thrombophilia rose marie meier reproductive medicine genk - belgium
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Thrombophilia
Rose Marie Meier
Reproductive
medicine
Genk - Belgium
Thrombophil
ia
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
Thrombophil
iaClassification
Hereditary
Acquired Antiphospholipid syndrome
Davenport W. Obstet Gynecol Clin N Am 2014
aPL antibodies interfere with phospholipids utilized to induce coagulationincreasing adhesion and aggregation of platelets
PL
PLPL
Anticoagulant
Pregnancy
PL
PLPL
Anticoagulant
Hypercoagulability state
Ovarian stimulation
PL
PLPL
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 3 - 8 %
✓ 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 1:10.000
Risk VTE
Risk poor rep outcome
RPL OR 2.05
Texto Rosendaal FR. Thromb Haemost. 1998
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 1:600 - 1:1000
Risk VTE
Risk poor rep outcome
OR 4.7
56 % 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?
MTHFRAssociation 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 LeidenScreening: APC resistance 90-95 % 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 deficiency antigen assay
activity assay
Antithrombin antigen assay
activity assay
Prot S deficiency activity assay
Free and total antigen assay
Lupus anticoagulant
Anticardiolipin
antibodiesIgG IgM
Khor B. Am J Hematol 2010
Marlar MA. Am J Hematol 2011
Clinical utilityA 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) 2008
83 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 2012
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
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 IgMAnti-cardiolipine as IgGLupus anticoagulansHomocysteïneFactor II (protrombine) mutatieAPC-resistentie (screening FV Leiden)Proteïne CProteïne SAnti-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
evidenceBefore start IVF
ideally Cost-effective?
Akthar MA. Cochrane Database Syst Rev 2013
Potdar N. Hum Repr Update 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