Antiphospholipid antibody syndrome

Pathogenesis: Antiphospholipid antibodies are produced by B cells. The major target of these antibodies is Beta2-glycoprotein I (B2GPI), a plasma protein that is in a closed state but when it binds to anionic surfaces it converts to the open, immunogenic B2GPI. Antiphospholipid antibodies avidly bind to the open B2GPI to form dimers. It is know that congenital deficiency of B2GPI is not associated with increased risk of thrombosis. The binding of antiphospholipid antibodies to B2GPI on cellular surfaces upregulates the expression of prothrombotic cellular adhesion molecules such as E-selectin and tissue factor. Tissue factor pathway inhibitor is suppressed, reduction of activated protein C activity, fibrinolysis and in placenta (reduction of hCG, and also inhibition of proliferation and synctia formation of trophoblast. Increase in expression of glycoprotein IIb/IIIa and platelets may play a key role in prothrombotic interactions between antiphospholpid antibodies and endothelial cells. Neutrophil activation including expression of tissue factor and release of neutrophil extracellular traps (NETosis) and IL-8. There is increased complement, E-selectin, VEGF, and in placenta (trophoblast apoptosis). Monocytes and monocytes-derived microparticles express high levels of tissue factor. There is upregulation of the mechanistic target of rapamycin (mTOR) complex on endothelial cells, leading to antiphospholipid-ab related vasculopathy.

Presentations:

    1. Patients are identified during evaluation for systemic autoimmune diseases, early miscarriages

    2. Elevated aPTT

    3. False positive syphilis test

    4. Symptomatic: thrombotic, obstetrical, or other clinical sequelae of antiphospholipid antibody syndrome.

      • Stroke, TIAs

      • VTE (DVT, PE)

      • Miscarriages >10 weeks of gestation or recurrent losses <10 weeks

      • SLE with antiphospholipid antibody patients have high incidence of thrombosis, pregnancy complications, VHD, pulmonary HTN, PE, livedo reticularis, thrombocytopenia, hemolytic anemia, acute or chronic renal vascular lesions, and moderate or severe cognitive impairment.

Key concepts:

    1. aPL are not only a diagnostic marker for APS but also a risk factor for thrombosis and pregnancy complications, which are commonly multifactorial. When evaluating patients who are positive for aPL, consider non-aPL thrombotic risk factors

    2. Transient aPL positive is common during infections.

    3. Not every positive aPL is clinically significant.

    4. LA testing is a 3 step function coagulation assay to detect aPL. The LA test correlates better with clinical events than do aCL and anti-B2GPI tests. A false positive LA test may be seen in patients on warfarin, heparin, or DOAC; thus the LA test should not be ordered for such patients.

    5. aCL and anti-B2GPI abs (IgG, IgM, IgA) are commonly detected by ELISA. Moderate to high titers (40 GPL or MPL or 99th percentile) of aCL or anti-B2GPI IgG or IgM (99th percentile) correlate better with aPL-related clinical events than do lower titers; IgG is more strongly associated with clinical events than is IgM. Isolated moderate to high-titer aCL or anti-B2GPI IgA is rare and of unknown clinical significance.

    6. Assessment of aPL profile has diagnostic implications and helps risk stratify patients who are persistently positive for aPL. "Persistent" is defined as tested "on two or more occasions at least 12 weeks apart" based on the revised Sapporo classification criteria; a high-risk aPL profile is more likely to remain positive when repeated, independent of the timing. For diagnostic purposes, both high and moderate risk aPL profiles are important; a high-risk profile provides more confidence in the diagnosis.

      • High risk profile is defined as a positive LA test with or without a moderate-to-high titer (aCL or anti-B2GPI IgG or IgM of 40 or more GPL or MPL units)

      • Moderate risk profile is defined as a negative LA test with moderate-to-high titer (aCL or anti-B2GPI IgG or IgM of 40 or more GPL or MPL units)

    • Low risk profile is defined as a negative LA test with low titer (aCL or anti-B2GPI IgG or IgM of 20 - 39 GPL or MPL units)

    • Clinical judgement is important if the LA test is performed on an anticoagulated patients, if the aPL profile is low-risk, if the aPL result for only a single time point is available, or if aCL or anti-B2GPI IgA is the only positive aPL test.

