Reproductive Thrombophilia medicine Rose Marie Meier Genk Belgium

Reproductive Thrombophilia medicine Rose Marie Meier Genk - Belgium

Thrombophilia Predisposition for thrombotic events Deep vein thrombosis Pulmonary embolism

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

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

Thrombophilia Classification Hereditary Acquired Antiphospholipid syndrome

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

Pregnancy PL PL PL Hypercoagulability state Anticoagulant

Ovarian stimulation PL PL PL Hypercoagulability state Hc. G effect Anticoagulant

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

Factor V Leiden ✓ Most common inherited thrombophilia ✓ Genetic mutation -> G-to-A substitution (G 1691 A) ✓ Heterozygote 3 - 8 % ✓ Homozygote 1: 5000 Risk VTE Homozygous OR 43. 4 Heterozygous OR 8. 3 Risk 1 in 500 pregnancies IVF? Risk poor rep outcome Battinelli EM. Thrombosis 2013

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

RPL Bradley LA. Genet Med 2012

Phrotrombin ✓ Second most common inherited thrombophilia ✓ Genetic mutation -> G-to-A substitution (G 20210 A) ✓ Heterozygote 2 - 3% ✓ Homozygote 1: 10. 000 Risk VTE Homozygote OR 24. 4 Heterozygote OR 6. 8 Risk poor rep outcome Risk 1 in 200 pregnancies IVF? RPL OR 2. 05 Texto Rosendaal FR. Thromb Haemost. 1998 Davenport W. Obstet Gynecol Clin N Am 2014

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

Bradley LA. Genet Med 2012

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 Prot S OR 3. 2 Risk poor rep outcome Risk 1 in 113 pregnancies IVF? Rey E. The Lancet 2003 Battinelli EM. Thrombosis 2013

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 Mc. Namee K. Best Pract Res Clin Obstet Gynaecol 2012 Davenport W. Obstet Gynecol Clin N Am 2014

MTHFR Association with thrombophilia is controversial Mutation in C 667 T 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

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

Antiphospohlipid Antibodies Risk VTE Risk poor rep outcome OR 15. 8 LAC late RFL OR 7. 79 a. CL early RFL OR 3. 56 late RFL OR 3. 57 Battinelli EM. Thrombosis 2013 Opatrny L. J Rheumatol 2006

Battinelli EM. Thrombosis 2013

Diagnosis Factor V Leiden Screening: APC resistance 90 -95 % likelihood of mutation Confirmation: DNA analysis of F 5 (gene encoding factor V) Factor II Screening: prothrombin level is not reliable Confirmation: DNA analysis of F 2 (gene encoding factor II) Prot C deficiency antigen assay activity assay Antithrombin antigen assay activity assay Marlar MA. Am J Hematol 2011 Khor B. Am J Hematol 2010 Prot S deficiency activity assay Bradley LA. Genet Med 2012

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

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

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

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

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

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

When we should ask for thrombophilia?

Davenport W. Obstet Gynecol Clin N Am 2014

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

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

Akthar MA. Cochrane Database Syst Rev 2013

Potdar N. Hum Repr Update 2013

Women with ≥ 3 RIF 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

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

Qublan H. Hum Fertil (Camb) 2008

Studies in article from Rey, The Lancet 200

APS

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