Anti-Phospholipid Syndrome (APS, “APLA”) a prethrombotic syndrome Diagnosis and management דר' דפנה פארן סגנית מנהל המחלקה ראומטולוגית בי"ח איכילוב

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 תרומבוציטופניה תרומבוס

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 -

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

Nomenclature change: APS - no associated rheumatic disease (50%) APS - associated rheumatic disease present in 10% of SLE patients aPL - antiphospholipid antibodies (no symptoms) CAPS - catastrophic APS ~ 238 worldwide reported cases

Clinical Presentations of APS Venous thromboembolism: Deep Vein Thrombosis Pulmonary Embolism

Clinical Presentations of APS Arterial Occlusion: Stroke and TIAs are the most common

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

Epidemiology of antiphospholipid antibodies in the normal population: % prevalence increases with age and chronic disease in SLE: % LAC: 11-30% aCL: 24-86% in first Stroke: % in recurrent fetal loss: 15 %

Antiphospholipid Syndrome Criteria Sydney revision of Sapporo criteria 2006 CLINICAL CRITERIA Vascular Thrombosis 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 LABOARATORY CRITERA anti-Cardiolipin IgG anti-Cardiolipin IgM Lupus anticoagulant (LAC) - medium - high titer - at least X 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)

Livedo reticularis

Livedo reticularis with necrotic finger tips in Antiphospholipid syndrome

Possible Clinical Presentations of APS not included in criteria Transverse myelitis Migraine Chorea Leg ulcers UBOs (white matter lesions) on brain MRI

“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 (  2 GPI) - prothrombin

Beta 2 Glycoprotein-I (  2GPI)  2GPI = a plasma protein with affinity for negatively charged phospholipids anti-  2GPI: are probably the major cause of APS

Antibodies and antigens Anticardiolipn abs recognize in most assays:  2 GPI Lupus Anticoagulant activity is caused by autoantibodies to: -  2 GPI - prothrombin

Laboratory Testing for antiphospholipid antibodies Solid phase assays usually anti-Cardiolipin abs Lupus Anticoagulant (LAC) MUST USE BOTH TESTS

Lupus Anticoagulant Tests Coagulation Assays Perform coagulation screen to detect prolongation in phospholipid dependent coagulation assay (usually use: 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: KCT or 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 Russell’s viper venom time more sensitive to presence of  2 GPI TTI - Tissue thromboplastin inhibition test No LAC shows 100% specificity and sensitivity because aPLs are heterogeneous. More than 1 test system is needed

Possible mechanisms of aPL induced thrombosis Endothelial-aPL interaction endothelial cell damage or activation, c oexisting anti-endothelial 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

Anticoagulation by direct or indirect thrombin inhibition AGENT COMPLEMENT PREGNANCY Heparin Inhibits protects Fondaparinux No effect does not protect Hirudin No effect does not protect

Occurrence of antiphospholipid antibodies in other conditions: Infection: - Syphilis, TB, Q-fever, Spotted Fever, Klebsiella, HCV, Leprosy,HIV. - The abs are usually transient, not  2 GPI dependent Malignancy: 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 low prevalence in general obstetric population (< 2% ): screening not warranted

Management of the Antiphospholipid Syndrome

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

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

Thrombocytopenia 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 Fetal protection Asymptomatic aPL no treatment Single loss <10wks no treatment Recurrent loss * <10wks prophylactic heparin +ASA up to 6-12 wks postpartum, ASA after(?) Recurrent loss < 10 wks therapeutic heparin + ASA, + thrombosis warfarin postpartum Prior thrombosis therapeutic heparin + ASA warfarin postpartum * Late fetal loss IUGR severe pre-eclampsia

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 Immunosuppression: azathioprine, plasmapheresis: numbers treated too small for conclusion IVIG: 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 wks If early diastolic notch seen: do 2 weekly growth scans due to high risk of IUGR

Antiphospholipid Syndrome Summary Due to the wide spectrum of manifestations any physician may encounter patients with APS This is a potentially treatable condition The best treatment, at present to prevent recurrent thrombosis is anticoagulation. The optimal duration and intensity is controversial.

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

Laboratory work-up ANA- negative Anti-DNA- negative Anticardiolipid IgG > 120 GPLU (N<10) (x2) Anticardiolipin IgM - normal Anti-  2 glycoprotein I > 100 (N<8) (x2) Lupus anticoagulant – negative

Diagnosis Primary Antiphospholipid syndrome with: - recurrent arterial thrombosis: CVA leg ulcer - recurrent venous thrombosis: DVT CRV occlusion - High titer antiphospholipid antibodies: anticardiolipin IgG anti-  2 GPI

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