  1. Although LA, aCL, and anti-B2GPI tests are the mainstay of APS diagnosis, several additional aPL tests have been developed recently; the clinical significance of other proposed aPL tests must be established with additional outcome based studies.

Antiphospholipid antibody syndrome is a systemic autoimmune disease defined by thrombotic or obstetrical events that occur in patients with persistent antiphospholipid antibodies. The thrombotic events are venous, arterial, or microvascular. In catastrophic antiphospholipid antibody syndrome, patients present with thrombosis of multiple organs. Obstetrical antiphospholipid antibody syndrome is characterized by fetal loss after the 10th week of gestation, recurrent early miscarriages, intrauterine growth restriction, or severe preeclampsia. The major non-thrombotic manifestations of antiphospholipid-antibody positivity include VHD, livedo, antiphospholipid-antibody related nephropathy, thrombocytopenia, hemolytic anemia, and cognitive dysfunction. The antiphospholipid syndrome is often associated with other systemic autoimmune diseases such as SLE; however, it commonly occurs without other autoimmune manifestations (primary antiphospholipid syndrome).

Revised Sapporo Classification Criteria (used as a guideline and not as a rigid formula)

  • ≥ 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 or more unexplained deaths of normal fetus ≥ 10 weeks gestational age

    • 1 or more 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 should be high levels in the absence of other coagulopathies.

    • aCL immunoglobulin (IgG and/or IgM) antibody in serum or plasma (titer > 40 IgG/glycopeptidolipid [GPL] or monophosphoryl lipid A [MPL] or > 99th percentile)

    • IgG or IgM anti-beta2 glycoprotein-I antibody in serum or plasma (titer > 99th percentile)

Major Clinical manifestations of Antiphospholipid syndrome that are not included in the Revised Sapporo Classification Criteria:

    1. Hematologic:

    • Thrombocytopenia:

      • Mild (more common) thrombocytopenia (platelet count of 50K - 150K per mm3), asymptomatic

        • Severe (less common) thrombocytopenia (platelet: count of <20 K per mm3), with or without thrombotic microangiopathy

      • Hemolytic anemia

        • Without schistocytes: suggest immune-mediated hemolytic anemia

        • With schistocyts, suggesting thrombotic microangiopathy

    1. Renal:

      • Acute thrombotic microangiopathy

      • Chronic vaso-occlusive lesions (cortical ischemia or infarction with arteriosclerosis, arteriosclerosis, arterial fibrous intimal hyperplasia, glomeural ischemia, interstitial fibrosis, tubular thyroidization, tubular atrophy, organized thrombi with or without recanalization, or combination of such lesions)

    2. Cardiac:

      • Valve vegetations or thickening of valve >3 mm, or irregular nodules on the atrial face of the edge of the mitral valve, vascular face of aortic valve or both)

    3. Dermatologic:

      • Livedo reticularis or racemosa

      • Livedoid vasculopathy (recurrent, painful skin ulcerations)

    4. Neurologic

      • Cognitive dysfunction (in the absence of stroke)

      • Subcortical white-matter changes.

Principles of Lupus anticoagulant testing and interpretation: The interpretations apply only to patients not taking anticoagulant agents.

    1. Screen: Is a phospholipid-dependent clotting time (aPTT or dRVTT) prolonged?

      • If NO: lupus antocoagulant is ruled out.

      • If YES: go to #2.

    2. Mix: Does the prolongation fully correct after 1:1 mix with normal pooled plasma?

      • If YES: lupus anticogulant is ruled out, consider clotting factor deficiency

      • If NO: go to #3.

    3. Confirm: Does the prolongation shorten significantly (ratio of clotting time before the addition of phospholipid to clotting time after addition of phospholipid) after the addition of phospholipid?

      • If NO: lupus anticoagulant not confirmed; consider inhibitor

      • If YES: Lupus anticoagulant confirmed.

Dx: antiphospholipid antibodies classified by method of detection.

