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Osama Sayed Daifallah abosehly Assisstant lecturer

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 (B2GPI) antibodies. The origin of APL antibodies is unknown but is hypothesized to be an incidental exposure to environmental agents inducing APL in susceptible individuals.

Epidemiology of antiphospholipid antibodies

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

in the normal population: 2-5%

prevalence increases with age and chronic disease

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

12 - 40 %

in first Stroke: in recurrent fetal loss:

10 - 26 % 15 %

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

Bleeding and Thrombosis

Defects in primary hemostasis Thrombocytopenia Defects in secondary hemostasis Clotting factor deficiencies Prethrombotic (hypercoagulable) states

Prethrombotic disorders
Inherited Acquired

Inherited prethrombotic disorders

Anti-thrombin deficiency Deficiencies of protein C and S Resistance to activated protein C ( factor V Leiden mutation) Prothombin gene mutation ( G20210A) Homocystinemia

Acquired prethrombotic disorders

Conditions associated with a hypercoagulable state: - pregnancy and postpartum - major surgery - obesity and immobility - malignancy - congestive heart failure - nephrotic syndrome Estrogen treatment Antiphospholipid syndrome

Venous thrombosis are more common than arterial thrombosis The most common site of DVT is the calf The most common site of arterial thrombosis is the cerebral circulation The initial and long-term manifestations of the disease are similar: in most, but not all the initial arterial thrombosis tends to be followed by an arterial event and the initial venous thrombosis by a venous event

The Antiphospholipid Syndrome

is characterized by:

Arterial or Venous Thrombosis Recurrent Fetal Loss Serum Anti-phospholipid antibodies (aPL)

The Antiphospholipid Syndrome

may be:

Primary: an isolated condition Secondary: secondary to SLE or other connective tissue diseases

Clinical Presentations of APS

Venous thromboembolism:
Deep Vein Thrombosis Pulmonary Embolism

ThromboThrombo-embolic disease

Pulmonary embolism

Clinical Presentations of APS

Arterial Occlusion:
Stroke and TIAs are the most common

Cerebrovascular accidents

Clinical presentations of APS

Pregnancy 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

Antiphospholipid antibodies (aPL)

anti-Cardiolipin IgG anti-Cardiolipin IgM Lupus anticoagulant (LAC) * false positive VDRL

Antiphospholipid Syndrome
A clinicopathologic diagnosis

Antiphospholipid Syndrome Criteria

Sydney revision of Sapporo criteria 2006

Vascular Thrombosis: -arterial, venous, in any organ or tissue Pregnancy Morbidity: a) death of normal fetus at > 10 wks b) premature birth at < 34 wks due to preeclampsia c) >3 consecutive abortions at <10wks d) placental insufficiency at < 34 wks

anti-Cardiolipin IgG anti-Cardiolipin IgM Lupus anticoagulant (LAC)

- medium - high titer - at least X 2 - 12 wks apart
Definite APS: 1 Clinical + 1 Lab criteria

Sydney Revision of Sapporo criteria (2006)

Clinical Criteria - Thrombosis: exclude other causes : male > 55 yrs female > 65 yrs - Pregnancy: placental insufficiency < 34 wks exclude other causes

Sydney Revision of Sapporo criteria (2006)

Laboratory Criteria - medium/high titer IgG or IgM aCL on 2 occasions 12 wks apart - LAC on 2 occasions 12 wks apart

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.

Cardiovascular disease

Libman-Sacks Vegetation
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

TTE; 10%, TEE; 30% Mitral and aortic valves < 1 cm2 in size Irregular borders Heterogenous echo density No independent motion Associated with thickening or regurgitation

(Cardiol Clin 1998;16;531)

Libman-Sacks Vegetation and MR

Myocardial infarction

Hematologic manifestations

Cutaneous manifestations

Livedo reticularis: a lattice like pattern of superficial veins.

Livedo reticularis with necrotic finger tips in Antiphospholipid syndrome

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.

Antiphospholipid antibodies
antibodies 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

Beta 2 Glycoprotein-I


F2GPI = a plasma protein with affinity for negatively charged phospholipids anti- F2GPI: are probably the major cause of APS

Antibodies and antigens

Anticardiolipn abs recognize in most assays: F2 GPI

Lupus Anticoagulant activity is caused by autoantibodies to: - F2 GPI - prothrombin

Laboratory Testing for antiphospholipid antibodies

Solid phase assays usually anti-Cardiolipin abs Lupus Anticoagulant (LAC)


Lupus Anticoagulant Tests

Coagulation Assays
Perform coagulation screen to detect prolongation in phospholipid dependent coagulation assay (usually use: Activated Partial Thromboplastin Time APTT) If APTT is prolonged: Mix with normal plasma - If due to factor deficiency: corrected - If due to inhibitor (antibody) not corrected Confirm inhibitor is phospholipid dependent : corrected by mixing with platelets or phospholipids Perform second test: Kaolin clotting time KCT or Dilute Russells viper venom time DRVVT

Tests for LAC

APTT: - variability in reagents result in inconsistent sensitivity. - acute phase reaction and pregnancy may shorten APTT and mask a weak LAC A normal APTT does not exclude LAC KCT- Kaolin clotting time more sensitive to presence of anti-II DRVVT- Dilute Russells viper venom time more sensitive to presence of F2 GPI

