Thrombophilia Rose Marie Meier Reproductive medicine Genk - Belgium

Thrombophilia Predisposition for thrombotic events Deep vein thrombosis Pulmonary embolism

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

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

Thrombophili a Classification Hereditary AcquiredAntiphospholipid syndrome

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

Pregnancy PL Anticoagulant Hypercoagulability state

Ovarian stimulation PL Anticoagulant Hypercoagulability state HcG effect

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 (G1691A) ✓ Heterozygote % ✓ Homozygote 1:5000 Risk VTE Risk poor rep outcome Homozygous OR 43.4 Heterozygous OR 8.3 Battinelli EM. Thrombosis 2013 Risk 1 in 500 pregnancies IVF?

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

Bradley LA. Genet Med 2012 RPL

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

RPL<13w Non RL RPL 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 Risk poor rep outcome Risk 1 in 113 pregnancies Prot S OR 3.2 Prot C OR 4.8 Battinelli EM. Thrombosis 2013 Rey E. The Lancet 2003 IVF?

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

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

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 Battinelli EM. Thrombosis 2013 aCL early RFL OR 3.56 late RFL OR 3.57 Opatrny L. J Rheumatol 2006

Battinelli EM. Thrombosis 2013

Diagnosis Bradley LA. Genet Med 2012 Factor V Leiden Screening: APC resistance % likelihood of mutation Confirmation: DNA analysis of F5 (gene encoding factor V) Factor II Screening: prothrombin level is not reliable Confirmation: DNA analysis of F2 (gene encoding factor II) Prot C deficiencyantigen assay activity assay Antithrombinantigen assay activity assay Prot S deficiencyactivity assay Free and total antigen assay Lupus anticoagulant Anticardiolipin antibodies IgG IgM Khor B. Am J Hematol 2010 Marlar MA. Am J Hematol 2011

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

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

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

Empson MB. Cochrane Database Syst Rev 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

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

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

When we should ask for thrombophilia?

Davenport W. Obstet Gynecol Clin N Am 2014

Evidence 1A in recurrent pregnancy loss 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

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

Akthar MA. Cochrane Database Syst Rev 2013

Potdar N. Hum Repr Update 2013

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

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 2003

APS

Clinical utility Since hypercoagulability might results in RPL, anticoagulant agents could potentially incerase the LBR 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 Qublan H. Hum Fertil (Camb) 2008