Antiphospholipid Syndrome

Antiphospholipid syndrome (APLS / APS) is an acquired autoimmune thrombophilia defined by arterial or venous thrombosis and/or pregnancy morbidity occurring in the presence of persistent antiphospholipid antibodies (aPL). It is the most common cause of acquired thrombophilia and a favourite of NEET PG examiners for its single most counter-intuitive fact: a clotting disorder that paradoxically prolongs the aPTT in vitro.

Definition & classification

APLS requires at least one clinical criterion and at least one laboratory criterion (revised Sapporo / Sydney classification, 2006). The antibodies must be persistent — confirmed on two occasions ≥12 weeks apart — to exclude transient antibodies from infection.

Clinically it is divided into:

• Primary APLS — occurs in isolation, no underlying connective tissue disease.
• Secondary APLS — associated with an autoimmune disease, most classically systemic lupus erythematosus (SLE). About 30–40% of SLE patients carry aPL; ~10–15% develop overt APLS.
• Catastrophic APLS (CAPS) — a fulminant, life-threatening variant with multi-organ small-vessel thrombosis developing over days (also called Asherson syndrome).
• Seronegative APLS — clinical picture of APLS but standard antibody panel negative (non-criteria antibodies may be present).

High-yield: APLS = thrombosis (arterial OR venous) and/or recurrent pregnancy loss plus persistent antiphospholipid antibody on two occasions ≥12 weeks apart. Both a clinical and a lab criterion are mandatory.

The antiphospholipid antibodies

Three antibodies are part of the classification criteria. Examiners love the distinction between the functional clotting-based assay (lupus anticoagulant) and the immunoassays (anticardiolipin, anti-β2-GPI).

Antibody	Assay type	Target / notes	Significance
Lupus anticoagulant (LA)	Functional clotting (phospholipid-dependent)	Prolongs phospholipid-dependent clotting tests in vitro	Strongest predictor of thrombosis
Anticardiolipin (aCL) IgG/IgM	ELISA immunoassay	Antibody to cardiolipin (a mitochondrial phospholipid)	Must be medium–high titre (>40 GPL/MPL or >99th percentile)
Anti-β2-glycoprotein I (anti-β2-GPI) IgG/IgM	ELISA immunoassay	β2-GPI is the true antigenic cofactor	High specificity for APLS

High-yield: β2-glycoprotein I (apolipoprotein H) is the true antigen — antiphospholipid antibodies actually bind the cofactor β2-GPI complexed to phospholipid, not the bare phospholipid. This explains the false-positive VDRL (cardiolipin-based test) seen in these patients.

Triple positivity (LA + aCL + anti-β2-GPI all positive) carries the highest thrombotic risk and the highest recurrence rate — a frequently tested point.

Etiology & pathophysiology

aPL are directed against plasma proteins bound to anionic phospholipids, the dominant one being β2-glycoprotein I. The thrombotic mechanism is multifactorial:

1. Endothelial activation → upregulation of adhesion molecules and tissue factor.
2. Platelet activation → increased GPIIb/IIIa expression and thromboxane A2.
3. Monocyte tissue-factor expression → activates the extrinsic coagulation pathway.
4. Complement activation (especially C5a) → central in pregnancy morbidity and CAPS.
5. Inhibition of natural anticoagulants → interference with protein C/S pathway and antithrombin; reduced fibrinolysis (annexin A5 "shield" disruption on trophoblast).

A "two-hit" hypothesis is invoked: aPL create a prothrombotic state (first hit), but a second trigger — infection, surgery, immobilisation, pregnancy, oestrogen, smoking — precipitates the actual thrombus.

High-yield: Pregnancy loss in APLS is driven less by simple placental thrombosis and more by complement-mediated (C5a) inflammation and inhibition of trophoblast annexin A5 — which is why heparin (anti-complement + anticoagulant) works but warfarin does not in pregnancy.

Clinical features

APLS is a multisystem disease. Memorise the spread across vascular, obstetric, haematological and dermatological domains.

Vascular thrombosis

• Venous: deep vein thrombosis (commonest overall manifestation), pulmonary embolism.
• Arterial: stroke and TIA (commonest arterial event; APLS is a leading cause of stroke in the young), MI, limb ischaemia.
• Unusual sites: Budd–Chiari syndrome, renal vein/artery thrombosis, retinal vessel occlusion.

Obstetric morbidity — any one of:

• ≥3 consecutive spontaneous abortions before 10 weeks, OR
• ≥1 fetal death ≥10 weeks (morphologically normal foetus), OR
• ≥1 premature birth <34 weeks due to eclampsia/severe pre-eclampsia or placental insufficiency.

Haematological

• Thrombocytopenia (mild–moderate, paradoxically without bleeding).
• Autoimmune haemolytic anaemia (Coombs positive); the combination of AIHA + APLS = part of Evans-like overlap.

