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Dr. Osama Sayed Daifallahabosehly

Assisstant lecturer

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the antiphospholipid antibodies syndrome is

defined as:

Vascular thromboses and\or pregnancy morbidity

occurring in persons with anti-phospholipid

antibodies(APL) most commonly anti-cardiolipin

antibodies(aCL), +ve results for lupus

anticoagulant(LA) test, and anti-B2 glycoprotien-I (B2-

GPI) antibodies.

The origin of APL antibodies is unknown but ishypothesized to be an incidental exposure to

environmental agents inducing APL in susceptible

individuals.

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10-20% of idiopathic thromboembolic disease

are due to APS

50% of patients younger than 50 years and

affected with strokes (without evident etiology)are due to APS

Epidemiology of antiphospholipid antibodies

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Epidemiology of antiphospholipid antibodies

in the normal population: 2 - 5 %

prevalence increases with age and chronic disease

in SLE: 12 - 40 %

LAC: 11-30% aCL: 24-86%

in first Stroke: 10 - 26 %

in recurrent fetal loss: 15 %

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Normal hemostasis

Disruption of vascular endothelial lining allows exposure of

blood to

subendothelial connective tissue:

Primary hemostasis (seconds)

- Platelet plug formation at site of injury

- Stops bleeding from capillaries, small

arterioles and venules

Secondary hemostasis (minutes)

- Fibrin formation by reactions of

the plasma coagulation system

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Bleeding and Thrombosis

Defects in primary

hemostasis

Thrombocytopenia

Defects in secondary

hemostasis

Clotting factor deficiencies Prethrombotic

(hypercoagulable) states

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Prethrombotic disorders

Inherited

Acquired

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Acquired prethrombotic disorders

Conditions associated with a hypercoagulablestate:

- pregnancy and postpartum

- major surgery

- obesity and immobility- malignancy

- congestive heart failure

- nephrotic syndrome

Estrogen treatment

Antiphospholipid syndrome

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APS

Venous thrombosis are more common thanarterial thrombosis

The most common site of DVT is the calf

The most common site of arterial thrombosisis the cerebral circulation

The initial and long-term manifestations of

the disease are similar: in most, but not allthe initial arterial thrombosis tends to befollowed by an arterial event and the initialvenous thrombosis by a venous event

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The Antiphospholipid Syndromeis characterized by:

Arterial or Venous Thrombosis

Recurrent Fetal Loss

Serum Anti-phospholipid antibodies (aPL)

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The Antiphospholipid Syndromemay be:

Primary:

an isolated condition

Secondary:secondary to SLE or other connective

tissue diseases

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Clinical Presentations of APS

Venous thromboembolism:

Deep Vein Thrombosis

Pulmonary Embolism

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ThromboThrombo--embolic diseaseembolic disease

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Pulmonary embolismPulmonary embolism

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Clinical Presentations of APS

Arterial Occlusion:

Stroke and TIAs are the most common

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Cerebrovascular accidents

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Clinical presentations of APSPregnancy morbidity

Recurrent fetal loss

In women with recurrent miscarriage due to APS fetal loss rate: as high as 90%

antiphospholipid abs are associated with:- placental insufficiency

- early preeclamapsia

- IUGR- intrauterine growth restriction

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Antiphospholipid antibodies (aPL)

anti-Cardiolipin IgG

anti-Cardiolipin IgM

Lupus anticoagulant (LAC)

* false positive VDRL

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Antiphospholipid Syndrome

Aclinicopathologicdiagnosis

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Antiphospholipid Syndrome CriteriaSydney revision of Sapporo criteria 2006

CLINICALCRITERIA

Vascular Thrombosis:

-arterial, venous, in any organ

or tissue Pregnancy Morbidity:

a) death of normal fetus

at > 10 wksb) premature birth at < 34

wks due to preeclampsia

c) >3 consecutive abortions

at

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Sydney Revision of Sapporo criteria

(2006)

Clinical Criteria

- Thrombosis:

exclude other causes : male > 55 yrs

female > 65 yrs

- Pregnancy:

placental insufficiency < 34 wksexclude other causes

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Sydney Revision of Sapporo criteria

(2006)

Laboratory Criteria

- medium/high titerIgG or IgM aCL on 2

occasions

12 wks apart

- LAC on 2 occasions 12 wks apart

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Sydney Revision of Sapporo criteria

(2006)

aPL associated manifestations (individual diagnosis)

Thrombocytopenia ( occurs in up to 50%)

Cardiac valve disease

Livedo reticularis

Nephropathy ( late manifestation: proteinuria,

hypertension and creatinine clearance) Non-thrombotic neurologic manifestations, including

multiple sclerosis-like syndrome, chorea, or migraine

headaches.

