Antiphospholipid Syndrome: Symptoms, Causes & Treatment
متلازمة المضادات الفسفولبيدية
Antiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies cause pathological clotting in veins and arteries, recurrent pregnancy loss, and thrombocytopenia.
What is Antiphospholipid Syndrome?
Antiphospholipid syndrome (APS), also known as Hughes syndrome, is an acquired autoimmune thrombophilia characterized by: (1) vascular thrombosis (venous and/or arterial); (2) obstetric complications (recurrent pregnancy loss, placental insufficiency, preeclampsia); occurring in the presence of persistently positive antiphospholipid antibodies (aPL): lupus anticoagulant (LA), anticardiolipin antibodies (aCL IgG/IgM), and anti-β2-glycoprotein 1 antibodies (anti-β2GPI IgG/IgM) — confirmed on two occasions ≥12 weeks apart.
APS affects women more than men (5:1 ratio). It occurs as secondary APS in ~50% of patients with systemic lupus erythematosus (SLE) and as primary APS without an underlying autoimmune disease in the remainder. The pathophysiology involves antiphospholipid antibodies binding to phospholipid-binding proteins (particularly β2-glycoprotein 1) on platelet and endothelial cell surfaces, activating procoagulant pathways and inhibiting natural anticoagulant proteins (protein C, annexin A5), creating a hypercoagulable state.
Venous thromboembolism (DVT, pulmonary embolism) is the most common thrombotic manifestation. Arterial thrombosis — stroke and TIA, particularly in young adults without conventional cardiovascular risk factors — is a hallmark feature that mandates aPL testing. Catastrophic APS (CAPS) is a rare but often fatal variant with simultaneous thromboses in multiple organs over days, triggering widespread organ failure; requires aggressive immunosuppression and anticoagulation.
Symptoms
- Venous thrombosis: DVT (painful swollen leg), pulmonary embolism (dyspnea, pleuritic chest pain, tachycardia)
- Arterial thrombosis: stroke or TIA (particularly in patients <50 without conventional cardiovascular risk factors), retinal artery occlusion
- Obstetric: recurrent early pregnancy loss (<10 weeks), unexplained fetal death (>10 weeks), preterm birth from severe preeclampsia or placental insufficiency
- Thrombocytopenia: petechiae, bleeding gums, bruising — immune-mediated, similar to ITP
- Livedo reticularis: lacy purple skin discoloration from microvascular thrombosis — particularly on the legs
- Cardiac valvular disease: Libman-Sacks endocarditis (thickened, vegetating mitral or aortic valve leaflets)
Causes
- Antiphospholipid antibodies (LA, aCL, anti-β2GPI) binding to phospholipid-binding proteins — activating platelets and endothelium, inhibiting anticoagulant pathways
- Secondary APS: underlying SLE (50% of SLE patients have aPL; 30–40% develop thrombosis), rheumatoid arthritis, Sjögren's syndrome, other connective tissue diseases
- Infections: some aPL antibodies are transiently induced by infections (syphilis, hepatitis C, HIV, CMV) — usually low-titer and non-pathogenic
- Drug-induced aPL: chlorpromazine, hydralazine, procainamide — typically non-pathogenic
- Genetic predisposition: HLADR4 and HLA-DQ associations identified
Diagnosis
APS diagnosis (Sapporo/Sydney criteria) requires one clinical criterion AND one laboratory criterion: Clinical: vascular thrombosis (confirmed by objective imaging or histology) OR pregnancy morbidity (≥3 consecutive unexplained spontaneous abortions <10 weeks, or ≥1 unexplained fetal death ≥10 weeks, or ≥1 premature birth <34 weeks from severe preeclampsia/placental insufficiency). Laboratory: positive aPL on ≥2 occasions ≥12 weeks apart: lupus anticoagulant (LA — detected by APTT-based tests + Dilute Russell's viper venom time [dRVVT]), aCL IgG/IgM (moderate-high titer ≥40 GPL/MPL), anti-β2GPI IgG/IgM. Triple positivity (all 3 positive) confers the highest thrombotic and pregnancy risk.
Treatment
Acute thrombosis: anticoagulation with unfractionated heparin or LMWH, transitioning to warfarin (VKA) — target INR 2.0–3.0 for venous events; 3.0–4.0 for arterial events despite anticoagulation. Direct oral anticoagulants (DOACs) such as rivaroxaban have been studied in APS but shown higher arterial thrombosis recurrence than warfarin — warfarin remains standard for high-risk APS. Duration: lifelong anticoagulation for unprovoked thrombosis. Obstetric APS: aspirin 75–100 mg/day + LMWH (prophylactic doses) throughout pregnancy — significantly improves live birth rates. Hydroxychloroquine (Plaquenil): added in secondary APS with SLE; reduces thrombotic recurrence and improves outcomes. Catastrophic APS (CAPS): anticoagulation + corticosteroids + IV immunoglobulin (IVIG) or plasma exchange.
Complications
- Recurrent venous and arterial thrombosis — highest risk after anticoagulation discontinuation
- Catastrophic APS (CAPS): multi-organ thrombotic crisis in <1% of APS patients but 30–50% mortality despite treatment
- Libman-Sacks endocarditis with valvular regurgitation requiring valve repair or replacement
- Pregnancy loss and preterm birth without appropriate anticoagulant prophylaxis
Prevention
- Lifelong therapeutic anticoagulation for documented thrombotic APS — the cornerstone of secondary prevention
- Avoid estrogen-containing contraceptives (increase thrombotic risk); use progestogen-only or non-hormonal contraception
- Low-dose aspirin for aPL-positive patients without prior thrombosis but with additional cardiovascular risk factors (primary prevention)
- Smoking cessation and management of other cardiovascular risk factors
- Antimalarial therapy (hydroxychloroquine) in secondary APS — reduces aPL titers and thrombosis risk
When to see a doctor
Seek evaluation from a rheumatologist or hematologist for: recurrent pregnancy loss (≥2 miscarriages), unexplained stroke or TIA in a young adult, DVT or pulmonary embolism without a conventional risk factor, or thrombocytopenia in a young person. Early APS diagnosis enables anticoagulant treatment that dramatically reduces recurrence risk and pregnancy loss rates.