Antiphospholipid Syndrome (APS) (bsh 2024)

Definition

An autoimmune disease characterised by thrombosis or a defined pregnancy morbidity in association with persistent antiphospholipid antibodies (APL)

Diagnosis

Classification Systems

Revised Sapporo is simple = 1 Clinical + 1 Laboratory criteria required
2023 ACR/EULAR is a scored system, incorporating non-thrombotic clinical features (see guideline)
- ACR/EULAR recommended for use in research studies, not routine clinical practice

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)

Non-Thrombotic Clinical Features

Thrombocytopenia (common, usually mild)
Heart valve disease - valve thickening, valve vegetation

the Antiphospholipid Antibodies (APL)

Lupus Anticoagulant (LA) is most predictive of thrombosis and miscarriage.

‘Triple positive’ patients are at highest risk of thrombosis and/or pregnancy complications.

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.
IgG more strongly associated with thrombosis
IgM more strongly associated with pregnancy complications

B2-Glycoprotein-1

An apolipoprotein, part of the complement control family. Binds to cell surface receptors.
IgG more strongly associated with thrombosis
IgM more strongly associated with pregnancy complications

who should be tested for aps?

BSH2024 recommends testing for APS in the following scenarios:

Unprovoked VTE, or minor provoking factors
VTE at unusual sites, e.g. splanchnic and cerebral venous sinus, in absence of clear risk factors
Arterial thrombosis in <50yo’s without clear risk factors
History of SLE, other AI disorders, pregnancy complications
Livedo reticularis / livedoid vasculopathy
Unexplained prolonged PT/APTT prior to starting anticoagulation
Recurrent thrombosis despite good adherence to anticoagulation
Thrombocytopenia
Recurrent miscarriages/stillbirth/severe pre-eclampsia or placental insufficiency <34wks of onset
Cardiac valve abnormalities, not otherwise explained

Management of aps

asymptomatic, persistently positive apl carriers

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.

Management

Improve modifiable risk factors - smoking, hypertension, diabetes, cholesterol etc
Recommend against routine use of aspirin or hydroxychloroquine as primary prevention
Recommend thromboprophylaxis in high risk situations for all patients with persistently positive APL
Recommend counselling regarding risk/benefit of oestrogen-containing medications
Consider case-by-case use of hydroxychloroquine for triple positive patients with additional RF’s

Observation Studies

119 asymptomatic carriers —> annual rate of first thrombosis 0.65% for single-positive (Puurunen 2014)

Risk comparable to general population
Doubled to 1.2% for double and triple positive patients
All thrombotic events were in patients with an underlying autoimmune disorder

258 asymptomatic carriers of APL followed for 3 years —> 1.8% annual incidence of thrombosis (Tincani 2011)

Compares to 0.1% in general population
Hypertension + LA were predictive of thrombosis
Prophy. LMWH during high risk periods was protective

100 triple positive carriers 5% had thrombosis per year, 25% at 5 years & 37% at 10 years (Iliceto 2011)

Aspirin was not seen to be protective

thrombotic APS

Venous Thrombosis

Offer indefinite anticoagulation following unprovoked VTE (or minor provoking factors if triple positive)
1st choice: Warfarin with INR target 2-3 for treatment and secondary prophylaxis
Definitely avoid DOACs in triple positive patients. Prefer to avoid in single/double positive.
See below for trial data on DOACs

Ischaemic Stroke

Lack of good evidence. NICE and BSH make differing recommendations
NICE NG128 advises APS stroke patients should be managed as for any other stroke
BSH suggests warfarin for all APS stroke patients (+ aspirin if additional vascular RF’s)
BSH recommends against use of DOACs.

Other Arterial Events

Warfarin with INR 2.5

Recurrent Thrombosis despite Anticoagulation

Recurrence risk is high in APS patients (up 30% over 10 yrs in triple positive patients)
If on DOAC, switch to warfarin
If on warfarin, check: Accuracy of INR, Time in therapeutic range, Dietary/Medication interactions
- Then, either increase target INR to 3.5 or add anti-platelet
- Consider addition of immunomodulatory agrents, e.g. hydroxychloroquine, rituximab
Consider referring these patients to specialist centres

Trial data related to DOAC in APS

Bikdeli et al 2023 - Meta-analysis of randomised trials. Use of rivaroxaban and apixaban associated with increased risk of arterial thrombosis, regardless of whether first event was venous or arterial.
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. A 2-yr post trial f/up found higher rate of VTE in patients who remained on rivaroxaban.

obstetric aps

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, typically triple therapy combinations of:

Anticoagulation (Rx-dose heparin or LMWH)
High dose Steroids
IVIg and/or Plasma Exchange
(Cyclophosphamide, Rituximab, Eculizumab)

laboratory testing for aPL

pre-analytical issues

Sample transport and storage affects coag assays, <4 hours from collection to centrifugation is preferable

Testing in the acute phase may lead to false negatives due to elevated FVIII levels shortening the APTT

Details in BSH2024 guideline

solid phase tests

Plasma or serum testing for Anti-cardiolipin (aCL) and Anti-B2-Glycoprotein-1 (aB2GP1)

Testing should include both IgG and IgM

Causes of false positives = rheumatoid factor, heterophile antibodies, recent IVIg, human anti-animal antibodies

Principle of testing for lupus anticoagulant

1. Prolonged phospholipid-dependent clotting tests by two different 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)

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

Warfarin = Taipan snake venom time (TSVT) can be used for patients on warfarin with INR >1.5

DOAC = Activated charcoal products (eg DOACRemove) can be used to treated samples before testing

LMWH/UFH/Heparinoids = Test at least 12 hours after the last dose of heparin, as close to a trough as possible

Warfarin monitoring in patients with LA

Do not use point of care machine

Ensure a LA-insensitive PT assay is used