Antiphospholipid Syndrome (APS)
Definition
APS is an autoimmune pro-thrombotic disease characterised by:
- Clinical evidence of thrombosis (arterial, venous, or small vessel) and/or pregnancy complications
- In the presence of persistently +ve antiphospholipid antibodies
Causes and Risk Factors
APS could be primary or secondary: [Ref]
| Primary | Idiopathic |
| Secondary | Occurs in association with other autoimmune diseases:
|
Pathophysiology
Antiphospholipids are pro-thrombotic → leads to a hypercoagulable state and thrombosis
Clinical Manifestation
Young female with unprovoked thrombosis or recurrent miscarriage → consider APS
Possible clinical manifestations:
| Category | Clinical manifestation |
|---|---|
| Thrombotic manifestation | Venous thrombosis (most common)
Arterial thrombosis
|
| Obstetric manifestation |
|
| Other features |
|
Catastrophic APS is a rare, life-threatening form of APS characterised by rapid, widespread small-vessel thrombosis, leading to multiorgan failure and requiring urgent treatment.
Diagnosis
APS Testing
| Indications for testing | ANY of the following:
|
| APS testing | Test for:
|
Do NOT routinely test for APS in patients with VTE provoked by a major transient risk factor (e.g. surgery, immobilisation) or in those with active cancer.
Diagnostic Criteria
Diagnostic criteria (revised Sapporo criteria):
- At least 1 clinical criterion (vascular or obstetric event), and
- Laboratory criterion
| Criterion category | Description |
|---|---|
| Clinical criterion | Vascular thrombosis event
|
Obstetric event (pregnancy morbidity) – any of the following (based on the assumption that it is NOT caused by fetal / parental anomalies):
|
|
| Laboratory criterion | To meet this criterion: +ve antiphospholipid antibodies (any of the following) on 2 occasions at least 12 weeks apart
|
Triple +ve APS
Defined as the persistent presence of 1) lupus anticoagulant, 2) anticardiolipin antibody, and 3) anti-β2 glycoprotein-1 antibody
Triple +ve APS is the highest-risk antibody profile, associated with:
- Significantly higher risk of thrombotic and obstetric events
- Poor responses to DOACs
Patients who meet the laboratory criteria but not the clinical criteria (i.e. those with antiphospholipid antibodies but no history of thrombotic or obstetric events) do NOT have antiphospholipid syndrome. Instead, they are described as asymptomatic antiphospholipid carriers.
Other Laboratory Findings
Haematological findings in APS (but not part of the diagnostic criteria): [Ref]
- Thrombocytopaenia
- Prolonged aPTT
Laboratory findings of SLE may also be present in secondary APS:
- FBC: haemolytic anaemia, leukopaenia
- Serology: +ve ANA, anti-dsDNA, anti-Smith antibodies
- Low C3 and C4
- ↑ ESR, normal CRP
Note: These findings are associated with APS with underlying SLE and are NOT typical of primary APS (or APS from other secondary causes).
See the Systemic Lupus Erythematosus (SLE) article for more information.
Management
Asymptomatic Antiphospholipid Carriers (Primary Prevention)
This refers to those with persistently positive antiphospholipid antibodies but no history of thrombotic or obstetric events
| Management aspect | Description |
|---|---|
| Cardiovascular risk factor management | Primary management aim in primary prophylaxis
|
| Low-dose aspirin | Routine use of low-dose aspirin for primary prophylaxis is NOT recommended
Exception: consider in those who have had a history of obstetric events but never had a thrombotic event (after careful risk and benefit assessment) |
| Hydroxychloroquine | Routine use of hydroxychloroquine for primary prophylaxis is NOT recommended
Exception: consider in those with triple +ve APS, esp. if additional vascular risk factors are present |
Anticoagulation is generally NOT recommended for primary prophylaxis.
BSH guidelines noted a conflict with EULAR guidelines.
- EULAR guidelines recommend low-dose aspirin in APS patients with high-risk profiles
- However, BSH guidelines maintain a recommendation against routine use because prospective studies have failed to show a significant benefit for aspirin in reducing first-time thrombotic events
Established Thrombotic Antiphospholipid Syndrome (Secondary Prevention)
This refers to those with established antiphospholipid syndrome who had a previous thrombotic event +/- obstetric event.
After First Thrombotic Event
| Thrombosis type | Management |
|---|---|
| Venous thrombosis | 1st line: warfarin
|
| Arterial thrombosis (stroke / TIA / MI) | 1st line: warfarin
If warfarin is contraindicated → consider dual antiplatelet therapy |
When initiating warfarin, a heparin lead-in is required. A fast-acting anticoagulant (usually LMWH) is started alongside warfarin and continued until the INR reaches the target therapeutic range, usually 2.0-3.0. The heparin can then be discontinued, and the patient is maintained on warfarin alone.
DOACs (e.g. apixaban, rivaroxaban) should be avoided (esp. in triple +ve APS) due to significantly higher risk of arterial thrombosis (esp. stroke), compared to warfarin.
If the patient is anticoagulated with DOACs, they should be switched to warfarin.
Recurrent Thrombosis Despite Anticoagulation
The following steps should be performed:
- Specialist referral
- Ensure the patient is on warfarin (if on DOAC → switch to warfarin)
- Optimise warfarin therapy (e.g. review drug interactions, adherence, accuracy of INR measurement)
If the patient is experiencing recurrent thrombosis despite optimal anticoagulation with warfarin (INR 2.0-3.0), escalation of therapy is necessary:
- Step 1:
- Increase target INR to 3.0-4.0 (on warfarin), OR
- Add an antiplatelet (aspirin) + maintain target INR of 2.0-3.0
- Step 2: consider adding hydroxychloroquine
- Step 3 (highly refractory cases): consider rituximab or complement inhibitors (e.g. eculizumab)
Obstetric Antiphospholipid Syndrome (Management in Pregnancy)
| Medication change upon confirmation of pregnancy |
|
| Fetal monitoring to detect signs of placental dysfunction |
Also see the Small for Gestational Age (SGA) and Fetal Growth Restriction (FGR) and Hypertension in Pregnancy (Gestational Hypertension, Pre-Eclampsia, and Eclampsia) articles |
Catastrophic Antiphospholipid Syndrome
Catastrophic APS is a medical emergency that requires a multidisciplinary approach involving haematologists, intensive care clinicians and other relevant specialists.
Acute management involves:
- 1st line: triple therapy with therapeutic dose IV heparin + high-dose corticosteroid + IVIG and/or plasma exchange
- 2nd line: consider cyclophosphamide, rituximab, eculizumab