Antiphospholipid Antibody Syndrome (1)

8/10/2019 Antiphospholipid Antibody Syndrome (1)

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Antiphospholipid AntibodySyndrome

Thomas L. Ortel, M.D., Ph.D.

Duke Hemostasis & Thrombosis Center

30 September 2006


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Patient History

59 yr old man admitted locally with chest pain,

found to have a non-Q-wave MI.

Remote history of DVT and PE, on chronic oralanticoagulant therapy (target INR?).

Warfarin discontinued, and cardiac

catheterization performed.


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Patient History

Complex LAD stenosis treated by angioplasty

and stent placement.

Recurrent chest pain during same admission.

Repeat catheterization found thrombus in stent.

LAD and 1stdiagonal branch restented.

Recurrent chest pain one week later resulted in

2-vessel CABG.


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Patient History

Re-admit one week later with fever, new CHF,and elevated liver function enzymes.

Echocardiogram revealed severe

cardiomyopathy. CT scan revealed multiple liver lesions, felt to be

either cysts or abscesses.

Transfer to Duke because of coagulopathy and

need to biopsy


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Patient Laboratory Data

PT 20.6 sec aPTT 100.3 sec

TCT 8.8 sec DRVVT No clot

Factor VIII Inhibitory Factor IX


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Mixing Studies

NormalDonor

(sec)

Patient +Normal Donor

(sec)

aPTT (Time = 0 min) 26.9 85.4

aPTT (Time = 60 min) 26.7 85.7

PT 12.9 18.6


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Antiphospholipid Syndrome

A clinicopathologicdiagnosis


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Sapporo Criteria (Updated)

International Consensus Statement onClassification Criteria for APS (2006).

Clinical criteria.

Vascular thrombosis.

Pregnancy morbidity.

Laboratory criteria.

Lupus anticoagulant.

Anticardiolipin IgG or IgM antibody.

Anti-b2glycoprotein I IgG or IgM antibody.

-- Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295


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Clinical criteria for APS

Vascular thrombosis*.

Venous thromboembolic disease (DVT, PE).

Arterial thromboembolic disease.

Small vessel thrombosis.

* Coexisting inherited or acquired thrombotic risk

factors are not reasons for excluding patients

from a diagnosis of APS trials.



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Clinical criteria for APS

Pregnancy morbidity.

One or more unexplained deaths of a

morphologically normal fetus at or beyond10th

week of gestation.

Three or more unexplained spontaneous abortions

at or prior to 10thweek of gestation.

One or more premature births at or before the 34th

week of gestation due to eclampsia or placental

insufficiency.



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Laboratory criteria for APS

Lupus anticoagulant: defined by a

functional, clot-based assay using the ISTH

guidelines.

Anticardiolipin IgG or IgM antibody. Anti-b2glycoprotein I IgG or IgM antibody.

--Measured on 2 or more occasions at

least 12 weeks apart.



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ISTH criteria for lupus

anticoagulants

Prolongation of a phospholipid-dependent

screening assay;

Evidence of inhibitory activity;

Evidence that inhibitory activity is phospholipid-

dependent; and,

Distinction from other coagulopathies


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Non-criteria APS findings

Thrombocytopenia and/or hemolytic anemia. Transverse myelopathy or myelitis.

Livido reticularis.

Cardiac valve disease. Nephropathy.

Non-thrombotic neurologic manifestations,

including multiple sclerosis-like syndrome,

chorea, or migraine headaches.



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Did our patient meet clinical

criteria for APS? Major criteria:

Deep venous thrombosis & pulmonary

embolism. Myocardial infarction and stent thrombosis (age

< 60 yrs.).

Non-criteria APS-associated parameters:

Thrombocytopenia.


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Did our patient meet clinical

criteria for APS? Major criteria:

Deep venous thrombosis & pulmonary

embolism. Myocardial infarction and stent thrombosis (age

< 60 yrs.).

Non-criteria APS-associated parameters:

Thrombocytopenia.Yes.


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Did our patient meet laboratory

criteria for APS?

Initial assessment:

Prolonged PT and aPTT that did not correct with

mixing studies.

Decreased factor VIII, IX, and XI levels.

A detectable factor VIII inhibitor by Bethesda assay.

Prolonged DRVVT but could not complete the

CONFIRM portion of the assay.


