ANTIPHOSHPOLIPID SYNDROME SPEAKER : Anunay Gupta MODERATOR : Dr. Uma Kumar Dr. Shefali Sharma Dr. Shefali Sharma

  Historical Perspective   Antiphospholipid antibodies   Epidemiology   Pathogenesis   Classification criteria   Clinical Spectrum   Management   Case study

A systemic autoimmune disorder characterized by : ◦ Thrombosis, obstetric complications and/or thrombocytopenia ◦ Antibodies against phospholipids or against proteins bound to phospholipids. .  Most common acquired thrombophilia. Hughes et al J Rheumatol 1986;13:486-9.

 1906: Wassermann antiphospholipid antibody VDRL Test  1906: Wassermann first described antiphospholipid antibody in patient of Syphilis which reacted with extracts from bovine heart and became the basis of VDRL Test VON WASSERMANN Wasserman et al Deutsche Med Wochenschr 1906;32:745-6

Conley and HartMann Lupus anticoagulant Anti cardiolipin Syndrome Anti Phospholipid Syndrome -Thrombosis (arterial and/or venous) -Recurrent abortion(>2) -Thrombocytopenia & -Positive aCL or LA, occurring twice with an interval of at least 3 months Circulating Anticoagulant in SLE Hughes Feinstein and Rapaport Asherson Harris 1952

APS IgG/IgM Anticardiolipin antibodies Other Antibodies IgG /IgM IgG /IgM Anti β 2 glycoprotein I Lupus anticoagulant 1.IgA aCL 2.IgA anti-β2 glycoprotein I Phospholipid Misnomer Predictor of thrombosis <24 weeks fetal loss Phospholipids Most sensitive Risk factor for first stroke Plasma protein Most specific Crowther et al Lancet 2010

  aPL antibodies bind directly to negatively charged phospholipids   Infections Syphilis Infectious mononucleosis AIDS   No clinical sequelae  Drugs Procainamide Quinidine Phenytoin Fritsma GA et al Saunders Elsevier; p. 605–28  Increased Risk

  Without underlying disorder   Triggering risk factor or double hit   Risk factors from transition ◦ Prior history of thrombosis ◦ Presenece of LAC ◦ Elevated level of aCL IgG Levine JS et al N Engl J Med 2002; 346(10):752–63

Detection of LAC by in vitro coagulation assays

  Step 1: ◦ Prolonged coagulation in at least one Phospholipids dependent in vitro coagulation assay ◦ To rule out LAC at least two or more assay should be negative   Step 2: ◦ Failure to correct the prolonged coagulation time by mixing patient plasma with normal plasma   Step 3: ◦ Shortening or correction by addition of excess phospholipids   Step 4: ◦ Exclusion of other coagulopathies Brandt J et al. Thromb Haemost 1995;74:

STEP 1 STEP 2 STEP 3

  Anticardiolipin (aCL) Antibodies ◦ ELISA assay in the presence of cardiolipin coated plates in the presence of bovine β 2GP I   Anti-Beta 2 Glycoprotein I Antibodies ( β2 GPI) ◦ ELISA assay using human β 2GP I coated plates Levine JS et al N Engl J Med 2002; 346(10):752–63

  In healthy subjects, the prevalence for both LAC and aCL: ◦ 1% to 5% ◦ Increases with age 1 ◦ Risk of thrombosis - 0.5% 1   Sex : F>M (8:2) 2   Mean age of onset: 34 ± 13 years 2 1. Petri.M etal J Autoimmun 2000; 15: Cervera R et al Europhospholipid Project Lupus 2009

  In SLE, prevalence of aPL: ◦ Much higher ◦ 12% to 30% for aCL ◦ 15% to 34% for LAC   APS may develop in 50% to 70% of patients with SLE who harbor aPL after 20 years of follow-up Petri M. et al J Autoimmun 2000;15: Cervera R et al Medicine (Baltimore) 1993;72:113-24

Cervera R et al Arthritis Rheum 2002; 46:1019–27

Familial occurrence of aPL Genetic associations include HLA-DR4, DR7, DRw53 and C4 null allele VZV HIV PARVOVIRUS B 19 CMV Hep C Environmental Factor(Infectious agent) Genetic Predisposition Antiphospholipid Syndrome