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Cardiovascular disease

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Libman-Sacks Vegetation

PrevalenceTTE; 10%, TEE; 30%

Mitral and aortic valves < 1 cm2 in size

Irregular borders

Heterogenous echo density No independent motion Associated with thickening or

regurgitation

Cauliflower-like or flat, red multiple spreading

masses of 2 4 mm in diameter present on the

free margins or line of closure of the heart valve

Echo findings

(CardiolClin 1998;16;531)

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Libman-Sacks Vegetation and MR

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Myocardial infarction

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Hematologic manifestations

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Cutaneous manifestations

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Livedo reticularis:

a lattice like pattern of superficial veins.

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Livedo reticularis with necrotic finger tips

in Antiphospholipid syndrome

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CAPS is a rare, lifethreatening complication of

apl which occure in multiple organs over a short

period of days.

Multiple thromboses of medium sized and small

vessels may occur despite of adequate

anticoagulation.

Mortality may reach up to 50% with therapy.

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Antiphospholipid antibodiesantibodies and antigens

Most of the abs are NOT directed against

phospholipids

Most of the antiphospholipid abs recognize

phospholipid binding proteins:

- beta 2 glycoprotein I (F2 GPI)

- prothrombin

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Beta 2 Glycoprotein-I (F2GPI)

F2GPI = a plasma protein with affinity for

negatively charged phospholipids

anti- F2GPI:

are probably the major cause of APS

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Antibodies and antigens

Anticardiolipn abs recognize in most assays:

F2 GPI

Lupus Anticoagulant activity is caused byautoantibodies to:

- F2 GPI - prothrombin

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Laboratory Testing for antiphospholipid

antibodies

Solid phase assays

usually anti-Cardiolipin abs

Lupus Anticoagulant (LAC)

MUST USE BOTH TESTS

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N LAC h 100%

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Tests for LAC

APTT:- variability in reagents result in inconsistent sensitivity.

- acute phase reaction and pregnancy may shorten APTT andmask a weak LAC

A normalAPTT doesnotexclude LAC

KCT- Kaolin clotting time

more sensitive to presence of anti-II

DRVVT- Dilute Russells viper venom timemore sensitive to presence of F2 GPI

TTI - Tissue thromboplastin inhibition test

No LAC shows 100%

specificity and sensitivity

because aPLs are

heterogeneous.

More than 1 test system is

needed

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Possible mechanisms of aPL induced

thrombosis

Endothelial-aPL interactionendothelial cell damage or activation, coexisting anti-endothelial abs, aPL induced monocyte adhesion,

increased tissue factor expression

Platelet-aPL interactionplatelet activation, stimulation of thromboxane production

Coagulation system-aPL interaction

inhibition of activation of protein C , interaction between aPLand substrates of activated protein C: factors Va VIIIa;

interaction between aPL and annexin V anticoagulant shield

Complement activation

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Occurrence of antiphospholipid antibodies

in other conditions:

Infection:

- Syphilis, TB, Q-fever, Spotted Fever, Klebsiella, HCV,

Leprosy,HIV.

- The abs are usually transient, not F2 GPI dependent

Malignancy:

Lymphoma, paraproteinemia

Drug induced:

phenothiazines, procainamide, quinidine, phenytoin,

hydralazine

I di ti f L b t t ti f ti h h li id

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Indications for Laboratory testing for antiphospholipid

abs

Spontaneous venous thromboembolism

Recurrent VT, even in presence of other risk factors

Stroke or peripheral arterial occlusive event at < 50yrs

In all SLE patients

In women with > 3 consecutive pregnancy losses

loss of morphologically normal fetus at II-III trimester

early severe preeclampsia

severe placental insufficiency

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APSTreatment

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Incidental finding of antiphospholipid antibodies

Anti-thrombotic therapy not usually indicated

Low threshold for thromboprophylaxis at times

of high risk

Some suggest low dose Aspirin prophylaxis

Reduce other risk factors for thrombosis

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Venous or Arterial thrombosis

1. Initial treatment with Heparin

2. Start Warfarin

3. Stop Heparin when therapeutic INR achieved

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ACCP Guidelines

Treatment of venous thromboembolism in patients 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 suggest indefinite anticoagulanttherapy for these patients (Grade 2C).

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

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Current Recommendations

Asymptomatic aPL no treatment (Aspirin?)

Venous thrombosis Warfarin INR 2.0-3.0

Arterial thrombosis Warfarin IN

R 3.0 Recurrent thrombosis Warfarin INR 3.0-4.0 +

low dose Aspirin

Thrombocytopenia>50000 no treatment

Thrombocytopenia50000 cs, i.v Ig

CAPS Anticoagulation + CS

+ IVIg or plasmapheresis

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Potentially usable

Non-aspirin antiplatelet agents

Hydroxychloroquine

Statins

Thrombin inhibitors

Rituximab

Recombinant activated protein C

Prostaglandin and prostacyclin Anti-cytokine

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Thrombocytopenia

Mild to moderate- Platelets > 50,000:

No treatment

Severe-

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Management of aPL positive patients with

adverse pregnancy history

Poor obstetric history - the most importantpredictor

The risk of fetal loss is related to aCL ab titer

Presence of aPL are a marker for a high riskpregnancy

Once APS is diagnosed, serial aPL testing isnot useful

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Current Recommendations

Pregnancy Fetal protection Asymptomatic aPL no treatment

Single loss

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Heparin and aspirin for recurrent

miscarriage without history of thrombosis

for recurrent miscarriage :

improved live birth rate from 40% to 70-80%

for late losses or intrauterine death:

results in 70-75% live birth

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Other therapies for aPL associated

pregnancy loss

Corticosteroids :

- associated with significant maternal and fetalmorbidity

- ineffective

Immunosuppression:

azathioprine, plasmapheresis:

numbers treated too small for conclusion

IVIG:

may be salvage therapy in women who fail on

Heparin + Aspirin

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Fetal Monitoring

US monitoring of fetal growth and amniotic fluid

every 4 weeks

US monitoring of uteroplacental blood flow:uterine artery waveforms assessed at 20-24 wks

If early diastolic notch seen: do 2 weekly growth

scans due to high risk of IUGR

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How long should patients with

APS and venous thrombosis betreated with warfarin?

Schulman, et al., 1998. Prospective study.

412 patients with 1st episode of venous

thrombo-embolism treated for 6 months

with warfarin.

68 patients (17%) with elevated antibody

levels when warfarin therapy stopped.

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Do any of the clinical laboratory

tests identify patients at risk for

thromboembolic problems?

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Risk factors for recurrent vascular

events despite anticoagulation

More than one prior thrombotic event

aCL levels: the risk of recurrence is

twice as high among pts with aCL

compared to those without such

antibodies (29#14%)

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Anticardiolipin Antibodies and Recurrent

Venous Thromboembolism

A A positi e

A A ne ati e

onths

umulatie

robabilito

Recurrence

-- Schulman, et al, Am J ed, 99 ; :

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What about patients with

recurrent thromboembolismdespite therapeutic warfarin?

Th ti ti f

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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.

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British Society of Haematology

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 treated

by long-term oral anticoagulation.

Recurrence while the INR is between 2.0 and

3.0 should lead to more intensive warfarin

therapy, target INR 3.5, but this is uncommon.

-- Greaves, et al., Br.J.Haematol., 2000; 109: 70

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Because of the high risk of recurrence and

likelihood of consequent permanentdisability 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).

British Society of Haematology

Guidelines

-- Greaves, et al., Br.J.Haematol., 2000; 109: 70

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ACCP Guidelines

Prevention of noncardioembolic cerebral

ischemic events.

For most patients, we recommend antiplateletagents over oral anticoagulation (Grade 1A).

For patients with well-documented

prothrombotic disorders, we suggestoral

anticoagulation over antiplatelet agents

(Grade 2C).

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

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Treatment of cardiac involvement

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Treatment of cardiac involvement

Asymptomatic valve thickening: low

dose aspirin (81 mg/d)

Embolic disease: Heparin followed by

warfarin

MI: Heparin followed by warfarin +aspirin

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Case description

35 year old male, single

Presented with:

- sudden vision loss- rt eye:

due to Central retinal vein occlusion

- Chronic leg ulcer

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Past Medical History

S\P Lt lower Leg DVT

S\P CVA with Lt. hemiparesis

Hypertension

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Physical examination

Marked cognitive impairment

Unstable gait

Lt. mild spastic hemiparesis Rt. blind eye

Edematous left calf with venous stasis

Large chronic leg ulcer- lt calf

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Laboratory work-up ANA- negative

Anti-DNA- negative

Anticardiolipid IgG > 120 GPLU (N 100 (N

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Diagnosis

Primary Antiphospholipid syndrome with:

- recurrent arterial thrombosis: CVA

leg ulcer

- recurrent venous thrombosis: DVT

CRV occlusion

- High titer antiphospholipid antibodies: anticardiolipin IgGanti-F2 GPI

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Management and course

Coumadin: INR = 3.0

Gradual complete healing of leg ulcer

No further thrombotic episodes

Some improvement in gait and cognition

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And what lies ahead?

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Future Directions

Can we predict which patients with

antiphospholipid antibodies will developthromboembolic complications?

Is there an inherited predisposition to

developing antiphospholipid antibodysyndrome?

F ili l A ti h h li id

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Familial Antiphospholipid

Syndrome 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

Diseases Clinical Research Consortium. For more information:

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

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Antiphospholipid Antibody Syndrome

Venous or arterial thrombosis, recurrent fetal loss,or thrombocytopenia accompanied by an increasedlevels of antiphospholipid Ab (aPLs)

Primary or secondary (SLE)

Valvular lesions Vegetation, thickening, or regurgitation

Prevalence

32% to 38% in primary APS

A significantly higher prevalence of valvulardefects in SLE pts with aPLs

TherapyLong-term, high intensity oral anticoagulation

(INR2.5-3)

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Thank you