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Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment A/Prof P Kuperan FRCP, FRCPA, FRCPath Head & Senior Consultant Department of Haematology Tan Tock Seng Hospital Singapore

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Page 1: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

A/Prof P Kuperan

FRCP, FRCPA, FRCPath

Head & Senior Consultant

Department of Haematology

Tan Tock Seng Hospital

Singapore

Page 2: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Antiphospholipid Syndrome

Autoimmune disorder with various clinical manifestations

Recurrent vascular thrombosis

Pregnancy morbidity

Presence of antiphospholipid antibodies

Page 3: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Laboratory Criteria

LupusAnticoagulant

ACAAnti-2GPI

Phospholipid dependent

Clotting tests

ELISA

Page 4: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Sapporo Criteria 1999

Clinical Criteria Laboratory Criteria

Vascular Thrombosis

Pregnancy Morbidity

LA ACA+

Page 5: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Revised Sapporo Criteria 2006

Clinical Criteria Laboratory Criteria

Vascular Thrombosis

Pregnancy Morbidity

LA ACA+

Anti-2GPI

Page 6: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Protein Targets for APA

2GPIProthrombin

Protein CProtein S

ThrombomodulinFactor XII/ HMWK

Annexin A5Oxidized LDL

Complement factor H & C4b

Page 7: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Antiphospholipid Antibody Syndrome

These patients may have APL other than

Lupus anticoagulant

ACA

Anti-β2GPI

Not included in the current consensus criteria

? What is the significance of these antibodies

Page 8: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Mechanism of thrombosis in patients with APS

Still unknown

Several mechanisms have been proposed

1. Interference with endogenous anticoagulant mechanism

Disruption of annexin A5 anticoagulant shield

Inhibition of protein C pathway

Inhibition of antithrombin

2. Binding and activation of platelets

3. Inducing expression of ahesion molecules and tissue factor by endothelial cells

4. Activation of complement cascade

Page 9: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Testing for antiphospholipid antibodies

No convincing evidence that APL antibodies we currently measure directly cause the disease

There is no convincing evidence that interventions based on antibody levels will have any influence on the disease

Antiphospholipid Syndrome

Page 10: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Sapporo criteria Sydney criteria

LAC Screening-, mixing and confirmation tests (ISTH guidelines)

Two or more occasions, at least 6 wk apart

Screening-, mixing and confirmation tests (ISTH guidelines)

Two or more occasions, at least 12 wk apart

Comparison of the Sapporo (10) and the revised laboratory criteria (1) for the antiphospholipid syndrome

Page 11: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Comparison of the Sapporo (10) and the revised laboratory criteria (1) for the antiphospholipid syndrome

Sapporo criteria Sydney criteria

aCL antibodies

Detected by standardised 2GPI dependent ELISA IgG and/or IgM

Detected by standardised ELISA IgG and/or IgM

Medium or high titre Medium or high titre

>40 GPL or MPL or

>99th percentile

Two or more occasions, at least 6 wk apart

Two or more occasions, at least 12 wk apart

Page 12: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Comparison of the Sapporo (10) and the revised laboratory criteria (1) for the antiphospholipid syndrome

Sapporo criteria Sydney criteria

Anti- 2GPI IgG and/or IgM

titre >99th percentile

Two or more occasions, at least 12 wk apart

Page 13: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Laboratory Criteria

Persistence of antibodies to be documented

8 weeks 12 weeks

Infections – HIV, TB, Hepatitis, Klebsiella

Drugs – procainamide, chlorpromazine, hydrolozine, quinidine, INH, methydopa

May be present in normal healthy population

Page 14: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

CAP External Quality Assurance Program 2009

Normal pooled plasma diluted to 10% normal

Lupus Anticoagulant

Present - 48 (24%)Absent - 154 (76%)

Page 15: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Assessment of the 2006 Revised Antiphospholipid Syndrome

Mala Kaul, Doruk Erkan, Lisa Sammaritano, Michael D LockshinAnn Rheum Dis 2007; 66: 927-930. doi: 10.1136/ard.2006.067314

200 patients with APS by 1999 Sapporo Criteria

Only 59% meet the 2006 APS classification criteria

Page 16: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Multiple Sources of Variation

Pre analytic factors

Analytic factors

Post analytic factors

More common in the testing of lupus anticoagulants

Page 17: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Lupus Anticoagulant Testing

Recommendation of SSC of ISTH

1. Phospholipid – dependent clotting test is prolonged

SCREENING TEST

2. Evidence of an inhibitor demonstrated when clotting time remains prolonged on addition of normal plasma

MIXING STUDY

4. No evidence of a specific inhibitor to a clotting factor

3. Confirmation of the phospholipid dependent nature of the inhibitor by correction of the prolongation in the presence of excess phospholipid