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Did our patient meet laboratory

criteria for APS?

Initial assessment:

Prolonged PT and aPTT that did not correct with

mixing studies.

Decreased factor VIII, IX, and XI levels.

A detectable factor VIII inhibitor by Bethesda assay.

Prolonged DRVVT but could not complete the

CONFIRM portion of the assay.

No... but


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Alternative strategies to

identify a lupus anticoagulant

Platelet neutralization procedure (PNP; uses

platelet membranes).

Hexagonal phase phospholipid assay

(StaClot LA; uses PE in a hexagonal phase

conformation).

Textarin/Ecarin clot time.

Factor V analysis by PT and aPTT-basedassays.


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Additional Laboratory Data

Factor V (aPTT) Inhibitory

Factor V (PT) 115%

Factor II 38%

Fibrinogen 795.6 mg/dl

D-dimer >4.37 mcg FEU/ml

Repeat DRVVT (ratio) 3.23

DRVVT Confirm (ratio) 2.17


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Assessment of

Coagulation Tests

Lupus anticoagulant detected and confirmed.

Multiple factor deficiencies in aPTT pathway

reflect high-titer lupus anticoagulant. Prolonged PT reflects mild factor II deficiency

and lupus anticoagulant effect.

Elevated D-dimer reflects recent thrombosis.

Elevated inhibitor titer due to lupus anticoagulant


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What are the clinical implications

of an elevated antiphospholipidantibody level?

F f ti h h li id


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Frequency of antiphospholipid

antibodies in different populations

Population aCL LAC

Normal individuals: 2-5% 0-1%

Normal pregnancy: 1-10% -

Elderly (>70 years of age): >50% -

Patients with SLE: 17-86% 7-65%

Family members of patients with APS: 8-31% -

Ri k f th b i i ti t ith


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Risk of thrombosis in patients with

antiphospholipid antibodies

Incidence of thrombosis: ~2-2.5%.

Coincident risk factors for thrombosis: up to 50%.

Odds Ratios for VTE

SLE with lupus anticoagulant 6.32 (3.80-8.27)*

Non-SLE with lupus anticoagulant 11.1 (3.81-32.3)**

Lupus (1997) 6: 467. ** Lupus (1998) 7: 15.

Am J Med (1996) 100: 530. J Rheumatol (2004) 31: 156


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Antiphospholipid antibodies in patients

with venous thromboembolism

Study VTE Patients aPL positive

Ginsberg, et al. (1995) 65 14%*

Simioni, et al. (1996) 59 8.5%*

Mateo, et al. (1997) 2,132 4.1%

Palomo, et al. (2004) 92 28.3%

* LAC only. Anticardiolipin & LAC. Anticardiolipin only.


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Do any of the clinical laboratorytests identify patients at risk for

thromboembolic problems?

L ti l t ti di li i


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Lupus anticoagulants, anticardiolipin

antibodies, and thrombosis

-- Galli, et al., Blood, 2003; 101: 1

A ti di li i tib d tit


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Anticardiolipin antibody titer

and thrombosis

-- Galli, et a

Blood, 2003;

1827.


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What is the optimal antithrombotictherapy for a patient with APS and

thromboembolism?


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Target INR in patients with APS and

venous thrombosis

Retrospective studies.

Prospective studies investigating oral

anticoagulant therapy that included patients

subsequently found to have antiphospholipid

antibodies.

Prospective randomized clinical trials.


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venous thrombosis

Retrospective studies.

1. Rosove & Brewer (1992): 70 patients with APS

and thrombosis. No thrombosis when INR 3.0.2. Khamashta, et al.(1995): 147 patients with APS

and thrombosis. Of 42 recurrent events on

warfarin, 3 occurred with an INR 3, compared to

39 with INR < 3.


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Recurrent Thrombosis in APS

-- Khamashta, et al., N Eng J Med, 1995; 332:

Warfarin, INR 3.0

ASA

Warfarin, INR < 3.0

None


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Caveats about the

retrospective studies

Retrospective study design.

Heterogenous management of anticoagulant

therapy.

Many patients had secondary APS.

Most of the patients had recurrent thrombosis.

Hemorrhagic complications relatively common.

T t INR i ti t ith APS d


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venous thrombosis

Prospective studies.

