Thrombophilia

1. Thrombophilia Reproductive medicine Rose Marie Meier Genk - Belgium

2. Thrombophilia Predisposition for thrombotic events Deep vein thrombosis Pulmonary embolism

3. Thrombo-embolic disease Mayor cause of maternal mortality Absolute incidence 1 / 1000 IVF increase 3 fold the risk (2.66 / 1000) Severe OHSS 4,1 % Asociation with poor reproductive outcome Implantation failure and recurrent pregnancy loss Women with >2 IVF-ET increase find of thrombophilia factor Qublan H. Hum Fertil (Camb) 2008 Scott N. Throm Res 2013

4. Venous thromboembolic events (VTE) & IVF Rova K. Fertil Steril 2012

5. Thrombophilia Classification Hereditary Acquired Antiphospholipid syndrome

6. PL PL PL aPL antibodies interfere with phospholipids utilized to induce coagulation increasing adhesion and aggregation of platelets Anticoagulant Davenport W. Obstet Gynecol Clin N Am 2014

7. Pregnancy PL PL PL Hypercoagulability state Anticoagulant

8. Ovarian stimulation PL PL PL Hypercoagulability state HcG effect Anticoagulant

9. Clinical validity What is the association between thrombophilia and VTE and poor reproductive outcomes ??

10. Factor V Leiden • Most common inherited thrombophilia • Genetic mutation -> G-to-A substitution (G1691A) • Heterozygote 3 - 8 % • Homozygote 1:5000 Risk VTE Homozygous OR 43.4 Risk 1 in 500 pregnancies Heterozygous OR 8.3 IVF? Risk poor rep outcome Battinelli EM. Thrombosis 2013

11. RPL<13w Non RL Non RL>19w Rey E. The Lancet 2003

12. RPL Bradley LA. Genet Med 2012

13. Phrotrombin • Second most common inherited thrombophilia • Genetic mutation -> G-to-A substitution (G20210A) • Heterozygote 2 - 3% • Homozygote 1:10.000 Risk VTE Homozygote OR 24.4 Risk 1 in 200 pregnancies Heterozygote OR 6.8 IVF? Risk poor rep outcome RPL OR 2.05 Texto Rosendaal FR. Thromb Haemost. 1998 Davenport W. Obstet Gynecol Clin N Am 2014

14. RPL RPL<13w Non RL Rey E. The Lancet 2003

15. Bradley LA. Genet Med 2012

16. Protein S and C deficiency • Both necessary for the activation of factors V and VIII • Inherited or acquired • Prevalence Prot C heterozygote 0,5 % Risk VTE Prot C OR 4.8 Risk 1 in 113 pregnancies IVF? Prot S OR 3.2 Risk poor rep outcome Rey E. The Lancet 2003 Battinelli EM. Thrombosis 2013

17. Antithrombin Deficiency • Small protein that inactivates factor Xa and thrombin • Asociation with severe coagulopathy • Inhereted or acquired thrombophilia • Prevalence 1:600 - 1:1000 Risk VTE OR 4.7 Risk 1 in 42 pregnancies IVF? Risk poor rep outcome 56 % pregnancy loss McNamee K. Best Pract Res Clin Obstet Gynaecol 2012 Davenport W. Obstet Gynecol Clin N Am 2014

18. MTHFR Association with thrombophilia is controversial Mutation in C667T gene results in higher level of homocysteine Risk TE disease OR 0.7 Risk poor outcome Battinelli EM. Thrombosis 2013 Rey E. The Lancet 2003

19. Antiphospholipid Antibodies • 1– 5 % of healthy women vs 18,8 % in IVF patients • Important treatable cause of recurrent miscarriage • Treatment increase live birth rate to 80 % Lupus anticoagulant Anticardiolipin antibodies Anti-beta 2 glycoprotein Lassere M. Throm Res 2004 Rai & Regan L. Lancet 2006

20. Antiphospohlipid Antibodies Risk VTE OR 15.8 Risk poor rep outcome LAC late RFL OR 7.79 aCL early RFL OR 3.56 late RFL OR 3.57 Battinelli EM. Thrombosis 2013 Opatrny L. J Rheumatol 2006

21. Battinelli EM. Thrombosis 2013

22. Diagnosis Marlar MA. Am J Hematol 2011 Khor B. Am J Hematol 2010 Bradley LA. Genet Med 2012

23. Clinical utility A test has clinical utility when results change clinical management, health outcomes improve, and the benefits outweigh known or potential harms

24. 83 women 3 or more IVF failures and at least 1 thrombophilic defect Enoxaparin 40mg/day vs placebo Qublan H. Hum Fertil (Camb) 2008

25. Thromboprophylaxis reduces the fetal loss 15 fold Folkeringa N. Br J Haematol 2007

26. 13 Studies (849 participants) Unfractionated heparin + AAS reduce fetal loss 54 % AAS alone no significant benefit Prednisone + AAS increase prematurity and gestational diabetes Intravenous inmunoglobulin +/- heparin or AAS increase prematurity, PL Empson MB. Cochrane Database Syst Rev 2012

27. Recommendations for inhereted thrombophilia (no IVF patients) Battinelli EM. Thrombosis 2013

28. Until now... Association Thrombophilia & IVF increase risk of VTE Thrombophilia & Recurrent implantation failure Thrombophilia & Recurrent Miscarriage Potential rol of LMWH in patients with RIF and thrombophilia

29. When we should ask for thrombophilia?

30. Davenport W. Obstet Gynecol Clin N Am 2014

31. Trombofilie screening Anti-cardiolipine as IgM Anti-cardiolipine as IgG Lupus anticoagulans Homocysteïne Factor II (protrombine) mutatie APC-resistentie (screening FV Leiden) Proteïne C Proteïne S Anti-trombine III Evidence 1A in recurrent pregnancy loss

32. Conclusion Thrombophilia screening ..... we need more evidence Cost-effective? Before start IVF ideally Recurrent miscarriage or Repeated implantation failure Evidence IA for aPL antibodies Antithrombotic therapy should be based on an individual risk/benefit assessment

34. Akthar MA. Cochrane Database Syst Rev 2013

35. Potdar N. Hum Repr Update 2013

36. Women with ≥3RIF LMWH + IVF/ICSI improve in 79% LBR and reduce in 78% MR NNT with LMWH would be 7.7 to achieve one live birth Potdar N. Hum Repr Update 2013

37. Data: 1. LMWH reduce venous thrombosis events in ART (RR 0,3) 2. ART increase the risk of VTE during pregnancy Chest 2012

38. Qublan H. Hum Fertil (Camb) 2008

40. Studies in article from Rey, The Lancet 2003

41. APS

43. Clinical utility LMWH prevent thrombin formation and has inhibitory effect on the binding of phospholipids with antibodies, thus protecting the trophoblast from injury; promoting the successful implantation and subsequent placentation Since hypercoagulability might results in RPL, anticoagulant agents could potentially incerase the LBR Qublan H. Hum Fertil (Camb) 2008