Background Information
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
Aetiology
APS could be primary or secondary.
| Primary | Idiopathic |
| Secondary | Occurs in association with other autoimmune diseases:
|
Pathophysiology
Antiphospholipids are pro-thrombotic Antiphospholipid antibodies have the following effects:
→ 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
Indications for APS Testing
- All newly diagnosed SLESystemic lupus erythematosus
- Unprovoked venous thrombosis
- <50 y/o with arterial thrombosis with no other vascular risk factors
- Obstetric clinical criteria – any of the following (based on the assumption that it is NOT caused by fetal / parental anomalies):
- ≥3 consecutive unexplained miscarriages <10 weeks
- ≥1 unexplained fetal death ≥10 weeks
- ≥1 premature birth <34 weeks due to eclampsia / pre-eclampsia / placental insufficiency
Do NOT routinely test for APS in patients with VTEVenous thromboembolism 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
Definition: persistent presence of 1) lupus anticoagulant, 2) anticardiolipin antibody, 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 DOACsDirect oral anticoagulants
If a patient meets the laboratory criteria but not the clinical criteria (i.e. no prior thrombotic or obstetric events), they are termed an asymptomatic antiphospholipid carrier.
Investigations
Important haematological findings (but not part of the diagnostic criteria):
- Thrombocytopaenia
- Prolonged aPTT
Key laboratory findings seen in SLE may also be present in secondary APS:
- FBC: anaemia, leukopaenia
- SLE serology (+ve ANA, anti-dsDNA, anti-Smith antibodies)
- Low C3 and C4
Note: These findings are associated with APS with underlying SLE and are NOT typical of primary APS (or APS from other secondary causes)
Management
Anticoagulation is generally NOT recommended for asymptomatic patients who have positive serology (suggesting APS) but no history of thrombosis or obstetric APS.
There are 2 main approaches
- Primary prophylaxis: asymptomatic APL carrier without any history of thrombotic or obstetric events
- Secondary prophylaxis: APL carriers with previous thrombotic or obstetric events
Primary Thrombosis Prophylaxis
Primary thrombosis prophylaxis is intended for asymptomatic antiphospholipid carriers (i.e. individuals who have persistently positive antibodies but no prior history of thrombotic or obstetric events).
The most important step is aggressive management of cardiovascular risk factors
- Lifestyle advice (including smoking cessation, regular physical activity, and weight loss)
- Strict control of hypertension and diabetes
- Manage hypercholesterolaemia
Pharmacological management:
- BSH guidelines do NOT recommend the routine use of low-dose aspirin and hydroxychloroquine.
- Exceptions:
- Low-dose aspirin can be considered in those who have had a history of obstetric events but never had a thrombotic event (after careful risk and benefit assessment)
- Hydroxychloroquine can be considered in those with triple +ve APS, esp. if additional vascular risk factors are present
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
Secondary Thrombosis Prophylaxis
Important concept: For secondary prophylaxis in APS:
- Warfarin is the anticoagulant of choice
- DOACsDirect oral anticoagulants (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.
After First Thrombosis
Venous Thrombosis
1st line: warfarin
- Target INR: 2.0-3.0
- Duration
- If unprovoked → offer indefinite anticoagulation
- If provoked → long-term anticoagulation is suggested if there is a high-risk antibody profile (e.g. triple +ve APS)
Arterial Thrombosis (Stroke / TIA / Myocardial Infarction)
1st line: warfarin
- Target INR: 2.0-3.0
- Duration: long-term
- If the patient has additional vascular risk factors and no significant risk of bleeding → consider adding an antiplatelet (e.g. aspirin) in addition to warfarin
If warfarin is contraindicated → consider dual antiplatelet therapy
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 has optimal anticoagulation with warfarin (INR 2.0-3.0), escalation of therapy is necessary:
- 1st line (either option)
- Increase target INR to 3.0-4.0 (on warfarin)
- Add an antiplatelet (aspirin) + maintain target INR of 2.0-30.
- If ineffective: consider adding hydroxychloroquine
- For highly refractory cases: consider rituximab or complement inhibitors (e.g. eculizumab)
Recurrent thrombosis despite adequate anticoagulation is unusual and should raise concern for APS. These patients require specialist referral, as further management and treatment escalation should be guided by a specialist.
Details regarding escalation of therapy are unlikely to be examined at a non-specialist level.
APS in Pregnancy
Once the woman has a confirmed pregnancy test:
- Stop warfarin immediately
- Give low-dose aspirin + LMWHLow molecular weight heparin throughout pregnancy
Close-monitoring is necessary to detect signs of placental dysfunction:
- Uterine artery doppler scan is recommended at 20-24 weeks gestation (strong predictor of pre-eclampsia and fetal growth restriction)
- If the dopper is abnormal → perform seral growth scans to monitor for fetal growth restriction
Catastrophic APS
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
References
BSH Guidelines on the investigation and management of antiphospholipid syndrome