CONFIRMATION TEST

Page 18: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Screening Test for LA

Prolongation of a phospholipid-dependent clotting assay

There is no gold standard test and no single testis 100% sensitive & specific

At least 2 methods to be used

? What 2 tests

APTT/ KCT/ LA-PTT/ DRVVT/…

Page 19: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Screening Test for LA

APTT

Amount of phospholipid

Source of phospholipid

Composition of phospholipids

Physical presentation of phospholipids

Type of activator

APTT – may be normal (acute phase reactants F VIII, Fibrinogen

? How do you ensure – platelet poor plasma <10 x 109/L

Page 20: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Evidence of an Inhibitor Demonstrated by Mixing Studies

Source of normal pooled plasma - ? ensure platelet free

? Corrected/ not corrected ? Cut off

Corrected – weak lupus may be missed

15% of LA may be time-dependent

Page 21: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

CAP External Quality Assurance Program 2009

Normal pooled plasma diluted to 10% normal

50 : 50 mixing studyAPTT immediate mix

50 : 50 mixing studyAPTT incubated mix

Inhibitor

Present 179 (29%)Absent 436 (71%)

137 (26%)393 (74%)

Page 22: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Confirmation of the Phospholipid –Dependent Nature of the Inhibitor

Various sources and types of phospholipids used

Cut off for positivity varies

? Seconds/ ratio/ normalised ratio

Platelet neutralization procedure (PNP)

Freeze-thawed platelets – source of phospholipids

PNP concept – but phosphatidyl ethanolamine in hexagonal configuration

Page 23: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Confirmation of the Phospholipid –Dependent Nature of the Inhibitor

Dilute Russel Viper Venom Test (DRVVT)

(screen + confirm) – integrated test

RVV directly activates factor X

Deficiencies of/ inhibitors to factors in the intrinsic pathway – limited impact

Interpretation of results?

Page 24: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

DRVVT

LA RatioLA screen clotting time----------------------------LA confirm clotting time

Patient Plasma------------------Normal Plasma

Normalised Ratio

LA 1 Ratio-------------LA 2 Ratio

LA screening test ratio = LA 1 Ratio

Patient Plasma------------------Normal Plasma

= LA 2 RatioLA confirm test ratio

Normalised ratio =

Page 25: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

DRVVT

50% NP + 50% PP-----------------------

Normal Plasma

Normalised Ratio (RCPA)

LA Screening test ratio---------------------------LA confirm test ratio

LA screening test ratio =

50% NP + 50% PP-----------------------

Normal PlasmaLA confirm test ratio =

Normalised ratio =

Page 26: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Lack of Specific Inhibition of Any Coagulation Factor

Clinical information is very important

Specific factor inhibitors may mimic LA

Specific factor assays may be necessary

? Interpretation of results

Page 27: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Update of the Guidelines for Lupus Anticoagulant Detection

Patient selection

LA testing should be limited to patients who have a significant probability of having APS

Blood collection

Double centrifugation should be performed

Plasma filtration is not recommended

Choice of test

Does not recommend dilute PT, KCT

Sensitive APTT & DRVVT is recommended

Official communication of the SSC of ISTHJ of Throm. Haem. 2009; 7: 1737-1740

Page 28: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Update of the Guidelines for Lupus Anticoagulant Detection

Mixing test

Pooled normal plasma – ‘home made’ by double centrifugation

Ensure

Platelets < 10 x 109/L

100% activity for all clotting factors

Confirmatory test

Freeze/ thawed platelets as a source of phospholipid is not recommended

Transmission of results

Comments such as ‘borderline LA’ are discouraged

- Instead ask to be ‘retested’

Official communication of the SSC of ISTHJ of Throm. Haem. 2009; 7: 1737-1740

Page 29: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Antiphospholipid Antibody Testing by ELISA

The interlaboratory reproducibility of ACL and anti- 2GPI measurement is unacceptably poor

Cooperative project by the European APL forum

Tincani A et al. Throm. Haemost. 2009; 86: 575-583

Tincani A et al. Throm. Research. 2004; 114: 553-558

Reber et al. Throm. Haemost. 2005; 95: 665-672

Revised criteria dropped the issue that the ACL ELISA should be performed in a 2GPI dependent way

Reduced the specificity of the ACL ELISA

Page 30: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Antiphospholipid Antibody Testing