1. Schulman, et al. (1998): 412 patients with a first

episode of venous thromboembolism treated for 6

months with oral anticoagulants with a target INRof 2.0 to 2.85.

68 patients (16.5%) had an anticardiolipin

antibody detected at the time anticoagulation was

stopped.

T t INR i ti t ith APS d


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venous thrombosis

Prospective randomized trials.

1. Crowther, et al. (2003): 114 patients with APS

and thrombosis. Higher target INR (3.1 to 4) was

not superior to standard target INR (2 to 3).

2. Finazzi, et al.(2005): 109 patients with APS and

thrombosis. Higher target INR (3 to 4.5) was not

superior to standard target INR (2 to 3).


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Recurrent Thrombosis

0 1 2 3 40.00

0.05

0.10

0.15

0.20

0.25

INR 3.1-4.0

INR 2.0-3.0

Time since Randomization (yr)

Patients

withRecurrent

Thro

mbosis(%)

-- Crowther, et al., N Eng J Med, 2003; 349: 11

C t b t th


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Caveats about the

prospective randomized trials

Patients with previous thrombotic recurrence

were excluded.

Few patients with secondary APS. Few patients with arterial thromboembolism.

Patients in the high-intensity group more

frequently subtherapeutic than those in the

standard intensity group.


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ACCP Guidelines

Treatment of venous thromboembolism inpatients with antiphospholipid antibodies.

We recommend a target INR of 2.5 (INR range,

2.0 and 3.0) (Grade 1A). We recommend against

high-intensity VKA therapy (Grade 1A).

-- Buller, et al., Chest, 2004; 126 (Supplement): 4

How long should patients with APS


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How long should patients with APS

and venous thrombosis be treated

with warfarin?

Schulman, et al., 1998.

Prospective study. 412 patients with 1stepisode of venous thrombo-

embolism treated for 6 months with warfarin.

68 patients (17%) with elevated antibody levels

when warfarin therapy stopped.

Anticardiolipin Antibodies and


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Anticardiolipin Antibodies and

Recurrent Venous Thromboembolism

0 6 12 18 24 30 36 42 48

0.0

0.1

0.2

0.3

ACLA positive

ACLA negative

Months

Cumulative

Probabilityof

Recu

rrence

-- Schulman, et al., Am J Med, 1998; 104: 33

ACCP G id li


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ACCP Guidelines

Treatment of venous thromboembolism inpatients with antiphospholipid antibodies.

We recommend a target INR of 2.5 (INR range,

2.0 and 3.0) (Grade 1A). We recommend against

high-intensity VKA therapy (Grade 1A). We recommendtreatment for 12 months (Grade

1C+).

We suggestindefinite anticoagulant therapy for

these patients (Grade 2C).

-- Buller, et al., Chest, 2004; 126 (Supplement): 4

British Society of Haematology


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Guidelines

For patients with APS and venous thrombosis,

treatment for 6 months with a target INR of 2.5

is reasonable.

Recurrent venous thrombosis should be treatedby long-term oral anticoagulation.

Recurrence while the INR is between 2.0 and

3.0 should lead to more intensive warfarintherapy, target INR 3.5, but this is uncommon.

-- Greaves, et al., Br.J.Haematol., 2000; 109: 704

How do I treat venous


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How do I treat venous

thromboembolism in APS?

Confirm baseline PT is normal.

For an initial event, oral anticoagulation with a

target INR of 2.5 for 12 months. Considerlonger pending clinical course.

Address additional prothrombotic risk factors.

For recurrent events, consider more aggressive

or alternative anticoagulation, or other strategy.


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Antiphospholipid Antibodies and


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Antiphospholipid Antibodies and

Recurrent Stroke

The APASS Investigators, 2004.

Prospective cohort study.

Conducted within the WARSS study.

Compared warfarin (target INR 1.4 to 2.8) vs.

ASA.

Analyzed antiphospholipid status afterstroke.

Composite outcome measure including death,ischemic stroke, or other thromboembolic events.

APASS St d O t


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APASS Study Outcomes

Warfarin Aspirin

0

10

20

30

aPL +

aPL -

Treatment Group

Propo

rtionwith

Eventat2Years

-- APASS Investigators, JAMA, 2004; 291:

Caveats about the APASS study


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Caveats about the APASS study

Patients were stratified according to a singledetermination of anticardiolipin antibody

status.