    • aPTT

    • Platelet count

      • Complement factor 3 and 4

    • anti-ds-DNA ab, ANA ab

    • aCL-IgG

    • dRVVT-ratio the anticardiolipin antibody

    • HIV

    • TPHA (serum and CSF)

    • Acanthocytes

    • Serum copper and ceruloplasmin

    • TSH

    • IgG and IgM anti-ß2-glycoprotein I (anti-β2GPI) antibodies by ELISA. Alternatively, some experts prefer to perform testing for anti-β2GPI antibodies only in patients suspected of aPL in whom the IgG and IgM aCL and lupus anticoagulant testing are negative.

    • Confirmatory aPL testing — In patients with initial positive testing for aPL, the test should be repeated after at least 12 weeks to confirm persistence of the aCL, anti-β2GPI, or LA test. Transiently elevated levels of IgG or IgM aCL, as well as a positive LA test, can occur in otherwise normal individuals and in the setting of viral or other infections. Confirmatory testing is required to satisfy the laboratory criteria for aPL

    • In patients with a strongly suggestive clinical history whose initial test result is a positive LA or a high titer aCL (>40) or anti-β2GPI, but whose second test is negative, perform a third test after several weeks and use the third result to help guide decision-making. Consider the result negative and do not perform a third test if the first test was a minimally positive aCL or anti-β2GPI and the second test was negative. Testing should be repeated if the patient has a clinical event.

Prevention and treatment:

  1. Risk stratification by age, antiphospholipid antibody profile, other risk factors for thrombosis, systemic autoimmune diseases. HTN, DM, HLP are controlled. Avoidance of aggressive postoperative prophylaxis against thrombosis, avoidance of estrogen supplements in moderate-to-high risk antiphospholipid antibody profile.

  2. The absolute risk of a first thrombosis in antiphospholipid-ab positive patients who do not have other risk factors is probably less than 1% per year. In moderate-to-high risk patient it may be as high as 5%.

  3. Low does ASA (81mg/day)

  4. Hydroxychloroquine 200 - 400 mg/day is a potential add-on treatment in recurrent thrombosis despite therapeutic dose anticoagulant therapy.

  5. Statin is a potential add-on treatment in recurrent thrombosis despite therapeutic dose anticoagulant therapy.

  6. Warfarin for secondary thrombosis prevention (INR: 2-3); target INR of 3-4 is a possible strategy for recurrent thrombosis despite therapeutic dose anticoagulant therapy.

  7. LMWH: enoxaparin 40 mg daily in pregnant patients with obstetrical APS, and thrombotic APS (enoxaparin 1.5 mg/kg daily or 1.5 mg/kg bid)

  8. UFH: part of 1st line treatment for catastrophic APS: 5000 units sc bid and thrombotic APS: 250 units/kg, sc bid

  9. DOAC: more data is needed.

  10. Glucocorticoids: IV methylprednisolone, 250 - 1000 mg for 3 days: pat of 1st line combination treatment for catastrophic APS; first line treatment for severe thrombocytopenia, hemolytic anemia, or both.

  11. IVIg: part of first or second-line combination treatment for catastrophic APS: 1-2 g/kg over 3 - 5 days; first or second line treatment for severe thrombocytopenia (1 g/kg can repeat once, usually 1-2 days after 1st dose)

  12. Plasma exchange: part of first- or second-line combination treatment for catastrophic APS; for acute thrombotic microangiopathy in patients with aPL-related nephropathy.

  13. Traditional immunomodulatory agents (azathioprine 100 - 150 mg/day, or mycophenolate mofetil, 1000 - 3000 mg/day) used as an option of severe thrombocytopenia, hemolytic anemia, or both; an option for aPL nephropathy.

  14. Rituximab, 1000 mg on days 0 - 15, repeated every 6 months. Used as an option for thrombocytopenia, hemolytic anemia, livedoid vasculopathy, and aPL nephropathy; an option for catastrophic APS that is refractory for standard treatment.

  15. Eculizumab is used as an option for catastrophic APS that is refractory to standard treatment; an option for acute thrombotic microangiopathy in patients with aPL-related nephropathy.

Tx: lifelong warfarin after a thrombotic event; goal INR (2 - 3). ASA prophylaxis for high risk asx Pts.