Cutaneous & other

• Livedo reticularis — the most characteristic skin sign.
• Cardiac valve disease — Libman–Sacks (non-bacterial thrombotic) endocarditis, classically mitral valve.
• Sneddon syndrome = livedo reticularis + recurrent stroke (aPL-associated).
• Migraine, cognitive dysfunction, chorea, transverse myelitis, aPL-nephropathy.

High-yield: A young patient with stroke + recurrent miscarriage + low platelets + livedo reticularis + prolonged aPTT is APLS until proven otherwise.

The paradoxical laboratory picture

This is the single most examined concept.

• Lupus anticoagulant prolongs phospholipid-dependent clotting assays in vitro (notably the aPTT) because the antibody binds and depletes the phospholipid reagent used in the test tube.
• In vivo, however, there is abundant cell-membrane phospholipid, and the antibody drives a prothrombotic, not anticoagulant, state.
• Hence: prolonged aPTT in the lab but thrombosis in the patient — the "lupus anticoagulant" is a misnomer.

Mixing study: aPTT of patient plasma + normal plasma fails to correct → indicates an inhibitor (rather than a factor deficiency, which would correct). Adding excess phospholipid then corrects it, confirming phospholipid dependence.

Three-step confirmation of lupus anticoagulant:

1. Prolonged phospholipid-dependent screening test (aPTT or dilute Russell viper venom time, dRVVT).
2. Failure to correct on mixing 1:1 with normal plasma (proves an inhibitor).
3. Correction on adding excess phospholipid (proves phospholipid dependence).

High-yield: dRVVT (dilute Russell viper venom time) is the most sensitive and specific screening test for lupus anticoagulant. PT/INR is usually normal — only the phospholipid-dependent intrinsic pathway tests are affected.

High-yield: APLS causes a biological false-positive VDRL/RPR (non-treponemal test uses cardiolipin antigen) with a negative TPHA/FTA-ABS — a classic give-away in NEET PG.

Diagnosis & investigation of choice

Diagnosis is clinico-serological. There is no single confirmatory test; persistence is the key.

Laboratory work-up:

• Lupus anticoagulant (functional, via dRVVT) — investigation of choice for the functional component.
• Anticardiolipin IgG/IgM (ELISA, medium–high titre).
• Anti-β2-glycoprotein I IgG/IgM (ELISA).
• Repeat all positives after ≥12 weeks to confirm persistence.

Pre-test cautions (commonly tested pitfalls):

• Lupus anticoagulant testing is unreliable during active thrombosis/acute phase and while on anticoagulation — defer or interpret cautiously.
• Heparin and DOACs interfere with the dRVVT; warfarin also affects results.

Feature	Inherited thrombophilia	Antiphospholipid syndrome
Nature	Genetic (e.g., Factor V Leiden, protein C/S deficiency)	Acquired, autoimmune
aPTT	Normal	Often prolonged (LA effect)
Mixing study	Corrects	Does not correct
Arterial events	Rare	Common (stroke, MI)
Pregnancy loss	Variable	Characteristic, recurrent
VDRL	Normal	False-positive

Management / drug of choice

The cornerstone is anticoagulation. Asymptomatic aPL carriers are generally not anticoagulated (low-dose aspirin ± risk-factor control may be considered, especially with triple positivity or SLE).

Acute thrombosis → heparin (LMWH or UFH) bridging to warfarin.

Long-term secondary prevention:

• First venous thrombosis: warfarin, target INR 2.0–3.0, usually lifelong (recurrence risk is high).
• Arterial thrombosis / recurrent events: higher intensity INR 3.0–4.0 or warfarin + low-dose aspirin (institution-dependent).

High-yield: DOACs (especially rivaroxaban) are NOT recommended in high-risk / triple-positive APLS — the TRAPS trial showed increased arterial thrombotic events. Warfarin remains the drug of choice for thrombotic APLS.

Management flow for acute thrombotic APLS:

Confirm thrombosis → Start LMWH/UFH → Overlap with warfarin (bridge ≥5 days, INR therapeutic ×2 days) → Stop heparin → Lifelong warfarin, INR 2–3 (venous) or higher for arterial → Address triggers / add hydroxychloroquine if SLE

APLS in pregnancy (a guaranteed exam theme):

• Warfarin is teratogenic (warfarin embryopathy: nasal hypoplasia, stippled epiphyses, CNS defects) and is contraindicated, particularly in the first trimester.
• Standard regimen: low-dose aspirin + prophylactic/therapeutic LMWH (heparin) throughout pregnancy.
• Aspirin is usually started pre-conception/early; heparin added once pregnancy confirmed.
• Continue 6 weeks postpartum (puerperium is highly prothrombotic).
• Hydroxychloroquine is a useful adjunct, especially in SLE-associated APLS.

High-yield: Pregnancy DOC = aspirin + heparin (LMWH). Heparin does not cross the placenta; warfarin does and is teratogenic.

