Antiphospholipid Syndrome (APS/APLS)

Definition

• Antiphospholipid syndrome (APS/APLS) is an acquired systemic autoimmune disease defined by vascular thrombosis and/or pregnancy loss or morbidity together with persistently positive antiphospholipid antibodies (aPL).
• You need a clinical event (arterial, venous, or small-vessel thrombosis, or qualifying obstetric morbidity) PLUS persistent aPL to diagnose APS. aPL alone is not APS.

Revised Sapporo (Sydney) classification: I. Laboratory criteria

• Only 1 of 3 has to be positive, on TWO occasions ≥12 weeks apart.
• Lupus anticoagulant (LA) = lupus inhibitor = phospholipid-dependent inhibitor, prolongs PTT by inhibiting conversion of X to Xa and II to IIa. See assay panel below.
• Anticardiolipin Ab (aCL) IgG and/or IgM: Sapporo cutoff >40 GPL or MPL units, or >99th percentile of your lab.
• Anti-β2-glycoprotein I (anti-β2GPI) IgG and/or IgM: Sapporo cutoff >99th percentile.
• Only one positive is enough to say aPL is present.
• Repeat in ≥12 weeks; if still positive, aPL is confirmed.
• False positives possible with acute illness and anticoagulation.
• Other antibodies (antiphosphatidylserine, antiphosphatidylcholine, antiphosphatidylethanolamine) are not established risk factors for thrombosis. Anti-phosphatidylserine may play a role in pregnancy complications. IgA is not part of the criteria.

Lupus anticoagulant assay panel and mixing-study logic

• A prolonged PTT that fails to correct on a 1:1 mix with normal plasma suggests an inhibitor; a phospholipid-dependent inhibitor (LA) is then confirmed by demonstrating phospholipid dependence (correction when excess phospholipid is added).

Revised Sapporo (Sydney) classification: II. Clinical criteria

• ≥1 vascular thrombosis: ≥1 clinical episode of arterial, venous, or small-vessel thrombosis.
• Pregnancy morbidity:
  • ≥1 unexplained loss of a morphologically normal fetus at ≥10 weeks (by ultrasound or direct fetal exam); or
  • ≥3 unexplained consecutive spontaneous losses at <10 weeks, without maternal anatomic or hormonal abnormalities and without paternal/maternal chromosomal abnormalities; or
  • ≥1 premature birth <34 weeks of a morphologically normal neonate due to eclampsia / severe preeclampsia OR placental insufficiency.

2023 ACR/EULAR APS classification criteria

• 2023 ACR/EULAR APS classification criteria (Barbhaiya Ann Rheum Dis 2023 / Arthritis Rheumatol 2023, supersedes Sapporo/Sydney 2006 for research classification). Entry criterion: ≥1 positive aPL test within 3 y of a clinical criterion. Weighted point system across 6 clinical domains (macrovascular VTE, macrovascular arterial, microvascular, obstetric, cardiac valve, hematologic) + 2 laboratory domains (coagulation-based LA; solid-phase aCL/anti-β2GPI). Threshold ≥3 points in each of the clinical and lab domains. Higher specificity than Sapporo; explicitly weights triple-positive high titer most heavily. Non-thrombotic manifestations (thrombocytopenia, livedo racemosa, cardiac valve disease) now formally counted.

APLS is associated with

• aPL antibodies are found in ~5% of the general population.
• Rheumatologic overlap: ~30 to 40% of SLE patients have antiphospholipid antibodies (lupus anticoagulant specifically is less common); ~40% of APLS patients have SLE.
• Also associated with certain drugs, infections, and cancer.
• Annual first-thrombosis risk depends on antibody profile and persistence: asymptomatic triple-positive carriers had ~5.3% per year (Pengo 2011); low-risk single-positive carriers are lower, but risk is not bounded by rheumatic-disease status.

Management

• aPL present but no thrombosis or pregnancy complication: aspirin for primary prevention in high-risk patients (LA-positive, double or triple positivity, or persistently high titers, with or without SLE). Some guidelines suggest aspirin even in low-risk patients (low-quality meta-analysis evidence).
• Venous thrombosis, long-term anticoagulation:
  • Warfarin, INR goal 2.0 to 3.0 for most nonpregnant individuals. If pregnant, switch to therapeutic-dose enoxaparin.
  • Warfarin is preferred over DOACs. DOACs are less effective for recurrent thrombosis prevention, especially with a history of arterial events. Consider DOACs only in lower-risk APLS (single venous VTE and low-risk aPL profile: isolated aCL or isolated anti-β2GPI at low to medium titer) or when warfarin cannot be tolerated or target INR cannot be achieved despite adherence. Do not use DOACs in patients non-adherent to VKA.
  • Do not use DOACs in patients with recurrent thrombosis on standard-intensity VKA; instead increase the INR goal, switch to standard treatment-dose LMWH (or fondaparinux), or add an antiplatelet agent.
• Arterial thrombosis, long-term anticoagulation:
  • Standard-intensity warfarin (INR 2.0 to 3.0) or higher-intensity warfarin (INR 3.0 to 4.0), chosen by bleeding vs recurrence risk; standard-intensity warfarin plus low-dose aspirin may also be considered (EULAR 2019).
  • If recurrent arterial thrombosis despite VKA adherence, increase INR to 3.0 to 4.0, add low-dose aspirin, or switch to LMWH. DOACs are not recommended.
• Duration: lifelong if unprovoked; discontinuation can be considered rarely, especially with low-titer aPL.