  Pregnancy  Decidual vasculopathy and infarction  Impair trophoblast invasion and hormone production  Displacement of Annexin V from trophoblast membranes by aPL antibodies  Complement activation 1 Errattum New Eng J Med 1997;42: Errattum New Eng J Med 1997;42: Pierangeli et al Ann N Acad Sci 2005

  Initially classified as: ◦ Primary :Without evidence of autoimmune diseases ◦ Secondary :With autoimmune or other diseases, especially SLE   The 2006 International Consensus Statement – stratified Definite APS on the basis of risk factors Miyakis et al. J. Thromb.Haemost. 2006; 4:

Persistently positive test for LAC and/or aCL and/or anti 2 GPI Thrombosis And/or Recurrent Pregnancy Loss Diagnosis APS PLUS International Consensus statement 2006 Miyakis et al. J. Thromb.Haemost. 2006; 4:

  Age (>55 in men, and >65 in women),   Risk factors for cardiovascular disease   Inherited thrombophilias   Oral contraceptives   Nephrotic syndrome   Malignancy   Immobilization   Surgery

  Vascular thrombosis ◦ Venous thromboembolic disease (DVT, PE) ◦ Arterial thromboembolic disease ◦ Small vessel thrombosis Superficial venous thrombosis not included Miyakis et al. J. Thromb.Haemost. 2006; 4:

  Pregnancy morbidity ◦ One or more unexplained fetal loss (a normal fetus) at or beyond10 th week ◦ Three or more unexplained spontaneous abortions at or prior to 10 th week ◦ One or more premature births at or before the 34 th week due to eclampsia or placental insufficiency Miyakis et al. J. Thromb.Haemost. 2006; 4:

  Lupus anticoagulant: A functional, clot-based assay using the ISTH guidelines   Anticardiolipin : IgG or IgM antibody present in medium or high titre (40 GPL or MPL) .  Anti- β2 glycoprotein 1: IgG or IgM antibody. Miyakis et al., J.Thromb.Haemost., 2006; 4: Measured on 2 or more occasions at least 12 weeks apart

No Thrombosis Thrombosis Present Asymptomatic Life Threatening Thrombosis Definite APS CAPS Asymptomatic aPL

  Most common manifestation

  Less common STROKE MYOCARDIAL INFARCTION

1.Valve disease – Commonest ◦ Libmann Sack endocarditis ◦ Mitral Regurgitation 2.Intracardiac thro 2.Intra cardiac thrombosis

  Stroke and TIA   Non thrombotic neurological symptoms : ◦ Migraine ◦ Chorea ◦ Sneddon syndrome ( triad of stroke, livedo reticularis and hypertension) ◦ Multiple sclerosis ◦ Cognitive Impairment ( aCL) 1 1.Tektonidou et al Arch Intern Med 2006

  Pregnancy loss greatest from 10 th week (Fetal period)   Complications: ◦ Preterm labor ◦ Low birth weight ◦ Preeclampsia ◦ HELLP ◦ Stillbirth ◦ IUGR Branch DW et al Obs Gyne 2003;101:

  May be first indication Vascular thrombosis (Non inflammatory ) Livedo Reticularis Frances C et al Ann Rheum 2005;52:

Other manifestation Sub-ungual splinter hemorrhage Digital Gangrene Purpura Cutanoeus ulcerations

  Pulmonary Embolism   Pulmonary Hypertension   Acute Respiratory Distress Syndrome   Alveolar Hemorrhage

  aPL associated nephropathy (APLN)   Clinical spectrum ◦ Hypertension with proteinuria ◦ Renal insufficiency ◦ Renal artery stenosis ◦ Malignant hypertension ◦ Renal vein thrombosis TMA FIH Organized Thrombus FIH- Fibrous intimal hyperplasia TMA-Thrombotic microangiopathy

  Liver involvement ◦ Budd-Chiari Syndrome   Intestinal infarction/angina   Rarely ◦ Splenic infraction ◦ Acute pancreatitis. Uthman et al Rheumatology 2007;46:1641–1647

  Adrenal insufficiency can be presenting symptom.   Less common ◦ Autoimmune thyroid disease ◦ Hypopituitarism ◦ Diabetes mellitus Endocrinologic manifestations of APS.Lupus 2006; 15: 485–9.