Patients in this study were older than mostpatients with APS.

Target INR was lower than what is frequently

used to prevent recurrent thromboembolic

events.

What about antiplatelet therapy


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What about antiplatelet therapy

alonein patients with APS and

stroke/TIA?

Aspirin for APS with ischemic stroke


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Aspirin for APS with ischemic stroke

Eight patients with ischemic stroke as the initial

thrombotic presentation of APS.

All were women, mean age of 35.5 years

(range, 26-47 years). Two patients sustained a recurrent stroke during

8.9 years of follow-up (recurrence rate of 3.5 per

100 patient-years). One sustained a DVT.

-- Derksen, et al., Neurology, 2003; 61: 1

ACCP Guidelines


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ACCP Guidelines

Prevention of noncardioembolic cerebralischemic events.

For most patients, we recommend antiplatelet

agents over oral anticoagulation (Grade 1A).

For patients with well-documented prothromboticdisorders, we suggest oral anticoagulation over

antiplatelet agents (Grade 2C).

-- Albers, et al., Chest, 2004; 126 (Supplement): 4



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Because of the high risk of recurrence and

likelihood of consequent permanent disability or

death, stroke due to cerebral infarction in APS

should be treated with long-term oral

anticoagulant therapy, target INR 2.5 (optimal

range 2.0-3.0) (level III evidence, grade B

recommendation).


Guidelines

-- Greaves, et al., Br.J.Haematol., 2000; 109: 704

How do I treat arterial


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How do I treat arterial

thromboembolism in APS?

Confirm baseline PT is normal.

For an initial event, oral anticoagulation with a

target INR of 3.0 for 12 months. Consider

longer pending clinical course.

Address additional prothrombotic risk factors.

For recurrent events, consider more aggressive

or alternative anticoagulation, or other strategy.


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What about our patient?

Arterial andvenous thromboembolism

necessitate anticoagulant therapy.

But what are the hepatic lesions?

And what is going on with his prothrombin

time and factor II?


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Subsequent course

Maintained on therapeutic enoxaparin.

Follow-up CT scan confirmed resolving

infarcts. Follow-up factor II consistently low, and

antiprothrombin antibodies detected

have therefore avoided warfarin.


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Antiprothrombin Antibodies

Anti-prothrombin antibodies are relatively

common in patients with APS (prevalence of

50-90%, dependent on assay). These antibodies may be associated with an

increased thrombotic risk.

Typically, factor II levels are notdecreased.

Hypoprothrombinemia


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Hypoprothrombinemia

Hypoprothrombinemia due to clearingantiprothrombin antibodies is an uncommon

complication.

Low factor II levels associated with increasedbleeding risk.

Treatment typically targets control of bleeding

(PCCs, factor VIIa) and elimination of the

antiprothrombin antibody (immunosuppression).


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Is the INR accurate in all

patients with APS?

Antiphospholipid antibodies and the INR


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Antiphospholipid antibodies and the INR

Study Patients Reagents Inaccurate INR

Robert, 1998 43 8 14% with Innovin

Sanfelippo, 2000 123 1 6.5%*

Tripodi, 2001 58 9 67% with Thromborel R

Rosborough, 2004 68 1 11%*

Perry, 2005 59 4 8% non-measurable

* Compared to chromogenic factor X resu


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Do point-of-care INR meters work in

patients with APS on warfarin?

POC INR Measurements in APS


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POC INR Measurements in APS

Patients followed by the Duke AnticoagulationManagement Service with the diagnosis of

either APS (n=52) or atrial fibrillation (n=46).

Stable warfarin therapy.

Capillary and citrated venous blood checked

on two different point-of-care PT meters,

compared to plasma-based INR and

chromogenic factor X assay.

Perry, et al, Thromb Haemost, 2005; 94:1196-

Non-measurable INR results


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Non measurable INR results

Five APS patients (8.8%) had non-measurableresults with the ProTime monitor.

All five had:

Elevated anti-b2GPI antibody levels (38-338 units).

Elevated anticardiolipin antibody levels (19-286 units)

Lupus anticoagulants.

Error message indicated lack of correction with

control level I.


