis can also occur in about one-fifth of patients.
    • CAPS develops in 1% of patients with APS, but is associated with a 30% mortality rate in the absence of treatment.
    • About 50% of cases follow a triggering factor such as:
      • Infections (the most common trigger)
      • Anticoagulation withdrawal
      • Surgery
      • Medications (e.g., oral contraceptive)
      • Obstetric complications

Compared to patients without SLE, those with underlying SLE more likely to have:

  • Arthritis
  • Livedo reticularis
  • Heart valve disease
  • Thrombocytopenia
  • Leukopenia

Diagnosis:

Consider the diagnosis of antiphospholipid syndrome (APS) (and testing for aPL) in a patient with:

  • An unusual site of or recurrent thrombosis
  • Thrombosis in the setting of:
    • Young age
    • Livedo
    • Signs or symptoms of another systemic autoimmune disease
    • Unexplained prolongation of the aPTT
    • Mild thrombocytopenia
  • Late pregnancy loss
  • Early or severe preeclampsia
  • The HELLP syndrome

Confirm diagnosis:

  • If patient meets updated Sapporo Criteria:
    • Sapporo Criteria first proposed in 1999, subsequently updated in 2006 at a meeting in Sydney, Australia and are now referred to as the updated Sapporo or Sydney Criteria.
    • The criteria include:
      • Clinical criteria:
        • Objectively confirmed venous, arterial or small vessel thrombosis, or
        • Pregnancy complications that may be attributed to placental insufficiency, including pregnancy loss or premature birth.
      • Laboratory criteria:
        • Positive laboratory test for aPLs be found on 2 or more occasions at least 12 weeks apart.
        • The aPLs recognized in the international criteria include:
          • Lupus anticoagulant (LA).
          • Anticardiolipin (aCL) antibody (IgG or IgM) exceeding 40 IgG or IgM phospholipid units.
          • Anti-beta-2-glycoprotein 1 (anti-beta-2-GP1) antibody (IgG or IgM) at titers exceeding the 99th percentile.
        • Notes:
          • It is important that all three aPL tests (LA, aCL and anti-beta-2-GP1) are performed as the aPL phenotype influences thrombotic risk. Triple aPL-positivity (i.e. the presence of LA, IgG and/or IgM anti-beta-2-GP1 and IgG and/or IgM aCL positivity) is correlated with the highest risk of thrombosis.
          • Not every APL test is clinically significant.
          • LA test correlates better with clinical events compared to aCL and anti-beta-2-GP1 tests.
    • Definite APS is present if at least one clinical and one lab criteria are met.

Consider diagnosis of CAPS in a patient with:

  • Known APS and/or presence of aPL
  • Thrombocytopenia
  • Hemolytic anaemia (often accompanied of schistocytes as in thrombotic microangiopathic hemolytic anaemia)
  • Disseminated intravascular coagulation (DIC)

Confirm diagnosis of CAPS:

  • If patient meets all 4 of the following International CAPS classification criteria:
    • Evidence of involvement of 3 organs, systems, and/or tissues.
    • Development of manifestations simultaneously or in less than a week.
    • Confirmation by histopathology of small vessel occlusion in at least 1 organ/tissue
    • Lab confirmation of the presence of APL (lupus anticoagulant and/or anticardiolipin and/or anti-beta-2-glycoprotein 1 antibodies)

Testing for APL:

  • Test all three criteria APL at same time:
    • Lupus anticoagulant (LA)
    • Anticardiolipin (aCL) – IgG
    • Beta-2-glycoprotein 1 (beta-2-GP1) – IgG and IgM
  • Do not test in patients taking anticoagulants since false positive results may occur.
  • LA:
    • Use two tests that are based on different principles, for example:
      • Dilute Russell viper venom time (DRVVT) aPTT
      • Silica clotting time (SCT)
  • aCL and anti-beta-2-GPI antibodies:
    • Most commonly detected by ELISA.
    • Moderate to high titers correlate better with aPL-related clinical events that do lower titers.
    • IgG is more strongly associated with clinical events compared to IgM.

Assessing the APL profile:

  • Important for risk stratification.
  • High-risk profile – positive LA with or without moderate-high titer aCL or anti-beta-2-GPI IgG or IgM.
  • Moderate-risk profile – negative LA test with moderate-high titer aCL or anti-beta-2-GPI IgG or IgM.
  • Low-risk profile – negative LA test with low titer aCL or anti-beta-2-GPI IgG or IgM.

Treatment:

Primary prophylaxis in patients with APL – consider prophylactic low-dose aspirin therapy (75-100 mg per day) in:

  • Asymptomatic patients who are carriers of aPLs, but not fulfilling thrombotic or obstetric APS classification criteria, with high-risk aPL profile with or without traditional risk factors.
  • Patients with SLE and APL but without history of thrombosis or pregnancy complications.

Patients with thrombotic APS:

  • Treatment of venous thrombosis:
    • Treat with vitamin K antagonist.
    • Target INR 2-3.
    • In patients with definite APS and thrombosis, administer antithrombotic therapy indefinitely.
    • American Society of Hematology (ASH) guidelines recommend against the use of DOACs in all APS patients, whereas British Society for Haematology (BSH), and International Society on Thrombosis and Haemostasis (ISTH) guidance provided more detailed indications stating that warfarin should be the first-choice treatment but DOACs may be considered in patients:
      • Already on a stable anticoagulation with a DOAC
      • With low-quality anticoagulation by warfarin
      • Unwilling/unable to undergo INR monitoring
      • With contraindications or serious adverse events under warfarin
  • Treatment of arterial thrombosis:
    • In unselected patients with stroke and single positive aPL test result, antiplatelet therapy and warfarin are equally effective for preventing recurrent stroke.
    • In patients with definite APS and first arterial thrombosis, consider VKA over treatment with low-dose aspirin only.

Patients with obstetric APS:

  • In women with history of recurrent pregnancy loss, administer antenatal heparin plus low-dose aspirin throughout pregnancy , with treatment beginning as soon as pregnancy is confirmed.
  • In women with history of delivery < 34 weeks of gestation as a result of eclampsia or severe pre-eclampsia due to placental insufficiency, consider low-dose aspirin or low-dose aspirin plus prophylactic dose heparin after taking into consideration patient risk profile.

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