Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia characterised by recurrent arterial and/or venous thrombosis and pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies (aPL). It is the most common acquired cause of thrombophilia and represents a significant cause of preventable stroke, pulmonary embolism, and pregnancy loss in Australia.

The 2023 ACR/EULAR classification criteria for APS require at least one clinical domain (thrombotic or obstetric) and at least one laboratory domain criterion, with a minimum cumulative score. This replaces the 2006 Sapporo (Sydney) criteria in research settings, though the Sydney criteria remain widely used in clinical practice in Australia.

APS is driven by antiphospholipid antibodies — primarily lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta-2 glycoprotein I (anti-β2GPI) antibodies. These antibodies bind phospholipid-binding proteins (principally β2-glycoprotein I) on cell surfaces, activating endothelium, platelets, and monocytes to produce a pro-thrombotic state.

Key Pathogenic Mechanisms

• Endothelial activation: aPL binding upregulates adhesion molecules (VCAM-1, E-selectin) and tissue factor expression, promoting thrombosis
• Platelet activation: anti-β2GPI antibodies activate platelets via GPIbα and apolipoprotein E receptor 2 (ApoER2), increasing aggregation
• Complement activation: C3, C4 and terminal complement complex deposition drives placental injury and obstetric complications
• Inhibition of natural anticoagulants: Interference with protein C pathway, annexin A5, and prothrombin binding impairs fibrinolysis
• mTOR pathway activation: Promotes endothelial proliferation and vascular nephropathy in APS nephropathy

Obstetric Pathophysiology

Placental thrombosis was historically considered the primary mechanism of pregnancy loss, but complement-mediated placental inflammation (independent of thrombosis) is now recognised as equally important. This explains why anticoagulation alone may be insufficient for some obstetric APS cases.

Antiphospholipid Antibody Profiles and Thrombotic Risk

APS presents with a heterogeneous range of clinical features. Thrombotic APS typically presents with deep vein thrombosis (DVT) or pulmonary embolism (PE), while obstetric APS presents with recurrent miscarriage, late pregnancy loss, or severe pre-eclampsia. Non-criteria manifestations are common and important.

Thrombotic Manifestations

• Venous thromboembolism (most common): DVT (usually lower limb), PE, cerebral venous sinus thrombosis
• Arterial thrombosis: Ischaemic stroke (most common arterial event), TIA, myocardial infarction, limb ischaemia
• Microvascular: Livedo reticularis, digital ischaemia, APS nephropathy (thrombotic microangiopathy)
• Unusual sites: Hepatic vein (Budd-Chiari syndrome), mesenteric, renal or adrenal vein thrombosis
• Cardiac: Libman-Sacks endocarditis (non-infective verrucous valve lesions), valvular thickening

Obstetric Manifestations

• Early pregnancy loss: ≥3 unexplained consecutive miscarriages before 10 weeks gestation
• Late pregnancy loss: ≥1 morphologically normal fetal death at or beyond 10 weeks
• Preterm birth: ≤34 weeks due to severe pre-eclampsia, eclampsia, or placental insufficiency
• Severe pre-eclampsia: Especially if early-onset or associated with fetal growth restriction
• Placental abruption

Non-Criteria Manifestations

• Thrombocytopaenia (immune-mediated, usually mild, 50–150 × 10⁹/L)
• Haemolytic anaemia (Coombs positive)
• Cognitive impairment, headache, migraine, chorea
• Livedo reticularis and livedo racemosa
• APS nephropathy — glomerular microthrombosis leading to hypertension and proteinuria
• Skin ulceration, pseudovasculitic lesions

Diagnosis requires persistent aPL positivity confirmed on two occasions at least 12 weeks apart. Single positive results may represent transient aPL (e.g. infection-related) and should not be used for diagnosis. Testing should be performed when the patient is clinically stable and not acutely thrombotic, as acute thrombosis may affect results.

• Essential
  Lupus Anticoagulant (LA)

  Most strongly associated with thrombosis. Screen with APTT and dRVVT; confirm with mixing studies and phospholipid neutralisation. NOTE: Cannot be tested reliably in patients on anticoagulation (especially rivaroxaban/apixaban — both falsely prolong dRVVT).
• Essential
  Anticardiolipin antibodies (aCL) IgG and IgM

  Clinically significant at ≥40 GPL or MPL units (medium-high titre). Low titres (<40) have limited diagnostic significance. Repeat in 12 weeks to confirm persistence.
• Essential
  Anti-β2 glycoprotein I (anti-β2GPI) IgG and IgM

  Clinically significant at ≥40 units. Triple positivity (LA + aCL + anti-β2GPI) confers the highest thrombotic risk. Repeat in 12 weeks.
• Essential
  Full blood count

  Assess for thrombocytopaenia (immune-mediated) and haemolytic anaemia. Thrombocytopaenia in APS is usually mild and rarely requires treatment.
• Essential
  Coagulation studies (APTT, PT/INR)