  Thrombocytopenia-seen in 20% to 40%   aPL-associated thrombocytopenia: ◦ aPL laboratory criteria plus ◦ Thrombocytopenia(platelet count <100,000)   Hemolytic Anemia Miyakis, et al., J.Thromb.Haemost., 2006; 4:

G Malatesha et al Ind J of Rheum 2006 ;14 : 17-15

Clinical Features in 1000 patient at disease onset Cervera R et al Arthritis Rheum 2002; 46:1019–27 EUROPHOSPHOLIPID STUDY

  Asherson Syndrome   <1 % patients   > 50 % mortality   Multiple small vessel occlusions(Thrombotic Storm)   Acute thrombotic microangiopathy   Precipitating Factor: Infection Asherson RA. CAPS:Lupus 2003;12:530–4.

  Organs Involved: ◦ Kidney (78%) ◦ Lungs (56%) ◦ Heart (50%), and ◦ Skin   DIC - 25% of patients   Clinical features include:  Renal failure  Acute respiratory failure  Stroke and Myocardial ischemia

. 1. Involvement of 3 or more organ systems and/or tissues 2. Development of manifestations simultaneously or in <1 wk 3. Histopathology of small-vessel occlusion in at least 1 organ/tissue 4. Laboratory confirmation Asherson et al Lupus 2003,12:530-34

Criteria 2, 3, and 4, plus involvement of only two organ systems and/or tissues All four criteria, except for the absence of laboratory confirmation at least 6 weeks after first positive result Criteria 1,2, and 4 Criteria 1,3, and 4, plus the development of a third event in >1 week but <1 month Asherson et al Lupus 2003,12:530-34

  Strong degree of suspicion ◦ DIC ◦ TTP ◦ HUS ◦ Disseminated embolization from myxoma/atrial thrombus

  Symptoms suggesting APS with aPL but lack clinical criteria of ‘‘definite’’ APS   Non criteria manifestations ◦ Livedo reticularis ◦ Thrombocytopenia ◦ Chorea ◦ Valvular lesions ◦ Nephropathy

  Conditions predisposing the patient to both venous and arterial thrombosis: 1. Heparin induced thrombocytopenia 2. Hyperhomocysteinemia 3. Myeloproliferative disorders 4. Hyper viscosity syndrome(Malignancies)

  Antibodies directed against PF4   5-14 days after initiation of Therapy   Rarely platelet <100,000 / μ l   Most specific test: Serotonin release assay   Management.  Heparin to be stopped  No platelet transfusion  Direct thrombin inhibitor  Avoid warfarin Keeling D et al.Br J Haematol 133;259-62

  Red flags ◦ Unexplained DVT or pulmonary embolism in patients < 50 ◦ Stroke/TIA in patients < 50 ◦ Recurrent thrombosis/Thrombosis at an unusual site ◦ Unexplained fetal loss after 10 weeks gestation ◦ Severe or early pre-eclampsia/IUGR ◦ Pre-eclampsia with severe thrombocytopenia ◦ Valvular disease (in combination with other symptoms) ◦ A new diagnosis of SLE Cohen D et al BMJ 2010;14:340-44

  Yellow flags ◦ Livedo reticularis ◦ Raynaud’s phenomenon ◦ Unexplained persistent thrombocytopenia ◦ Recurrent early pregnancy loss ◦ Unexplained adrenal insufficiency Cohen D et al BMJ 2010;14:340-44

  Primary Prophylaxis   Secondary Prophylaxis   Pregnancy and APS   Catastrophic APS

  Asymptomatic aPL-positive Patients ◦ No role of aspirin ◦ Avoidance of reversible thrombotic risk factors and prophylaxis in high-risk periods.   Asymptomatic aPL-positive SLE Patients ◦ Hydroxy chloroquine and Low dose aspirin   Obstetric APS ◦ Low dose aspirin or no therapy Erkan et al Arthritis Rheum 2001;44: Erkan et al Arthritis Rheum. 2007;56(7):

 What is the optimal intensity?  High-intensity anticoagulation (INR 3.1 to 4)is not superior to moderate-intensity(INR 2- 3) therapy.

