Antiphospholipid Antibody Syndrome (APS)

Background

• APS is a systemic autoimmune disorder characterized by thrombotic events, or pregnancy morbidity and persistently elevated titers of antiphospholipid antibodies (aPLs).
• APS occurs mainly in young women of fertile age and rarely in children.
• Reported prevalence is 40-50 cases per 100,000 persons, with an estimated annual incidence of 5 new cases per 100,000 persons.
• While presence of aPLs are necessary for the development of APS, they are likely to be insufficient for causing thrombotic or obstetric complications. Other risk factors may be needed to drive development of manifestations associated with APS.
• APS may be classified:
  • by presence of other clinical conditions:
    • Primary - occurs without clinical or laboratory evidence of any other disease condition
    • Secondary - associated with other diseases mainly systemic lupus erythematosus (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
  • based on diagnostic criteria, APS can be definite or probable. Definite APS is defined by the presence of ≥ 1 of clinical criteria and ≥ 1 of laboratory criteria.
    • Clinical and laboratory criteria should be separated by > 12 weeks and < 5 years.
    • Clinical criteria:
      • vascular thrombosis including clinical episode of arterial, venous, or small vessel thrombosis in any organ or tissue
      • ≥ 1 unexplained deaths of normal fetus ≥ 10 weeks gestational age
      • ≥ 1 premature births of normal neonate < 34 weeks gestational age due to eclampsia, severe preeclampsia, or placental insufficiency
      • ≥ 3 unexplained abortions before 10 weeks gestation
    • Laboratory criteria (on 2 or more occasions ≥ 12 weeks apart):
      • lupus anticoagulant in plasma
      • immunoglobulin (IgG and/or IgM) anticardiolipin antibody in serum or plasma (titer > 40 glycopeptidolipid [GPL] or monophosphoryl lipid A [MPL] or > 99th percentile)
      • IgG or IgM anti-beta2 glycoprotein-1 antibody in serum or plasma (titer > 99th percentile)

Evaluation

• In all adults with clinical features of APS, definite diagnosis is based on revised Sapporo classification criteria for APS.
• Evaluation of patients suspected of having APS:
  • Assess clinical manifestations (both criteria and noncriteria manifestations).
  • Consider testing for aPLs (lupus anticoagulant and either immunoglobulin (Ig) G antibeta-2 glycoprotein 1 or anticardiolipin antibodies), with tests repeated after 12 weeks to demonstrate persistence (Weak recommendation):
    • in patients with unexplained venous thromboembolism (VTE)
    • in women with recurrent pregnancy loss (≥ 3 losses before 10 weeks gestation)
    • to confirm diagnosis of CAPS but without delaying empiric treatment
  • Risk stratification of patients according to aPL profile (taking into consideration presence of type of aPLs present, isotype, and titer) may help determine risk of first and recurrent thrombosis, as well as help guide management.
  • Thrombosis should be confirmed by findings of appropriate imaging studies or histopathology.
• Additional evaluation may be required to:
  • rule out microangiopathic hemolytic anemia in patients with CAPS
  • rule out other causes for recurrent pregnancy loss in women with obstetric APS