Difference plotsDifference Plot for Plasma & ProTime INR in Atrial Fibrillation Patients

1 2

1.6

AF


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for INR results

with the ProTimeand plasma-

based assays-1.6

-1.2

-0.8

-0.4

0

0.4

0.8

1.2

0 1 2 3 4 5

Mean INR (Plasma and ProTime INR)

Plasm

a-ProTimeINR

Difference Plot for Plasma & ProTime INR in APS Patients

-1.6

-1.2

-0.8

-0.4

0

0.4

0.8

1.2

1.6

0 1 2 3 4 5

Mean INR (Plasma and ProTime INR)

Plasma-ProTimeINR

Mean absolute differences

between the INR results for the

ProTime and the plasma based

assays were generally small, but

overall significantly different.

Perry, et al, Thromb Haemost, 2005; 94:1196-202.

AF

APS

POC INR Testing in APS


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g

For most patients with APS, the ProTime meter

provided INR results comparable to the plasma-

based INR results.

However, variation between the INR results

obtained by the ProTime meter and the plasmamethod were greater for APS patients than AF.

For a subset of APS patients (8.8%), the INR

could not be determined with the ProTime

meter.


What about patients with recurrent


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What about patients with recurrent

thromboembolism despite

therapeutic warfarin?

Therapeutic options for recurrent


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Therapeutic options for recurrent

thromboembolism in APS

Warfarin with a higher target INR (> 3.0).

Addition of an antiplatelet agent to warfarin.

Change to an alternative anticoagulant (e.g.,

low molecular weight heparin).

Immunomodulatory therapy.

What options are there for


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What options are there for

prevention or treatment ofthromboembolism during

pregnancy?

ACCP Guidelines: Pregnancy and aPL


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g y

Manifestation Recommendation Grade

Antiphospholipid

antibody; no prior

VTE or pregnancy

loss.

Surveillance, or mini-dose

heparin, or prophylactic

LMWH, &/or aspirin

2C

Antiphospholipid

antibody; prior

thrombotic event.

Adjusted dose UFH or

LMWH, plus low-dose

aspirin.

1C

-- Bates, et al., Chest, 2004; 126: 627S-6

What about the asymptomatic


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What about the asymptomatic

individual with an antiphospholipidantibody?

Preventive Therapy with aPL


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py

Patients: 77 with APS and non-gravidthrombosis; 56 asymptomatic aPL-positive.

Study periods:

For patients with thrombosis, 6 months prior to

thrombotic event. For asymptomatic individuals, 6 months prior to

most recent clinic visit.

Study variables included use of aspirin,

hydroxychloroquine, and corticosteroids.

-- Erkan, et al., Rheumatology, 2002; 41:

Preventive Therapy with aPL


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py

Characteristic APS aPL P

Age at event (yr) 34.9 13.4 46.0 13.8


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Prior

thrombosis

No prior

thrombosis

P

Aspirin 1/77 (1%) 18/56 (32%)


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asymptomatic individual with aPL

a low threshold for the use of

thromboprophylaxis at times of high risk is

indicated. Greaves, et al. Br.J.Haematol.,2000; 109: 704.

In most instances there was consensus in

adding low dose aspirin Alarcon-Segovia, et al. Lupus,2003; 12: 499.


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And what lies ahead?

Future Directions


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Future Directions

Can we predict which patients with

antiphospholipid antibodies will develop

thromboembolic complications?


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Discovery ModePreliminary data with patients and controls


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y p

Controls with VTE APS NormalaPLA

Up regulated Down regulated

-- Potti, et al., Blood, 2006; 107: 139

Future Directions


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Future Directions

Can we predict which patients with

antiphospholipid antibodies will develop

thromboembolic complications? Is there an inherited predisposition to developing

antiphospholipid antibody syndrome?

Family history


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Asymptomatic

daughter tests

positive for a lupanticoagulant.

Mother developed arterial

thrombosis and thrombocytopenia

prior to her death.

Familial Antiphospholipid Syndrome


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Family members of patients with APS have an

increased incidence of autoimmune disorders.

Genetics of APS is a clinical trial being

developed by the Rare Thrombotic DiseasesClinical Research Consortium.

For more information:

http://rarediseasesnetwork.epi.usf.edu/rtdc/

Documents

Antiphospholipid Antibody Syndrome (1)