  Baseline before anticoagulation; APTT prolonged in LA-positive patients. INR monitoring for warfarin if used.
• Recommended
  ANA and anti-dsDNA, complement (C3, C4)

  Screen for co-existing SLE or other CTD — present in ~35% of APS patients. Hypocomplementaemia supports active SLE.
• Recommended
  Renal function and urinalysis

  Proteinuria and haematuria suggest APS nephropathy; elevated creatinine warrants renal biopsy consideration.
• Recommended
  Doppler ultrasound (limbs)

  Preferred first-line imaging for suspected DVT. Also assess for post-thrombotic changes in recurrent DVT.
• Recommended
  CT pulmonary angiography (CTPA)

  Investigation of choice for suspected pulmonary embolism.
• Recommended
  MRI brain / CT brain

  For ischaemic stroke, TIA, or cognitive impairment. White matter changes on MRI are common in APS.
• Recommended
  Echocardiogram

  Assess for Libman-Sacks endocarditis (verrucous valve lesions) and valvular regurgitation, particularly in patients with cardiac symptoms or prior to anticoagulation decisions.
• Specialist
  Renal biopsy

  Indicated for proteinuria >0.5 g/day or unexplained renal impairment — distinguishes APS nephropathy (thrombotic microangiopathy) from lupus nephritis.
• Specialist
  Thrombophilia screen

  Consider factor V Leiden, prothrombin gene mutation, protein C/S deficiency, antithrombin deficiency if initial aPL negative. Concurrent thrombophilia significantly increases thrombotic risk.

Risk stratification in APS is essential for determining anticoagulation intensity and duration. The Global Anti-Phospholipid Syndrome Score (GAPSS) and the aPL score incorporate antibody profile, cardiovascular risk factors, and clinical history to estimate individual risk. The key determinant of management is the aPL antibody profile (single, double, or triple positive).

APS Risk Stratification Framework

Pregnancy Risk Assessment

• High-risk obstetric APS: Triple positivity, prior thrombosis, or history of severe obstetric complications — requires LMWH + aspirin throughout pregnancy
• Low-risk obstetric APS: Single/low-titre positivity, prior early pregnancy loss only — low-dose aspirin may suffice (debated)
• Asymptomatic aPL in pregnancy: Low-dose aspirin from ≤12 weeks gestation if additional risk factors present
• All pregnant women with aPL should be co-managed by obstetric medicine/maternal-fetal medicine and rheumatology

Management of APS depends on the clinical presentation: thrombotic APS requires anticoagulation, obstetric APS requires aspirin and LMWH during pregnancy, and asymptomatic aPL carriers require risk factor modification with or without aspirin. Hydroxychloroquine (HCQ) has an emerging role across all APS subtypes due to its anti-thrombotic and anti-inflammatory properties.

Thrombotic APS — Anticoagulation

Refractory / High-Risk APS

Catastrophic APS (CAPS) — Emergency Management

Acute thrombotic events in APS require immediate anticoagulation. Unfractionated heparin (UFH) infusion is preferred for haemodynamically significant PE or large arterial thrombosis where thrombolysis may be considered. LMWH is appropriate for DVT and stable PE. Transition to warfarin (not DOAC in high-risk APS) is standard.

Long-term monitoring focuses on anticoagulation safety (bleeding, INR stability), thrombotic recurrence, organ complications (APS nephropathy, Libman-Sacks endocarditis, cognitive impairment), and management of underlying SLE or co-morbidities. Hydroxychloroquine requires specific ocular monitoring.

Monitoring Schedule for APS Patients on Long-term Anticoagulation

Anticoagulation Quality Indicators

• Time in therapeutic range (TTR) target ≥65–70% for warfarin in APS — below this, reconsider dosing strategy or self-testing
• Point-of-care INR self-testing improves TTR in motivated patients — consider referral to anticoagulation clinic
• Record all bleeding events (major vs minor) and thrombotic events
• Educate patient on signs of supratherapeutic INR (unusual bruising, prolonged bleeding from cuts, blood in urine/stool) and subtherapeutic INR (leg swelling, pleuritic chest pain, neurological symptoms)

Pregnancy and Obstetric APS

Obstetric APS requires a multidisciplinary approach with rheumatology, maternal-fetal medicine, haematology, and neonatology. Antenatal aspirin (100 mg daily from ≤12 weeks) and LMWH are the standard of care for high-risk obstetric APS. Warfarin is contraindicated in the first trimester (weeks 6–12) due to warfarin embryopathy. LMWH must be substituted from 36 weeks or earlier if delivery anticipated.