Lack of reproducibility

Lack of standardization

Attempts at standardization

European forum on APL

Australian ACL working party

Page 31: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

Giannakopoulos, B. et al. Blood 2009;113:985-994

Figure 4 Schematic representation of the cardiolipin ELISA, which detects a number of antibody specificities, including {beta}2GPI

Page 32: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

ACL and Anti-2GPI by ELISA

Recommendations by

European forum on antiphospholipid antibodies

Australian ACL working party

Cut off value

At least 50 normal subjects

>99th percentile

Page 33: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Management of Patients with APS

1st VTEwith reversible

risk factors

OthersNo othermedical

problems

+SLE

Symptomatic PregnancyAsymptomatic

Page 34: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Limited data on its natural history

Only a few randomised treatment trials

Treatment of APS

Mainstay of treatment is antithrombotic therapy

Balance between thrombosis and bleeding in patients with bleeding risks

No single laboratory test to confirm diagnosis

Laboratory tests available are not standardised

Page 35: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Asymptomatic Patients with APS

Erkan et al. Arthritis. Rheum. 2007; 56: 2682-2391

Randomised controlled study

>60% patients with SLE

APL – 6 weeks apart

No difference between aspirin and placebo

Page 36: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Asymptomatic Patients with APS

Erkan et al. Rheumatology (Oxford) 2002; 41: 924-929

Those who developed thrombosis had additionalrisk factors for thrombosis

Patients with SLE prophylaxis with aspirin ±hydroxychloquinine appear to reduce the frequency of thrombotic events

Page 37: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Asymptomatic Patients with APS

Giron-Gonsalez et al. J. Rheumtoid 2004; 31: 1560-67

Aspirin or LMWH given during high risk periods (surgery or prolonged immobilization)

No thrombotic events occurred

Page 38: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Asymptomatic Patients with APS

Individualised assessment of thrombotic risk

No good quality evidence to support routine use of aspirin

In asymptomatic patients with SLE, aspirin and HCQ may be beneficial

Thromboprophylaxis appears to be warranted during periods of increased thrombotic risk

The optimal type and duration of thromboprophylaxis remains unknown

Page 39: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS & Venous Thromboembolism

Identical to that for patients without APS

Patients with risk of bleeding (thrombocytopenia)

?UFH > LMWH

Initial Treatment

Page 40: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS and Venous Thrombosis

What is the optimal intensity of

anticoagulation

What is the optimal duration of therapy

Page 41: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS and Venous Thrombosis

Duration of treatment

No randomised control studies in which patients satisfy the APS classification criteria have been undertaken to date

Page 42: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS & Venous Thromboembolism

Optimal duration of anticoagulation is unknown

Because of the high risk of recurrence

Duration of Treatment

IndefiniteAnticoagulation

to all patients?

Reversible risk factors

Risk factors for bleeding

Patient compliance

Patient preferences

Page 43: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS and Venous Thrombosis

Duration of Anticoagulation

Transient/ reversiblerisk factor

Variables associated with increased risk for bleeding

• Age > 75 years• uncontrolled hypertension• Renal/ liver impairment• Thrombocytopenia• Drug/ alcohol abuse

Page 44: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS & Venous Thromboembolism

Oral anticoagulants (warfarin) with target INR of 2.0 – 3.0

Recommendation based on 2 randomised control trials

High intensity warfarin (INR >3.0) was not superior to standard internationally (INR 2.0 – 3.0) for preventing recurrent thrombosis

Long Term Treatment

Crowther MA et al. NEJM 2003; 349: 1133-1138Finazzi G et al. J. Thromb. Haemost 2005; 3:848-853

Page 45: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome

Mark A. Crowther, M.D., M.Sc., Jeff S. Ginsberg, M.D., Jim Julian, M.Math., Judah Denburg, M.D., Jack Hirsh, M.D., James Douketis, M.D., Carl Laskin, M.D., Paul

Fortin, M.D., David Anderson, M.D., M.Sc., Clive Kearon, M.D., Ph.D., Ann Clarke,

M.D., William Geerts, M.D., Melissa Forgie, M.D., David Green, M.D., Lorrie Costantini, M.Sc., Wendy Yacura, Sarah Wilson, M.P.H., Michael Gent, D.Sc. and

Michael J. Kovacs, M.D.

