Antiphospholipid Syndrome (APS) (BSH 2012, Blood 2015, BSH Addendum 2020)
Definition
A patient with thrombosis or a defined pregnancy morbidity who has persistent antiphospholipid antibodies (APL)
Diagnosis
1 Clinical + 1 Laboratory criteria required
Clinical Criteria
Vascular thrombosis - ≥1 clinical episodes of arterial/venous/small vessel thrombosis
Pregnancy morbidity
≥3 consecutive spontaneous miscarriages before 10th week, not otherwise explained
≥1 unexplained death of a morphologically normal fetus after the 10th week
≥1 pre-term birth of a morphologically normal fetus before 34th week due to eclampsia, pre-eclampsia or placental insufficiency
Laboratory Criteria
≥1 or the following present in plasma on 2 occasions more than 12 weeks apart
Lupus Anticoagulant (LA)
Anti-cardiolipin IgG or IgM Antibodies at med-high titre (>99th centile)
Anti-B2-Glycoprotein-1 IgG or IgM Antibodies at med-high titre (>99th centile)
Antiphospholipid Antibodies (APL)
Lupus Anticoagulant (LA) is most predictive of thrombosis. Presence of the other two increases specificity.
Small number of patients have all three and they are at highest risk.
Lupus Anticoagulant (LA)
An in vitro phenomenon causing prolongation of phospholipid-dependent coagulation tests, due to antibodies directed against phospholipid binding proteins.
LA can rarely cause bleeding problems!
Either by causing hypothrombinaemia, or by thrombocytopenia secondary to another underlying autoimmune disorder
Cardiolipin
Component of the mitochondrial membrane in most cells.
B2-Glycoprotein-1
An apolipoprotein, part of the complement control family. Binds to cell surface receptors.
Principle of testing for a LA
1. Prolonged phospholipid-dependent clotting tests by two methods (e.g. DRVVT + Silica)
2. Demonstrate the presence of an inhibitor by use of a mixing study
3. Demonstrate the phospholipid dependence of the inhibitor (e.g. by use of high concentration phospholipid)
How does detection of an APL affect management?
Incidental finding:
Do not use primary thromboprophylaxis
LA present in 0.9% of asymptomatic individuals
Anti-Cardiolipin (aCL) found in 6% of healthy blood donors —> no thrombosis in 12 months f/up.
178 asymptomatic carriers of APL followed for 3 years —> no thrombosis
25 of 100 triple positive carriers had thrombosis over 5 years (5% per year)
Which patients with VTE should be tested?
Test in unprovoked VTE after 3 months of treatment if would otherwise plan to stop anticoagulation. If APL detected, risk/benefit supports long term anticoagulation
VTE recurrence is higher in unprovoked events
In unprovoked VTE, being aCL positive doubled the risk of recurrence
Insufficient evidence to support LT AC if APL detected following a provoked VTE
Features indicating an increased likelihood of APS:
History of SLE or other AI disease, livedo reticularis, prolonged APTT, recurrent thrombosis, VTE at unusual sites, arterial thrombosis without risk factors, thrombocytopenia, recurrent pregnancy complications (miscarriage/still birth/severe pre-eclampsia), cardiac valve abnormalities in the absence of other explanations.
Testing in Stroke
Routing testing not recommended
Consider testing if stroke in <50-year-old. If positive, consider warfarin > aspirin (weak evidence)
anticoagulant (AC) choice
BSH recommendations:
Arterial thrombosis - Warfarin for treatment and 2o prophylaxis
Triple Positive APS + VTE - Warfarin for treatment and 2o prophylaxis. Specifically recommend against DOAC and any patient on a DOAC should be advised to switch to warfarin.
Non-Triple Positive APS + VTE - Lacking evidence. Warfarin preferred. Suggest against the initiation of DOAC. Patients already on DOAC may continue or switch to warfarin after individualised discussion.