Crowther et al

Thrombotic Risk and Minor bleeding more with High Intensity Anticoagulation Finazzi G J Thromb Haemost. WAPS 2005;3(5):

  What is the optimal Duration? ◦ Till date not defined ◦ The occurrence of a single thrombotic event in APS has recurrence between 20% and 70%.. Khamashta MA et al N Engl J Med 1995;332:993-7.

  Unprovoked Thrombosis ◦ Long-term(life long) anticoagulation in whom who had a first unprovoked VTE 1   Provoked Thrombosis ◦ For a finite 3-6 months of anticoagulation for a 1 st VTE 1. 1.Kahn SR et al. Chest.2008;133(6 suppl):454S-545S

Proportion with events at 2 year Treatment group APASS Investigators, JAMA, 2004; 291: 576. p value 0.94 p value 0.73  Cerebral Antiplatelet or Vitamin k Antagonist? ◦ Either Aspirin or moderate to high intensity (INR 3.0) warfarin 1 ◦ Dipyridamole (200 mg BD) plus aspirin is superior to aspirin( mg) alone 2 ◦ Clopidogrel (75 mg) alone is equivalent to dipyridamole 3 plus aspirin. 1.Levine SR, et al.JAMA 2004;291:576–584 2.Halkes PH et al. Lancet. 2006;367(9523): Sacco RLet al. NEJM. 2008; 359(12):

  Cerebral If Vitamin K antagonist ? ◦ To be started after the acute period (at least 48 hours)(INR ) ◦ Aspirin should be used in interim. Paciaroni M et al Stroke. 2007;38(2):

  Non Cerebral ◦ Renal arteries with moderate-intensity indefinite oral anticoagulation 1 1.Dubois Lupus Erythematous 7 th edition 1279 ◦ ACS and MI according to the evidence base treatment of general population.

Long Term anticoagulation Moderate intensity anticoagulation INR Therapeutic Range Higher intensity (INR 3 to 3.5). Venous Recurrence INR Sub therapeutic Therapeutic LMWH After Cessation of Tt Arterial Recurrence Higher Intensity/Add Low dose Aspirin Moderate intensity anticoagulation

 :  Factors that can affect the INR: ◦ Time of day ◦ Drug interactions ◦ Antiprothrombin antibodies ◦ Variations in thromboplastin reagents ◦ Lupus anticoagulant

Hydroxychloroquine   Mechanism ◦ Reduction of platelet activation and clotting ◦ Inhibits binding of aPL- β 2 glycoprotein complexes to phospholipid surfaces ◦ Formation of Annexin V shield Erkan et al Rheumatology

Rituximab   Mechanism ◦ B cell depletion therapy   Case Reports   Response >90%   Thrombocytopenia and hemolytic anemia   RITAPS TRIAL (Phase II) 1.Erre GL et al Lupus 2008;17:50-55

Statins (Fluvastatin)   Mechanism ◦ Decreases expression of CAM ◦ Inhibits aPL effect on TF 1   Pilot Trial 2   No controlled clinical data   Category X for pregnancy 1.Ferrara et al J Throm Hem Jajoria et al Ann N Y Acad 2009

Autologous hematopoietic stem cell transplantation   19 persistently LAC or aCL-positive lupus patients (11 with definite APS fulfilling the Sapporo criteria)   Result: ◦ Anticoagulation was stopped in 9 of 11 definite APS who were on warfarin ◦ But 3 of 9 develop recurrent thrombosis(median follow up 2 yr) Statkute et al Blood 2005

Women with APS desires Pregnancy Preconception consultation, Initiate LDA Confirm live embryo at 5.5 to 6.5 weeks Initiate Heparin Clinical Care Diagnostic Test ANC visit every 2-4 wk untill wk then every 1-2 weeks Monitor for fetal death, preeclampsia, IUGR Obstetric USG every 3-4 weeks at weeks Fetal surveillance testing at least weekly from wk Rheumatologic Visit every 2-4 wk