Catastrophic APLS (CAPS / Asherson syndrome):

• Rapid (≤1 week) multi-organ failure from widespread small-vessel thrombosis; mortality ~30–50%.
• Triple therapy: anticoagulation (heparin) + high-dose corticosteroids + plasma exchange and/or IVIG.
• Treat the precipitant (infection, surgery, drug withdrawal). Rituximab or eculizumab (anti-C5) in refractory cases.

High-yield: CAPS triad of therapy = anticoagulation + steroids + plasmapheresis/IVIG. Suspect CAPS when ≥3 organs are involved within a week.

Mnemonic for clinical APLS — "CLOT":

• C — Coagulation defect (thrombosis, arterial & venous)
• L — Livedo reticularis / Libman–Sacks endocarditis / Low platelets
• O — Obstetric loss (recurrent miscarriage, fetal death)
• T — Thrombocytopenia

Complications

• Recurrent thromboembolism despite anticoagulation (especially if subtherapeutic INR).
• Stroke and vascular dementia in young patients.
• Pregnancy: recurrent loss, severe early pre-eclampsia, IUGR, placental insufficiency, abruption, HELLP.
• aPL nephropathy → hypertension, renal impairment, thrombotic microangiopathy.
• CAPS — multi-organ failure, ARDS, high mortality.
• Cardiac valve thickening/regurgitation (Libman–Sacks) → embolic stroke.
• Bleeding from anticoagulation; rare hypoprothrombinaemia–LA syndrome (acquired factor II deficiency causing actual bleeding — an exception worth noting).

Key differentials

• Inherited thrombophilias — Factor V Leiden, prothrombin G20210A, protein C/S, antithrombin deficiency (mixing study corrects, aPTT normal).
• Thrombotic thrombocytopenic purpura (TTP) / HUS — thrombocytopenia + microangiopathic haemolysis; ADAMTS13 deficiency distinguishes TTP.
• Heparin-induced thrombocytopenia (HIT) — thrombosis + thrombocytopenia, but temporally linked to heparin and PF4 antibodies.
• Disseminated intravascular coagulation — consumptive, prolonged PT and aPTT, low fibrinogen, raised D-dimer (in APLS, PT and fibrinogen are typically normal).
• SLE itself — overlaps; APLS may be secondary to it.
• Other causes of recurrent miscarriage — anatomical, chromosomal, endocrine, infective.

Clue	Points toward
aPTT prolonged + mixing not corrected	Lupus anticoagulant (APLS)
Thrombocytopenia + schistocytes + ↓ADAMTS13	TTP
Thrombosis 5–10 days after heparin, falling platelets	HIT
↑PT + ↑aPTT + ↓fibrinogen + ↑D-dimer	DIC
False-positive VDRL, negative TPHA	APLS

Recently asked / exam angle

• Single best clue questions: young woman with recurrent abortions + DVT/stroke + prolonged aPTT not correcting on mixing study → APLS; investigation of choice = dRVVT for lupus anticoagulant.
• Paradox question: "Coagulation test prolonged but patient has thrombosis?" → lupus anticoagulant.
• Pregnancy management: DOC = aspirin + LMWH; warfarin contraindicated (teratogenic — nasal hypoplasia, stippled epiphyses).
• Antibody with highest specificity → anti-β2-glycoprotein I; true antigen → β2-glycoprotein I (apolipoprotein H).
• Highest thrombotic risk profile → triple positivity.
• CAPS / Asherson syndrome management triad → anticoagulation + steroids + plasmapheresis/IVIG.
• DOAC pitfall: rivaroxaban contraindicated in high-risk APLS (TRAPS trial) — warfarin preferred.
• False-positive serology: biological false-positive VDRL with negative treponemal test.
• Eponym matches: Libman–Sacks endocarditis, Sneddon syndrome, Asherson (CAPS), Sapporo/Sydney criteria.
• Target INR: 2.0–3.0 for venous events.

Rapid revision

1. APLS = clinical (thrombosis/pregnancy loss) + persistent aPL on two occasions ≥12 weeks apart (Sapporo/Sydney criteria).
2. Three criteria antibodies: lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I.
3. β2-glycoprotein I (apolipoprotein H) is the true antigen.
4. Lupus anticoagulant prolongs aPTT in vitro yet causes thrombosis in vivo — the central paradox.
5. dRVVT = most sensitive/specific functional test for lupus anticoagulant.
6. Mixing study does NOT correct (inhibitor); corrects on adding excess phospholipid.
7. Triple positivity = highest thrombotic and recurrence risk.
8. Biological false-positive VDRL with negative TPHA/FTA-ABS.
9. DVT = commonest manifestation; stroke = commonest arterial event; livedo reticularis = most characteristic skin sign.
10. Thrombotic APLS DOC = warfarin INR 2–3, lifelong; avoid DOACs in high-risk/triple-positive disease.
11. Pregnancy DOC = low-dose aspirin + LMWH heparin; warfarin teratogenic (nasal hypoplasia, stippled epiphyses).
12. CAPS (Asherson) = multi-organ thrombosis <1 week → anticoagulation + steroids + plasmapheresis/IVIG.