thrombophilia rose marie meier reproductive medicine genk - belgium

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