Treatment framework, post-2023 criteria

• Triple-positive APS with prior thrombosis, warfarin INR 2 to 3 (DOACs inferior: TRAPS halted early for excess arterial thrombosis with rivaroxaban; RAPS failed surrogate non-inferiority; ASTRO-APS stopped early for excess strokes with apixaban, 6/23 vs 0/25). Single-/double-positive after unprovoked VTE, DOAC may be considered in selected patients, mainly if VKA is not tolerated or target INR cannot be achieved; never triple-positive or arterial (EULAR 2019, ISTH 2020 guidance). Obstetric APS, low-dose aspirin + prophylactic LMWH. Catastrophic APS (CAPS), anticoagulation + steroids + PEX/IVIG ± rituximab ± eculizumab; 2024 CAPS registry mortality still ~35% to 40%.

Monitoring anticoagulation

• If baseline PT is prolonged (rare), use an alternative thromboplastin reagent (a combination of thromboplastins, or one demonstrated to be insensitive to the patient's aPL or LA).
• If baseline aPTT is prolonged by the LA (common) and the patient needs a heparin drip, use an anti-Xa nomogram.

Other clinical manifestations

• Cardiac: nonbacterial thrombotic endocardial deposits (NBTE); anticoagulate (VKA favored in thrombotic APS) after weighing embolic and bleeding risk. Adding aspirin needs an individual indication; incidental valve disease without thromboembolism does not mandate combined therapy.
• CNS: in addition to stroke, nonspecific white matter lesions on MRI.
• Kidney: aPL nephropathy, thrombosis of arteriovenous grafts in hemodialysis patients, and thrombosis after kidney transplant.
• Thrombocytopenia: ITP, TTP, drug-induced, and HIT.
• Skin: splinter hemorrhages, livedo reticularis and racemosa, cutaneous necrosis and infarction, digital gangrene, skin ulcerations, pseudovasculitic nodules/macules, and livedoid vasculopathy.
• Eye: amaurosis fugax, retinal venous and arterial occlusion, and anterior ischemic optic neuropathy.
• Adrenal insufficiency: from bilateral adrenal vein thrombosis with hemorrhagic infarction.

Coagulopathy in APLS and mixing-study patterns

• Patients with a lupus inhibitor (APLS) are at NO increased risk of bleeding. Rarely, they can carry an anti-FII (anti-prothrombin) antibody that does not block prothrombin but increases its clearance, lowering prothrombin levels.
• Acquired FII (prothrombin) deficiency with APLS (PT and aPTT both prolonged, but only PT corrects): prolonged PT (e.g., 22 sec) and prolonged aPTT (e.g., 80 sec); PT mix corrects (e.g., 15 sec, a factor deficiency, PT covers FVII, FX, FV, FII, FI); aPTT mix stays prolonged (e.g., 55 sec, an inhibitor, the lupus inhibitor). The low prothrombin reflects ↑↑↑ clearance by the anti-FII antibody, so PT corrects with mixing.
• Acquired FVIII deficiency with APLS: normal PT; prolonged aPTT (e.g., 90 sec) with prolonged aPTT mix (e.g., 63 sec), so an inhibitor is present; FVIII <1% with Bethesda titer 45, a FVIII inhibitor. A prolonged DRVVT (e.g., 68 sec) with prolonged DRVVT mix (e.g., 55 sec) cannot be due to the FVIII inhibitor, because Russell viper venom activates FX directly (bypassing the VIIIa/IXa complex), so FVIII deficiency or inhibitors do not affect the DRVVT; another inhibitor (LA) must be invoked.

Catastrophic APS (CAPS)

• Occurs in <1% of APLS patients.
• Diagnostic criteria:
  • Involvement of ≥3 organs, systems, and/or tissues.
  • Manifestations developing simultaneously or in <1 week.
  • Histopathology confirming small-vessel occlusion in at least one organ or tissue.
  • Laboratory confirmation of antiphospholipid antibodies (LA, aCL, anti-β2GPI).
• Classification: definite CAPS requires all four criteria; probable CAPS = all four criteria except only 2 organs involved; or an early-death exception preventing repeat aPL confirmation in a previously untested patient; or criteria 1, 2, and 4 (no histology); or criteria 1, 3, and 4 with a third event 1 week to 1 month apart despite anticoagulation. Mortality ~30% to 40% (CAPS registry).
• Treatment:
  • Anticoagulation (heparin drip, then bridge to warfarin once stable).
  • Pulse-dose steroids (methylprednisolone 0.5 to 1 g/day IV for 3 days, then prednisone 1 mg/kg).
  • IVIG 400 mg/kg per day for 5 days.
  • Plasma exchange for 5 days (can reduce aCL IgG and IgM by 95%).
  • If resistant, rituximab or eculizumab (anti-C5) off label.
• Complement link: complement is required for aPL-mediated thrombosis in animal models, and aPL activate complement. In CAPS, 85.7% show complement activation on a functional (modified Ham) assay and 60% (6/10) have rare germline variants in complement genes; eculizumab has been used successfully, but a clinical trial is needed.

High yield

• Need clinical event (thrombosis or pregnancy morbidity) PLUS persistent aPL on 2 occasions ≥12 weeks apart; aPL alone is not APS.
• LA prolongs aPTT in vitro but causes thrombosis in vivo; confirm phospholipid dependence using the assay's own validated cutoff (generally 99th percentile); the dRVVT uses a normalized ratio = (patient/normal screen) / (patient/normal confirm), the values shown being illustrative.
• Triple-positive APS = warfarin INR 2 to 3; DOACs inferior (TRAPS).
• Pregnant APS, switch warfarin to therapeutic enoxaparin; obstetric APS, low-dose aspirin + prophylactic LMWH.
• Rare lupus-inhibitor patient with bleeding, look for acquired anti-FII (prothrombin) deficiency (PT corrects, aPTT does not).
• Catastrophic APS: anticoagulation + pulse steroids + IVIG or PEX ± rituximab or eculizumab.