  Recurrent fetal loss >10 wk or early delivery <34 wk ◦ LDA plus Prophylactic dose Heparin (UFH or LMWH) during Pregnancy ◦ Heparin/LMWH/Warfarin Post partum 4-6 weeks   Multiple Pregnancy loss <10 wk (pre embryonic and embryonic) ◦ LDA alone/ Plus Prophylactic dose UFH/LMWH ◦ Heparin/LMWH/Warfarin Post partum 4-6 weeks No Prior Thrombosis Empson et al Cochrane Database Syst Rev. 2005

Prior Thrombosis   Low dose aspirin plus ◦ UFH (adjusted to maintain aPTT or heparin conc. {anti Xa activity}) in therapeutic range or ◦ LMWH therapeutic doses.   Warfarin life long Postpartum (INR 2-3) Empson et al Cochrane Database Syst Rev. 2005

UFHLMWH Dose Prophylactic 5000 I U sc BDEnoxaparin 40 mg SC OD Therapeutic Dose BD s.c every 8-12 hr to maintain aPTT times 1mg/kg BD Efficacy Same Risk Of HIT MoreLess Osteopenia MoreLess Cost LessMore Nobel LS et al Fertil Steril 2005 Stephenson MD et al J Obst Gyne 2004

  Treatment Failure ◦ Intravenous immune globulin 1 ◦ Plasmapheresis 2 ◦ Hydroxychloroquine 3 1.Triolo G et alArthritis Rheum 2003 Mar;48(3): Fulcher, D Lancet 1989; 2: Espinola RG et al Thromb Haemost 2003 Mar;87(3):

  Multi Modality Treatment   Treatment of precipitating Factor most likely infection   Anticoagulation   Corticosteroids   IVIG or Plasmapheresis Asherson et al. Lupus. 2003;12(7):

  No role of anticoagulation   Corticosteroids and/or IVIG are initial therapies for platelet less than 50 X10 3   Danazol (streoid refractory)

History of PriorThrombosis Proximal DVT/PE Pregnancy Arterial Thrombosis Warfarin INR 2-3 Provoked-6 months Unprovoked-Life long CerebralNon cerebral Cardioembolic Non cardioembolic Warfarin INR 3-4 Warfarin or aspirin+ dipyrimadole or clopidogrel Cardiac Non Cardiac Warfarin INR 3-4 Aspirin + clopidogrel + stent Recurrent episodes while receiving warfarin Therapeutic LMWH/UFH+LDA Warfarin INR 2-3 post partum Higher Intensity(INR 3-4),LMWH, Mod Intensity + LDA

What laboratory testing should be ordered and when should the testing be performed? Screen for acquired or inherited thrombophilia before starting anticoagulant. 25-year-old nulliparous woman presents with left leg deep vein thrombosis without precipitant

? What is optimal type and intensity of anticoagulant therapy?. What is the Diagnosis? ?APS Lab testing is positive for LAC. aCL levels (IgG and IgM) are within normal limits Started on rapidly acting anticoagulant(UFH or LMWH) and warfarin After at least 4 to 5 days of “overlap,” and stable (INR) b/w 2.0 and 3.0 can be treated with Warfarin alone

Positive for LACNegative For LAC Definite APS Life long anticoagulation No Repeat Testing in future Repeat testing at 12 wk With hold warfarin (1 week ) Six month later she returns with a 6 week of gestation. Treat as DVT

◦ Warfarin to be stopped ◦ Requires counseling ◦ “Therapeutic doses” of either LMWH or UFH with low dose aspirin ◦ Warfarin - Resume after delivery ◦ Warfarin - Safe in breastfeeding mother

  Under-diagnosed autoimmune disease, requires high index of suspicion   Significant cause of thrombo embolic disease in young and recurrent pregnancy loss   Pregnancy outcome significantly(>70%) improves with appropriate management   UFH or LMWH have similar efficacy   No role of anticoagulation in Non thrombotic manifestations

Well-designed studies are required for complete understanding of the APS