No LAC shows 100% specificity and sensitivity because aPLs are heterogeneous. More than 1 test system is needed

TTI - Tissue thromboplastin inhibition test

Possible mechanisms of aPL induced thrombosis

Endothelial-aPL interaction
endothelial cell damage or activation, coexisting antiendothelial abs, aPL induced monocyte adhesion, increased tissue factor expression

Platelet-aPL interaction
platelet activation, stimulation of thromboxane production

Coagulation system-aPL interaction

inhibition of activation of protein C , interaction between aPL and substrates of activated protein C: factors Va VIIIa; interaction between aPL and annexin V anticoagulant shield

Complement activation

Occurrence of antiphospholipid antibodies in other conditions:

- Syphilis, TB, Q-fever, Spotted Fever, Klebsiella, HCV, Leprosy,HIV. - The abs are usually transient, not F2 GPI dependent

Lymphoma, paraproteinemia

Drug induced:
phenothiazines, procainamide, quinidine, phenytoin, hydralazine

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 < 50 yrs 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



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

Venous or Arterial thrombosis

1. Initial treatment with Heparin 2. Start Warfarin 3. Stop Heparin when therapeutic INR achieved

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 highintensity VKA therapy (Grade 1A).

We recommend treatment for 12 months (Grade 1C+). We suggest indefinite anticoagulant therapy for these patients (Grade 2C).

-- Buller, et al., Chest, 2004; 126 (Supplement): 40

Current Recommendations
Asymptomatic aPL no treatment (Aspirin?) Venous thrombosis Warfarin INR 2.0-3.0 Arterial thrombosis Warfarin INR 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

Potentially usable
Non-aspirin antiplatelet agents Hydroxychloroquine Statins

Thrombin inhibitors Rituximab Recombinant activated protein C Prostaglandin and prostacyclin Anti-cytokine

Mild to moderate- Platelets > 50,000: No treatment Severe- <50,000: - corticosteroids - corticosteroid resistant cases: HCQ , IVIG, Immunosuppressive drugs, Splenectomy

Management of aPL positive patients with adverse pregnancy history

Poor obstetric history - the most important predictor The risk of fetal loss is related to aCL ab titer Presence of aPL are a marker for a high risk pregnancy Once APS is diagnosed, serial aPL testing is not useful

Current Recommendations
Pregnancy Asymptomatic aPL Single loss <10wks Recurrent loss* <10wks after(?) Fetal protection no treatment no treatment prophylactic heparin +ASA up to 6-12 wks postpartum, ASA

Recurrent loss < 10 wks + thrombosis Prior thrombosis

* Late fetal loss IUGR severe preeclampsia

therapeutic heparin + ASA, warfarin postpartum therapeutic heparin + ASA warfarin postpartum

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

Other therapies for aPL associated pregnancy loss

Corticosteroids :
- associated with significant maternal and fetal morbidity - ineffective

azathioprine, plasmapheresis: numbers treated too small for conclusion

may be salvage therapy in women who fail on Heparin + Aspirin

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

How long should patients with APS and venous thrombosis be treated 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.

Do any of the clinical laboratory tests identify patients at risk for thromboembolic problems?

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%)

Anticardiolipin Antibodies and Recurrent Venous Thromboembolism

umulati e robabilit o Recurrence

A positi e

A ne ati e

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

What about patients with recurrent thromboembolism despite therapeutic warfarin?

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.

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: 704-1

British Society of Haematology Guidelines

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).

-- Greaves, et al., Br.J.Haematol., 2000; 109: 704-1

ACCP Guidelines
Prevention of noncardioembolic cerebral ischemic events.
For most patients, we recommend antiplatelet agents over oral anticoagulation (Grade 1A). For patients with well-documented prothrombotic disorders, we suggest oral anticoagulation over antiplatelet agents (Grade 2C).
-- Albers, et al., Chest, 2004; 126 (Supplement): 48

Treatment of cardiac involvement

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

Case description
35 year old male, single Presented with: - sudden vision loss- rt eye: due to Central retinal vein occlusion - Chronic leg ulcer

Past Medical History

S\P Lt lower Leg DVT S\P CVA with Lt. hemiparesis Hypertension

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

ANA- negative

Laboratory work-up

Anti-DNA- negative Anticardiolipid IgG > 120 GPLU (N<10) Anticardiolipin IgM - normal Anti-F2 glycoprotein I > 100 Lupus anticoagulant negative (N<8)
(x2) (x2)

Primary Antiphospholipid syndrome with:
- recurrent arterial thrombosis: CVA leg ulcer - recurrent venous thrombosis: DVT CRV occlusion - High titer antiphospholipid antibodies: anticardiolipin IgG anti-F2 GPI

Management and course

Coumadin: INR = 3.0 Gradual complete healing of leg ulcer No further thrombotic episodes Some improvement in gait and cognition

And what lies ahead?

Future Directions
Can we predict which patients with antiphospholipid antibodies will develop thromboembolic complications? Is there an inherited predisposition to developing antiphospholipid antibody syndrome?

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:

Antiphospholipid Antibody Syndrome

Venous or arterial thrombosis, recurrent fetal loss,
or thrombocytopenia accompanied by an increased levels 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 valvular defects in SLE pts with aPLs Therapy Long-term, high intensity oral anticoagulation (INR2.5-3)

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