Antiphospholipid Syndrome (BCSH 2012, Blood 2015 (CAPS))

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 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

o   Lupus Anticoagulant (LA)

o   Anti-cardiolipin IgG or IgM Antibodies at med-high titre (>99th centile)

o   Anti-B2-Glycoprotein-1 IgG or IgM Antibodies at med-high titre (>99th centile)

 

Antiphospholipid Antibodies (APL)

 

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!

o   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

-       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

-       aCL found in 6% of healthy blood donors à no thrombosis in 12 months f/up.

-       178 asymptomatic carriers of APL followed for 3 years à 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 + doubled the risk of recurrence

-       Insufficient evidence to support LT AC if APL detected following a provoked VTE

 

Testing in Stroke

 

Routing testing not recommended

Consider testing if stroke in <50-year-old. If positive, consider warfarin > aspirin (weak evidence)

 

Which anticoagulant should be used?

 

Currently warfarin preferred AC

-       Systemic review in 2016 – 122 patients with APS treated with DOAC à 19 recurrent thromboses and triple positive patients had a 3.5-fold increased risk of recurrence.

-       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.

 

Warfarin monitoring in patients with LA

-       Do not use point of care machine

-       Ensure a LA-insensitive PT assay is used

 

 

Pregnancy

 

Check anti-Ro and anti-La antibodies à increased risk of heart block

Increased risk of pre-eclampsia à uterine dopplers from 22 weeks

 

Management

1.     If APL in recurrent miscar à Aspirin + LMWH from positive preg test à 7 days postpartum

2.     If previous VTE (+/- APS) à LMWH throughout pregnancy and 6 weeks postpartum

3.     If APS + previous pre-eclampsia à aspirin only throughout pregnancy

 

Catastrophic Antiphospholipid Syndrome (CAPS)

 

1% of patients with APS

Acute onset multiple micro and macrovascular thromboses à 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 presentà diagnostic challenge

 

CAPS Registry 2000 Classification Criteria:

caps.png

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 à Clot time

2.     Patient plasma + dilute phospholipid + DRVV + Calcium à Clot time

3.     Calculate ratio:  (NR 0.9-10.5)

 

Result & Next Step

 

DRVVT Ratio >1.05 suggest possible LA

-       If it corrects with normal plasma à Possible deficiency of FII, FV, FX or Fibrinogen

-       If it corrects with phospholipid (see below) à 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)