• Contraception: Combined oestrogen-progestogen OCP is contraindicated in aPL-positive women — increases VTE risk. Progestogen-only pill, Mirena (levonorgestrel IUD), or barrier methods preferred
• Breastfeeding: Warfarin is safe during breastfeeding. LMWH is safe. Hydroxychloroquine: limited data, generally continued in SLE-APS given risks of SLE flare with cessation
• Postpartum: Highest risk period for thrombotic APS — continue therapeutic anticoagulation for at least 6 weeks postpartum; indefinite if prior thrombosis

Elderly Patients

• Warfarin in elderly patients with APS requires careful management — increased fall risk, polypharmacy interactions, and renal impairment affecting INR stability
• Consider HAS-BLED score to assess bleeding risk; do not withhold anticoagulation on fall risk alone without specialist input
• Cognitive impairment is more common in elderly APS — may be related to small vessel disease; baseline cognitive assessment valuable

Paediatric APS

• Less common than adult APS; secondary APS (associated with SLE or infection) more common in children than primary APS
• Stroke is the most common thrombotic presentation in children
• Warfarin target INR 2.0–3.0; LMWH preferred in younger children where INR monitoring difficult
• Refer to specialist paediatric rheumatology/haematology

APS with Concurrent SLE

• Present in ~35% of SLE patients; aPL positivity associated with increased risk of damage accrual
• Hydroxychloroquine is strongly recommended for all SLE-APS patients — reduces thrombotic risk and aPL titres
• Active SLE (especially nephritis flares) increases thrombotic risk — optimise disease control
• Belimumab and other biologics used for SLE may also benefit concurrent APS manifestations

Appropriate anticoagulation selection, duration, and monitoring are central to APS stewardship. Key areas include: avoiding DOACs in high-risk patients, ensuring aPL confirmation at 12 weeks before committing to lifelong anticoagulation, and minimising unnecessary anticoagulation in low-risk aPL carriers.

Thromboprophylaxis in Hospitalised APS Patients

• Continue established anticoagulation where possible during hospitalisation; if interruption required, use appropriate bridging strategy
• For APS patients not yet on anticoagulation admitted for non-thrombotic illness: pharmacological VTE prophylaxis recommended (LMWH preferred over UFH for efficiency)
• Mechanical prophylaxis (graduated compression stockings, pneumatic compression devices) for all hospitalised APS patients unable to receive pharmacological prophylaxis
• Early mobilisation; avoid prolonged bed rest

All patients with confirmed APS should be under long-term specialist follow-up. The frequency and setting depend on disease complexity, anticoagulation stability, and concurrent autoimmune conditions. Shared care between rheumatology, haematology, and the GP is appropriate for stable patients.

Follow-up and Referral Framework for APS

Patient Education Key Points

• Never stop warfarin or anticoagulation without medical advice — even brief lapses increase thrombosis risk
• Carry an anticoagulation alert card and medical ID bracelet/wallet card
• Inform all healthcare providers (including dentists, surgeons, pharmacists) of APS diagnosis and anticoagulation
• Seek urgent medical attention for symptoms of DVT, PE (breathlessness, pleuritic chest pain), stroke (FAST), or unusual bleeding
• Women of childbearing age: contraception choices critical — discuss with treating team before any change
• Avoid NSAIDs (including ibuprofen, diclofenac) without medical advice — increase bleeding risk and affect platelet function

• 01
  Tektonidou MG, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296-1304.
• 02
  Barbhaiya M, et al. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol. 2023;75(10):1687-1702.
• 03
  Pengo V, et al. Rivaroxaban vs Warfarin in High-Risk Patients with Antiphospholipid Syndrome (TRAPS). Blood. 2018;132(13):1365-1371.
• 04
  Cohen H, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome (RAPS). Lancet Haematol. 2016;3(9):e426-36.
• 05
  Woller SC, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome (ASTRO-APS). Blood Adv. 2022;6(6):1661-1670.
• 06
  Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (Sydney Criteria). J Thromb Haemost. 2006;4(2):295-306.
• 07
  Cervera R, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period (Euro-Phospholipid project). Ann Rheum Dis. 2015;74(6):1011-8.
• 08
  Bates SM, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317-3359.
• 09
  Knight CL, Nelson-Piercy C. Management of systemic lupus erythematosus during pregnancy: challenges and solutions. Open Access Rheumatol. 2017;9:37-53.
• 10
  Cervera R, et al. Catastrophic antiphospholipid syndrome (CAPS) — descriptive analysis of a series of 280 patients from the "CAPS Registry". J Autoimmun. 2009;32(3-4):240-5.
• 11
  Erkan D, et al. A Cross-Sectional Study of Clinical Thrombotic Risk Factors and Preventive Treatments in Antiphospholipid Syndrome. Rheumatology. 2002;41(8):924-929.
• 12
  Sciascia S, et al. Diagnosing antiphospholipid syndrome: extra-criteria manifestations and technical advances. Nat Rev Rheumatol. 2017;13(9):548-560.
• 13
  Schreiber K, et al. Antiphospholipid Syndrome. Nat Rev Dis Primers. 2018;4(1):17103.
• 14
  Australian Commission on Safety and Quality in Health Care. Venous Thromboembolism Prevention Clinical Care Standard. Sydney: ACSQHC; 2020.