Trial data related to DOAC in APS:
Woller et al 2021 - Apixaban vs Warfarin. Trial stopped early due to high rate of thrombosis in apixaban arm vs no events in warfarin arm. Patients were a mix of single/double/triple positive APS.
Meta-Analysis 2018 - 447 APS patients treated with DOAC. 16% recurrent thrombosis after a mean period of 12.5 months. Risk of recurrence four-fold higher for triple positive APS compared to single or dual positive.
RCT by Pengo et al 2018 - 120 triple positive APS patients with history of thrombosis. Rivaroxaban vs Warfarin. 12% thrombotic events in rivaroxaban arm, none in warfarin. Trial terminated early.
RAPS Trial 2016 – 100 pts with thrombosis and APL. Rivaroxaban vs warfarin. Rivaroxaban did not reach non-inferiority, but there were no recurrent VTE in either arm at six months.
Warfarin monitoring in patients with LA
Do not use point of care machine
Ensure a LA-insensitive PT assay is used
Pregnancy
Check for anti-Ro and anti-La antibodies —> increased risk of heart block
Increased risk of pre-eclampsia —> uterine dopplers from 22 weeks
Management
1. If APL in recurrent miscarriage —> Aspirin + LMWH from positive preg test until 7 days postpartum
2. If previous VTE (+/- APS) —> LMWH throughout pregnancy and 6 weeks postpartum
3. If APS + previous pre-eclampsia —> aspirin only throughout pregnancy
Catastrophic Antiphospholipid Syndrome (CAPS)
1% of patients with APS
Acute onset multiple micro and macrovascular thromboses —> multi-organ failure
Precipitant often present – e.g. infection, medication change, surgery, anticoag withdrawal
50% of cases are the first presentation of that patient’s antiphospholipid syndrome
Thrombocytopenia and haemolysis frequently present —> diagnostic challenge
CAPS Registry 2000 Classification Criteria:
No standardized treatment, combinations of:
Anticoagulation
Steroids, IVIg
Plasma Exchange for 3-5 days
(Cyclophosphamide, Rituximab, Eculizumab)
DRVVT – Dilute Russell Viper Venom Time
Principle
Russell’s viper venom is a potent activator of FX
Added to phospholipid, prothrombin and calcium it will clot fibrinogen to fibrin
Activates FX so the test is unaffected by deficiencies of FVIII, IX, XI and XII
If a LA is present this will bind to phospholipid and prolong the clotting time
Method
1. Pooled normal plasma + dilute phospholipid + DRVV + Calcium —> Clot time
2. Patient plasma + dilute phospholipid + DRVV + Calcium —> Clot time
3. Calculate ratio: (NR 0.9-1.05)
Result & Next Step
DRVVT Ratio >1.05 suggest possible LA
If it corrects with normal plasma —> Possible deficiency of FII, FV, FX or Fibrinogen
If it corrects with phospholipid (see below) —> LA
% Correction
% Correction calculated following a neutralization step when extra phospholipid (+PL) is added and the DRVVT repeated.
(Patient DRVVT / Control DRVVT) – (Patient DRVVT+PL / Control DRVVT +PL)
Test DRVVT / Control DRVVT
A positive correction of >10% is considered consistent with a lupus anticoagulant.
Silica Clotting Time (2nd Method)
Method
SCT is performed as per an APTT (Silica is the contact activator)
SCT Screen – performed with a low concentration of phospholipid
SCT Confirm – performed with a high concentration of phospholipid
Result
Looking to assess the degree of correction in clotting time achieved by the +PL
1. SCT Screen ratio = Patient SCT Screen / Mean of SCT Screen Reference Range
2. SCT Confirm ratio = Patient SCT Confirm / Mean of SCT Confirm Reference Range
3. Normalised ratio = Screen ratio / Confirm ratio
An increased normalised ratio suggests presence of a lupus anticoagulant
(>1.16 or >1.24 depending on analyser and reagents used)
testing on anticoagulation
Taipan snake venom can be used for lupu testing in patients on warfarin
DOAC Remove can be used to treated samples before testing in patients on DOACs