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Antiphospholipid syndrome: from diagnosis to treatments

Antiphospholipid syndrome: from diagnosis to treatments. P. de Moerloose Service d’Angiologie et Hémostase. Mrs B. 1971. 1991: premature birth (6th month) 1992 and next: 6 «spontaneous» abortions 2006: DVT (oral contraceptive) 2011: DVT and PE LA, aCL and anti-  2 GP1 ++.

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Antiphospholipid syndrome: from diagnosis to treatments

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  1. Antiphospholipid syndrome: from diagnosis to treatments P. de Moerloose Service d’Angiologie et Hémostase

  2. Mrs B. 1971 1991: premature birth (6th month) 1992 and next: 6 «spontaneous» abortions 2006: DVT (oral contraceptive) 2011: DVT and PE LA, aCL and anti-2GP1 ++

  3. Antiphospholipid syndrome criteria • APS is a syndrome characterized by • clinical criteria (thrombosis and/or pregnancy morbidity) • AND • laboratory criteria (aPLA detected by coagulation and/or immunological assays) Miyakis et al.JTH 2006;4:295-306

  4. Presentation • Laboratory criteria • Clinical criteria • Pathogenic mechanisms • Treatments

  5. Three lab criteria: 1st= lupus anticoagulant • LA are defined as antibodies that prolong the phospholipid-dependent coagulation tests by interfering with the coagulation reactions dependent on protein-phospholipid complexes in vitro. • Double misnomer: present in > half of the cases in non SLE patients and induce in vivo a prothrombotic state

  6. Problems • Differences between reagents and machines • A normal aPTT does not exclude a LA • Quantification of LA?

  7. Three laboratory criteria: 2nd Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer on 2 or more occasions, at least 12 weeks apart, measured by a standardized ELISA

  8. 12 weeks apart (+) • Frequent in children, transient • Frequent in intensive care patients • Frequent after an acute event

  9. Problem No standardized assay

  10. 3rd criteria: Anti-2-glycoprotein I antibodies

  11. Three laboratory criteria: 3rd Anti-2 glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma, present on 2 or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures

  12. “Invitation to a debate on the serological criteria that define the antiphospholipid syndrome” “Based on the (lack of) evidence discussed, we have the following proposals for the next update of the criteria of APS: 1) Implementation of strict guidelines for the performance of LA assay, 2) Exclusion of aCL measurements in their current application from the criteria, 3) Limitation of the measurement of aβ2-GPI antibodies to IgG” M. Galli, G. Reber, P. de Moerloose & P. de Groot. JTH 2008;6:399

  13. Laboratory criteria Clinical criteria Pathogenic mechanisms Treatments Presentation

  14. Clinical criteria Thrombosis in any organ and/or Pregnancy morbidity

  15. DVT 31.7% Stroke 20.4% Superficial phlebitis 9.1% Pulmonary embolism 9.0% Transient ischemic attack 7.0% Myocardial infarction 2.8% Amaurosis fugax2.8% Thrombotic features at disease onset in a cohort of 1000 APS cases,820 women, mean age at diagnosis 34 ± 14 yr Cervera et al.Arthritis Rheum 2002;46:1019

  16. Pregnancy morbidity • One or more unexplained deaths of a fetus at or beyond the 10th week of gestation, with normal fetal morphology, or • One or more premature births before the 34th week of gestation, because of a) eclampsia or severe eclampsia, or b) recognised features of placental insufficiency, or • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation

  17. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients Cervera et al (32 authors!). Annals of the Rheumatic Diseases 2009;68:1428-1432

  18. Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry Avcin T et al. Pediatrics 2008;122:e1100-e1107

  19. Catastrophic APS • Clinical evidence of multiple organ involvement • Developing over a very short period of time • Histopathological evidence of multiple small vessel occlusions • Laboratory confirmation of the presence of aPL, usually in high titer. • Furthermore the majority of CAPS are preceded by a • precipitating event, mainly infections Cervera et al. J Autoimmun 2009;32:240

  20. Other criteria?

  21. Thrombocytopenia 29.6% Livedo reticularis 24.1% Heart valve lesions 14.3% ……. 1000 cases of APS Cervera et al. Arthritis Rheum 2002;46:1019 Minor criteria + aPLA: « probable » APS?

  22. The association between circulating antibodies against domain I of beta2-glycoprotein1 and thrombosis: an international multicenter study 9 centers, 442 patients with confirmed aβ2GP1+ IgG class anti-domain I ab were present in plasma of 243/442 patients (55%) For thrombosis OR 3.5 (2.3-5.4) for anti-domain I vs 0.4 (0.3-0.6) for non-domain I aβ2GP1 Conclusion: detection of anti-domain I ab is associated with a higher specificity than the classical aβ2GP1 De Laat et al. J Thromb Haemost 2009;7:1767

  23. Antiphospholipid syndrome • Laboratory criteria • Clinical criteria • Pathogenic mechanisms? • Treatments

  24. Pathogenic mechanisms of aPLA Persistent activation of coagulation - increased markers of thrombin generation - interference with anticoagulant systems - reduced fibrinolytic activity Facilitated platelet activation and aggregation Complement activation ………………………

  25. Blood 2011;117:5523

  26. Pathogenic mechanisms Many mechanisms plausible c

  27. Antiphospholipid syndrome • Laboratory criteria • Clinical criteria • Pathogenic mechanisms? • Treatments

  28. Management of asymptomatic aPL Tuthill JI, Khamashta MA. J Autoimmun 2009;33:92-8

  29. Management of APS, according to type of previous event

  30. aPL and pregnancy: recommendations • APL and pregnancy morbidity: aspirin • + prophylactic UFH or LMWH (grade 2B) • Bates et al. Chest 2008;133:844S • APL and a history of thrombosis: • therapeutic doses of LMWH or UFH + • low dose aspirin (grade1C)

  31. Espinosa G et al. Arthritis Res Ther 2008;10:230

  32. Conclusions • Heterogeneous syndrome • Association  causality • Pathophysiology still many ??? • Thrombosis ≠ from pregnancy morbidity • Need better tests + randomized studies • Syndrome in evolution, many challenges remain

  33. One recent review Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment Tripodi et al. J Intern Med 2011:270:110-122

  34. Choukran li ehtimamikom

  35. Mechanisms of pregnancy morbidity • aPL impair embryonic implantation • aPL affect trophoblast differentiation • Induction of apoptosis • Interference with the protein C pathway • Induction of receptors for cell adhesion molecules • Altered eicosanoid synthesis • aPL affect annexin V anticoagulant activity • Complement activation Abrahams V. Thromb Res 2009;124:521

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