Management

• Primary thromboprophylaxis in patients with aPL:
  • First step in the treatment of patients with antiphospholipid antibodies in the absence of thrombosis is risk stratification based on age, antiphospholipid antibody profile, concomitant risk factors for thrombosis, and other systemic autoimmune disease.
  • 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, consider prophylactic low-dose aspirin therapy (75-100 mg per day) (Weak recommendation).
  • In patients with SLE without history of thrombosis or pregnancy complications, consider prophylactic low-dose aspirin therapy (Weak recommendation).
  • In nonpregnant women with history of obstetric APS only (with or without APS), consider prophylactic low-dose aspirin therapy after taking into account risks and benefits (Weak recommendation).
  • Thromboprophylaxis may be of benefit in patients with aPLs in high risk settings such as surgery, prolonged immobilization, and puerperium.
  • In all patients with high risk aPL profile with or without history of thrombosis, concomitant SLE, or additional features of APS, strict control of cardiovascular risk factors should be considered.
• Patients with thrombotic APS:
  • Treatment of venous thrombosis (in patients who are not pregnant):
    • Administer vitamin K antagonist for secondary prevention of thrombosis (Strong recommendation).
    • Target INR 2-3 for VKA therapy (Strong recommendation).
    • Duration of therapy:
      • In patients with definite APS and thrombosis, administer antithrombotic therapy indefinitely (Strong recommendation).
      • If venous thrombosis was provoked, consider anticoagulation therapy duration recommended by international guidelines for patients without APS (Weak recommendation). In patients with consistently high-risk aPL profile or with other risk factors for thrombosis recurrence, consider longer duration of anticoagulation (Weak recommendation).
      • Benefits of indefinite anticoagulation therapy is unclear in patients with aPLs and thrombosis that was provoked and those that become negative for aPL over time.
  • Treatment of arterial thrombosis (in patients who are not pregnant):
    • In unselected patients with stroke and single positive aPL test result, antiplatelet therapy and warfarin are equally effective for preventing recurrent stroke (Strong recommendation). Antiplatelet therapy is preferred on grounds of convenience.
    • In patients with definite APS and first arterial thrombosis:
      • consider VKA over treatment with low-dose aspirin only (Weak recommendation).
      • consider 1 of (Weak recommendation):
        • VKA with target INR 2-3 or INR3-4 depending on patient's risk of bleeding and recurrent thrombosis
        • VKA with target INR 2-3 plus low-dose aspirin
  • For patients with either arterial or venous thrombosis and aPL who do not meet criteria for APS, manage in the same manner as patients without aPL with similar thrombotic events (Strong recommendation).
  • In patients refractory to treatment with VKA, management options include ensuring that anticoagulation is within therapeutic range and if target INR has been achieved, consider:
    • increasing INR target to 3-4, low-molecular-weight heparin (LMWH) or low-dose aspirin (Weak recommendation)
    • addition of hydroxychloroquine or statin
    • combination treatment with above options
    • B-cell inhibition using rituximab
    • addition of IV immunoglobulin (IVIG)
• Women with obstetric APS:
  • Goals of management of pregnant women with APS include:
    • prevention of pregnancy complications by use of low-dose aspirin and/or heparin (unfractionated heparin [UFH] or LMWH)
    • close observation for maternal thrombosis, aPL-related renal manifestations, and features of preeclampsia
    • monitoring of fetal growth
  • In women with history of recurrent pregnancy loss, administer antenatal heparin plus low-dose aspirin throughout pregnancy (Strong recommendation), 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 (Weak recommendation).
  • In women with history of preeclampsia or fetal growth restriction, low-dose aspirin is recommended.
  • In women with criteria obstetric APS with recurrent pregnancy complications despite low-dose aspirin and prophylactic heparin therapy:
    • consider 1 of (Weak recommendation):
      • increasing heparin dose to therapeutic dose
      • addition of hydroxychloroquine or low-dose prednisolone in first trimester
      • IV immunoglobulins (IVIG) in highly selected case
    • addition of pravastatin is another option
  • In women who have had a thrombotic event, consider low-dose aspirin plus therapeutic dose heparin during pregnancy (Weak recommendation).
  • Consider supplementary fetal surveillance with Doppler ultrasound and biometric parameters especially in third trimester to screen for placental insufficiency and small for gestational age fetuses (Weak recommendation)
• Additional considerations are required for the management of noncriteria manifestations which includes nephropathy, livedoid vasculopathy, hematologic manifestations including thrombocytopenia, and heart valve disease.
• For patients with catastrophic APS
  • consider combination therapy with glucocorticoid, heparin and plasmapheresis or IV immunoglobulins (IVIg) over single agents or other combination therapies (Weak recommendation).
  • in patients with refractory catastrophic APS, consider B-cell depletion (for example, rituximab) or complement inhibition (for example, eculizumab) (Weak recommendation).