ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS

Antiphospholipid syndrome

David Goldemund M.D.
Updated on 21/06/2024, published on 28/04/2023
  • antiphospholipid syndrome (APS) is an acquired autoimmune disease
  • the diagnosis is based on the presence of clinical symptoms (thrombosis or pregnancy morbidity) along with persistently elevated titers of antiphospholipid antibodies (APLA or aPL)
  • most people are diagnosed between the ages of 20 and 50, and it affects 3-5 times as many women as men

Classification

I. Primary APS
II. Secondary APS
  • connective tissue disease (collagenosis) – SLE, RA
  • malignancy (e.g., lung cancer, leukemia and lymphoma, paraproteinemia)
  • other systemic diseases (diabetes, Crohn’s disease, autoimmune thyroiditis)
  • exotoxic conditions – drugs, infections (HIV, malaria, syphilis)
  • renal failure and post-transplant syndrome

Pathophysiology

Antiphospholipid syndrome (APS)

Clinical presentation

Neurologic signs and symptoms

  • amaurosis fugax
  • occlusion of retinal arteries and veins
  • TIA/stroke (thromboembolic etiology)
  • transverse myelitis (in patients with SLE)
  • dural sinus thrombosis
  • dementia
  • epileptic seizures
  • migraine

Other signs and symptoms

  • pulmonary hypertension
  • arterial and venous thromboses and/or pulmonary embolism
  • livedo reticularis
  • valvular vegetations
  • autoimmune thrombocytopenia
  • autoimmune hemolytic anemia
  • the rare microangiopathic form can lead to fatal Multiple Organ System Dysfunction (MOSD) – known as catastrophic antiphospholipid syndrome (CAPS)

Pathologic conditions related to pregnancy

  • repeated early abortions
  • unexplained fetal deaths in the 2nd and 3rd trimesters
  • severe pre-eclampsia
  • chorea gravidarum
  • severe fetal growth restriction

Diagnostic evaluation

Laboratory tests

The 3 main types of antiphospholipid (aPL )antibodies are:

  • lupus anticoagulans (LA)
  • anticardiolipin antibodies (ACLA)
  • anti-β2-glycoprotein I (anti-β2GPI)
  • LA is most specific for predicting thrombosis; the concurrent presence of both ACLA and anti-β2GPI further increases the risk
  • testing should be performed before or after the discontinuation of heparin/warfarin
    • after 3 months, discontinue warfarin for a short period and collect the blood samples
    • a prophylactic dose of LMWH does not affect the test results
  • testing outside pregnancy is recommended for patients with pregnancy-related disorders
  • detection of antibodies alone, especially at low titers, is highly nonspecific and cannot be used to establish a diagnosis ⇒ in antiphospholipid syndrome, antibodies should be high and repeatedly present at high titers (a minimal interval of ∼ 3 months between the 2 samples) to confirm the diagnosis
  • testing asymptomatic individuals for the presence of antiphospholipid antibodies is not recommended; even if antibodies are present, primary thromboprophylaxis is not indicated (AHA/ASA 2010 III/B)
  • routine testing of individuals with TIA/stroke is not recommended unless they have other symptoms of APS and no evident stroke etiology (AHA/ASA 2014 III/C)

Neuroimaging

CT+CTA, MRI+MRA, SPECT

  • regional blood flow disorders
  • infarcts, white matter lesions Hyperintense lesions on MRI (FLAIR) in a patient with antiphospholipid syndrome  → FAZEKAS
  • cortical atrophy
  • venous sinus thrombosis
  • arterial occlusion or stenosis

Diagnostic criteria

 I. Clinical criteria
1. Thrombosis  –  ≥ 1 attack of venous /arterial thrombosis
2. Pregnancy-related disorders

  • ≥ 1 abortion after 10 weeks of pregnancy in a morphologically normal fetus
  • ≥ 1 preterm birth (before 34 weeks) due to pre-/eclampsia or placental insufficiency
  • ≥ 3 miscarriages during the first 10 weeks of pregnancy
 II. Laboratory criteria
  • LA present in ≥ 2 samples at least 12 weeks apart
  • ACLA IgG and/or IgM in ≥ 2 samples at least 12 weeks apart (titer > 40GPL)
  • anti-β2-GPI antibodies IgG and/or IgM in ≥ 2 samples at least 12 weeks apart
Antiphospholipid syndrome is present if at least one clinical and one laboratory criterion is present

Therapy

Primary thromboprophylaxis

  • testing of asymptomatic individuals and primary thromboprophylaxis are not recommended

Secondary stroke prevention

  • the decision to initiate antiplatelet or anticoagulant therapy depends on the assessment of the individual risk of thrombosis and the risk of bleeding with anticoagulant therapy
  • the risk of thrombosis depends on:
    • titer and type of antibodies detected
    • extent or frequency of thrombotic events and their location
  • according to the APASS trial, there was no statistically significant difference between ASA and low-dose warfarin (INR 1.5-2.8)
    • only a minority of patients had high LA and ACLA titer
  • antiplatelet therapy is recommended for patients with low antibody titers who do not meet APS criteria (AHA/ASA 2021 1/B-NR)
  • initiate anticoagulation therapy in patients with repeated high titers who meet APS criteria
    • prefer warfarin with INR 2.5-3  (AHA/ASA 2021 2a/B-R)
    • DOACs – insufficient data, higher risk of recurrence compared to warfarin according to observational studies; ASTRO-APS trial with apixaban is ongoing
    • rivaroxaban is specifically not recommended in patients with a history of thrombosis and triple antibody positivity due to increased risk of bleeding (AHA/ASA 2021 3/B-R)
  • dual antiplatelet therapy (DAPT)  ASA + clopidogrel could be an alternative, but strong data are not yet available to make a strong recommendation  (AHA/ASA 2021)  [Ohnishi, 2019]
  • the usefulness of a combination of warfarin + ASA is not established; there is a consensus in favor of anticoagulation alone

Deep vein thrombosis and APS

  • long-term WARFARIN with INR 2.5-3
  • DOAC rather not, further RCTs are required → more here
    • rivaroxaban –  TRAPS trial showed worse results than warfarin
    • apixaban – ASTRO-APS trial is ongoing

Management of pregnant women with APS

  • APS patients without a history of thrombosis and miscarriage: no clear recommendation; LWMH or LMWH+ASA can be used
  • patients with APS + recurrent miscarriage (≥3):  LMWH + aspirin 50 mg once daily
    • treatment should be initiated as soon as possible after confirmation of pregnancy
  • patients with APS + history of pre-eclampsia/eclampsia: aspirin 50mg once daily
  • patients with APS + history of thrombosis: LMWH as thromboprophylaxis
  • postpartum thromboprophylaxis with LMWH
    • 6 weeks in patients with a history of thrombosis, 7 days for all others
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Antiphospholipid syndrome
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