APS
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This document discusses antiphospholipid antibody syndrome (APS), a condition characterized by vascular thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies. It covers the etiology, pathogenic mechanisms, diagnostic criteria, clinical manifestations, and treatment principles for APS. Key points include that APS is the most common acquired thrombophilia, can be primary or secondary to other conditions like SLE, is diagnosed based on both clinical and laboratory criteria including positive tests for lupus anticoagulant, anticardiolipin antibodies, or anti-beta 2 glycoprotein I antibodies, and treatment involves anticoagulation and immunosuppression.
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APS
- 2. Antiphospholipid Antibody SyndromeDrSaid El-Barshomy
- 3. ObjectivesEtiology and pathogenic mechanisms of APSDiagnostic methodsClinical presentationTreatment principles and future directions
- 4. Antiphospholipid SyndromeMost common acquired thrombophiliaDescribed by Hughes (1983) A syndrome characterized by the association of:thrombosis, obstetric complications and/or thrombocytopeniaantibodies against phospholipids or against proteins bound to phospholipids.
- 5. Antiphospholipid syndromePrimaryNo other evidence of another autoimmune diseaseSecondaryAssociated with autoimmune or other diseases, most commonly SLESneddon’s syndrome: stroke livedoreticularis hypertension may represent undiagnosed antiphospholipid syndrome.
- 8. Antiphospholipid Syndrome - EtiologyCombination of genetic background and environmental factors: infection, trauma, drugs - infections – molecular mimicry with B2GPI
- 9. Antiphospholipid Antibodies10% of healthy donors, 30-50% of SLE patientsLA antibodies are directed against plasma proteins bound to anionic phospholipidsaCL antibodies are directed against phospholipids bound to proteinsCan be IgA, M, or G (subclasses 1-4)IgG (esp G2) associated with a greater risk of APSAnti b2GPI antibodies are directed against a plasma protein that binds phospholipid with high affinity
- 10. Antiphospholipid AntibodiesLupus Anticoagulant (LA) AntibodiesProlonged coagulation in phospholipid-dependent in vitro tests (aPTT, PT, dRVVT)Failure to correct with 50:50 mixCorrection of coagulation time by adding phospholipidAnticardiolipin (aCL) AntibodiesELISA assay in the presence of bovine B2GPIAnti-Beta 2 Glycoprotein I Antibodies (b2GPI) ELISA assay using human B2GPI coated platesmost specific
- 11. Beta 2 Glycoprotein Inatural inhibitor of coagulation and platelet aggregationInhibits contact activation of coagulation cascadeInhibits conversion of prothrombin to thrombinmost aPL antibodies recognize Domain I of b2GPIbinding of antibody increases binding affinity for phospholipids
- 12. APS PathophysiologyaPLplateletsComplement systemPlacental tissueCoagulation cascadeEndothelial cellsActivate platelet aggregationTrophoblastic cell growth, apoptosisIL-3Inhibit Protein C, Protein S, thrombomodulin, antithrombin III fibrinolysis TF, adhesion molecules and proinflammatory cytokines
- 14. Diagnosis - Clinical CriteriaVascular thrombosis: arterial, venous, or small vessel, in any tissue or organ, confirmed by objective validated criteriaPregnancy morbidity: - Unexplained fetal death at or beyond 10 weeks gestation - Premature birth before 34 weeks gestation because ofeclampsia, severe pre-eclampsia, or placental insufficiency - Three or more consecutive spontaneous abortions before10 weeks gestation
- 15. Diagnosis - Laboratory criteriaLupus anticoagulant, present on at least 2 occasions, at least 12 weeks apartAnticardiolipin antibodies (ACA), IgG or IgM >30 units for both, present on at least 2 occasions, at least 12 weeks apartAnti-beta-2-glycoprotein I antibodies (anti-B2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apartA diagnosis of APS should not be made if a period of greaterthan five years separates the clinical event and positivelaboratory test.
- 17. Arterial thrombus + prolonged PTTAPSANA pos + anti-dsDNA pos SLEOther considerationsEndocarditisVasculitisThromboangiitis obliterans
- 18. Catastrophic APSPreliminary criteria:1. Involvement of three or more organs or tissues2. Development of manifestations simultaneously or in < 1 week3. Histopathologic evidence of small-vessel occlusion in at least one type of tissue4. Presence of LA , ACLA antibodies or bothDefinite diagnosis: All four criteria met
- 19. Catastrophic APSProbable diagnosis:2 organs or tissues involved, and the 2nd, 3rd and 4th criteria met; or All 4 criteria met and negative test for LA or anticardiolipin antibody > 6 wks after the first positive test or death within that period; or First, 2nd and 4th criteria met; or First, 3rd and 4th criteria met and development of a third manifestation in >1 wk but <1 month despite anticoagulationModified from N Engl J Med 358:275-89, 2008
- 20. APS TreatmentPregnancy loss - 90% benefit with ASA and LMW heparin In pregnancy, treat with ASA + LMWH even without history of thrombosisVenous thrombosis - high risk of recurrenceIf INR > 3, improved outcome over 2 years10% risk of recurrence on anticoagulantsAsymptomatic - no treatment (?ASA)Plasmapheresis in resistant cases
- 21. Lim, W. et al. JAMA 2006;295:1050-1057.
- 22. Future directions of treatment of APSPeptide-specific therapy: peptide with B2GPI epitopes recognized by aPL or B2GPI blocking AbInhibitors of intracellular signaling triggered by aPLComplement activation inhibitorsAnti-TNFα agentsAnti CD20 agents
- 25. Thank you