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
a
Classification
Hereditary
Acquired
Antiphospholipid syndrome
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
Pregnancy
PL
PL
PL
Hypercoagulability state
Anticoagulant
Ovarian stimulation
PL
PL
PL
Hypercoagulability state
HcG 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 (G1691A)
✓
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<13w
Non RL
Non RL>19w
Rey E. The Lancet 2003
RPL
Bradley LA. Genet Med 2012
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
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<13w
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 1 in 113
pregnancies
IVF?
Risk poor rep
outcome
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
McNamee K. Best Pract Res Clin Obstet Gynaecol 2012
Davenport W. Obstet Gynecol Clin N Am 2014
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
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
aCL
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 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
Marlar MA. Am J Hematol 2011
activity assay
Khor B. Am J Hematol 2010
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 40mg/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 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
Conclusion
Thrombophilia screening ..... we need more
evidence
Before start IVF
ideally
Recurrent miscarriage or
Repeated implantation
failure
Cost-effective?
Evidence IA for aPL
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 ≥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
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