N Engl J MedVolume 349;12:1133-1138

September 18, 2003

Page 46: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Base-Line Characteristics of the Patients

Crowther, M. et al. N Engl J Med 2003;349:1133-1138

Page 47: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Outcomes and Duration of Follow-up in the High-Intensity and Moderate-Intensity Warfarin Groups, According to Subgroup

Crowther, M. et al. N Engl J Med 2003;349:1133-1138

Page 48: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Conclusions

High-intensity warfarin was not superior to moderate-intensity

warfarin for thromboprophylaxis in patients with antiphospholipid

antibodies and previous thrombosis

The low rate of recurrent thrombosis among patients in whom the

target INR was 2-3

Suggests that moderate-intensity warfarin is appropriate for

patients with the antiphospholipid antibody syndrome

Page 49: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS & Arterial Thromboembolism

No clinical study data are available

APS patients with arterial thromboembolism other than ischaemic stroke

Patients with myocardial infarction/ peripheral arterial thromboembolism

Typically treated with Warfarin INR (2.0 – 3.0)

No studies evaluating optimal duration of treatment for patients with APS and arterial thromboembolism

Page 50: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS & Arterial Thromboembolism

The risk of recurrent arterial thromboembolism in patients with APS is not well defined

APS and stroke study (APASS)

Randomised double blind trial

Comparing Warfarin (1.4 – 2.8) vs. Aspirin 325mg/ day

Similar risk for recurrence in both groups

Limitations of this study

Only one measurement of APA was made

Low titre ACL patients also included

Mohr et al. N. Eng. J. Med 2001; 345: 1444-1451

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Mohr J et al. N Engl J Med 2001;345:1444-1451

Follow-up of Patients and Imputation of Events

Page 52: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Mohr J et al. N Engl J Med 2001;345:1444-1451

Kaplan-Meier Analyses of the Time to Recurrent Ischemic Stroke or Death According to Treatment Assignment

Page 53: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

APS and Thrombocytopenia

Need to distinguish APS from

Thrombotic Thrombocytopenia Purpura (TTP)

Heparin Induced Thrombocytopenia (HIT)

Disseminated Intravascular Coagulation (DIC)

Diagnosis of APS requires documentation of persistent APL (>12 weeks)

APL have been documented in TTP, HIT, HELLP

Uthman I et al. Blood Rev. 2008; 22: 187-194Pauzar et al. J. Thromb. Haemost. 2009; 7: 1070-74

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Thrombocytopenia in APS

Not typically associated with bleeding complications

Thrombotic events still occur in severelythrombocytopenic patients

? Platelet threshold at which antithrombotic agents can be safely used

? Trials/ guidelines on optimal use of antithrombotic agents

Risk/ benefit of antithrombotic therapy balanced against potential risk of bleeding

Some patients may need treatment to raise platelet count to 30 – 50 x 109/L

Page 55: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Management of Obstetric APS Without a History of Thrombosis

Empson et al: Cochrane Database Syst. Review 2005

Meta analysis of trials in the prevention of miscarriages/ fetus loss

Aspirin alone compared to placebo – does not reduce the risk of miscarriage

UFH + aspirin beneficial compared to aspirin

There does not appear to be a role for prednisolone or Iv IgG

Page 56: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Management of Patients with APS & Recurrent Pregnancy Loss

Treatment is aimed at prevention of further pregnancy loss

Prospective study by

Kutteh WH. Am. J. Obst. Gynae 1996; 174: 1584-89

Treatment with heparin and low dose aspirin is superior to low dose aspirin alone

ACCP guidelines

Chest 2008; 133: 844S-886S

Low dose aspirin + prophylactic or intermediate dose UFH

or

Low dose aspirin + prophylactic dose LMWH

Treatment must be individualised based on patient specific risk factors and preferences

Page 57: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Summary I

Challenges in the Diagnosis and Treatment of APS

The correct identificationof pathological APL

Establish the risk profileof the individual patient

To guide his/ her primary or secondary

thromboprophylaxis

Page 58: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Summary II

Testing for APL

The guidelines are not strict enough for LA assay

ACL measurements may be non-specific

Reproducibility is poor

Lack of standardisation

Challenges in the Diagnosis and Treatment of APS

Page 59: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Summary III - Laboratory Diagnosis of Antiphospholipid Syndrome

No single test has sufficient sensitivity and specificity

More stringent guidelines are needed until the availability of a single test

Choice of tests

Page 60: Antiphospholipid Syndrome Challenges in the Laboratory ...haematology.org.my/afh2010/slides/17a.pdf · Antiphospholipid Syndrome Challenges in the Laboratory Diagnosis and Treatment

Summary IV - Laboratory Diagnosis of APS

Adequate laboratory diagnosis is clinically relevant

May be given indefinite oral anticoagulation

Falsely diagnosed high risk of bleeding without any benefit

May not be the markers to assess the risk for thrombosis

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Thank You

For Your

Attention