Thrombophilia are hereditary and/or acquired conditions that predispose patients to thrombosis. The association between thrombophilia and recurrent pregnancy loss (RPL) has become an undisputed fact. Women with heritable or acquired thrombophilic disorders have significantly increased risks of pregnancy loss

1. Hereditary and Acquired
Thrombophilia in RIF & Recurrent
Abortion
Amir Abbas Hedayati-Asl
Hematologist, Oncologist & Ped. Stem Cell Transplantation
Cancer Stem Cell Group
Stem Cell Biology and Technology Department, Royan Institute

2. Thrombophilia
• Thrombophilia are hereditary and/or acquired
conditions that predispose patients to
thrombosis.
• The association between thrombophilia and
recurrent pregnancy loss (RPL) has become an
undisputed fact.
• Women with heritable or acquired
thrombophilic disorders have significantly
increased risks of pregnancy loss

3. Thrombophilia
• Thrombophilia creates a
hypercoaguable state which
leads to arterial and/or
venous thrombosis at the
site of implantation or in
the placental blood vessels.
Predisposition
for thrombotic events

4. Inherited
• Antithrombin III, protein S, protein C,
Factor V Leiden mutation, prothrombin
gene (Factor II) mutation
Acquired
• Antiphospholipid Syndrome (APS)
• Lupus anticoagulant, anticardiolipin,
Beta-2 glycoprotein-1
• Antithrombin, protein S, and protein C
deficiencies
Mixed type- combination of inherited and
acquired
• E.g.- Methylene tetrahydrofolate
reductase (MTHFR)- genetic mutation +
nutritional deficiency of folate and
vitamin B12

5. Thrombophilia
Thrombo-embolic disease
• cause of maternal
mortality
• Absolute incidence 1 /
1000
• IVF increase 3 fold the
risk (2.66 / 1000
• Severe OHSS 4,1 %
Association 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

6. Venous thromboembolic events & IVF
Rova K. Fertil Steril 2012

7. Definition RM
• Recurrent miscarriage (RM) is defined as the loss
of three or more consecutive and clinically-
recognised pregnancies before 20 weeks’
gestation; this affects 1–2% of women.
• This incidence increases to 5% when it is defined
as a loss of two or more clinically-recognised
pregnancies before 20 weeks’ gestation.
• Thrombophilia is a common cause of RPL and may
be seen in 40–50% of cases.

8. RPL Definition

10. Causes of Recurrent Pregnancy Loss

11. Hypercoaguable state
• Pregnancy is a hypercoaguable state and if the
pregnancy is affected by thrombophilia, the
hypercoaguable state becomes worse and
may impair blood flow through the maternal
veins, leading to deep vein thrombosis, and
clots in the placental blood vessels, leading to
fetal growth restriction and/or fetal demise.
• Due to this fact, anticoagulants have become
very popular for treating RPL.

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

15. Clinical validity
• What is the association between
thrombophilia and VTE and poor
reproductive outcomes?
• To review the evidence (RCT & meta-
analyses) concerning the best
practices in contemporary Recurrent
Pregnancy Loss and Thrombophilia
depending on Eshre guideline 2017
and other EBM sources

17. Mechanism of action
• Thrombosis on maternal side of the placenta 
impaired placental perfusion
• Late fetal loss, IUGR, abruption, or Htn
• Relationship with early loss is less clear

18. Recurrent Pregnancy Loss
Inherited Thrombophilia Testing…
• Controversial
issue with few
if any good
quality studies
for guidance.

19. Who do We test?:
ACOG Recommendations
ACOG Practice Bulletin 124, September 2011
• Women with a personal history of thrombosis, or a
first degree relative with thrombosis at age < 50 yr
should be offered testing for hereditary
thrombophilias

20. • Testing for inherited thrombophilias in women who
have experienced recurrent fetal loss or placental
abruption is not recommended.
• Although there may be an association in these cases,
there is insufficient clinical evidence that antepartum
prophylaxis with unfractionated heparin or low
molecular weight heparin (LMWH) prevents
recurrence in these patients

22. Inherited Thrombophilia
• There is usually a family history of excessive clotting.
• More commonly, the diagnosis is based on the
demonstration of a gene mutation such as a Factor V
Leiden (FVL) mutation MTHFR (C677T)MTHFR (1298A),
a hyperhomocysteinaemia mutation (A506G), a
prothrombin mutation (G20210A) or prothrombin II
(PTII) mutation, FXIII Val34Leu polymorphism or a
protein S and/or C , AT III deficiency.
• High frequency of Val34Leu polymorphism in RM/RIF
presumably speaks in favor of a multifactorial RM
genesis, where an altered thrombophilia status plays a
role.

23. Inherited thrombophilic defects
• Activated protein C resistance (most commonly due to
factor V Leiden gene mutation)
• Deficiencies of protein C/S and antithrombin III
• Hyperhomocystenemia- Probably interference in embryonic
development through defective chorionic villous vascularization
• Prothrombin gene mutation- Higher plasma prothrombin
concentrations, augmented thrombin generation

24. Thrombophilia in RIF & Recurrent Abortion

26. Battinelli EM. Thrombosis 2013

27. Maternal Thrombophilias are not associated with early
pregnancy loss.
Roqueet alThromb Haemost91:290-5, 2004
Thrombophilia RPL < 10 wks RPL 10-14 wks Losses after 14
wks
Factor V Leiden 0.229
(0.03-1.66)
1.07
(0.46-2.5)
3.71
(1.68-8.23)
Prothrombin Gene
Mutation G20212A
0.21
(0.03-1.67)
0.37
(0.08-1.74)
2.47
(0.71-8.65)
Fasting
Homocysteine
0.23
(0.03-1.81)
1.12
(0.32-3.89)
2.37
(0.66-8.44)
Protein C 0.58
(0.06-5.26)
2.13
(0.34-13.05)
1.16
(0.13-10.62)
Protein S 0.54
(0.2-1.49)
0.103
(0.01-1.77)
2.5
(1.04-6.01)
ATIII - 1.88
(0.53-6.63)
0.39
(0.05-3.14)
>1 thrombophilia 0.48
(0.29-0.78)
1.66
(1.03-2.68)
3.68
(2.26-6.59)

28. Factor V Leiden
Most common inherited thrombophilia
✓Genetic mutation -> G-to-A substitution (G1691A)
✓ Heterozygote 3 - 8 %
✓ Homozygote 1:5000
✓Rare in Asian/African populations
Risk VTE
Risk poor rep. outcome
Homozygous OR 43.4
Heterozygous OR 8.3
Battinelli EM. Thrombosis 2013
Risk 1 in 500 pregnancies
increased thrombin generation and a mild hypercoagulable state

29. Factor V Leiden
• Factor V Leiden(FVL) heterozygous most
common
• Approx. 4-fold increase in risk for VTE
• Ziakas(2015)-May not be difference in VTE
rates between hetero- and homozygous for
FVL

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

31. Prothrombin
✓ 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
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

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

33. 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
pregnanciesProt S OR 3.2
Prot C OR 4.8
Battinelli EM. Thrombosis 2013
Rey E. The Lancet 2003

34. 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

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

36. Hyperhomocysteinemia
• Defined as elevated plasma levels of homocysteine is described as a risk
factor for:
– venous thromboembolism, and
– adverse pregnancy outcomes
– neural tube defects
– pre-eclampsia
– placental abruption
• Plasma homocysteine levels are determined by several factors:
– blood levels of vitamin B6
– vitamin B12
– folate
– MTHFR mutations
– increased age
– hypothyroidism (Hague, 2003),
which have all been suggested to be associated with RPL
• Need to high-dose folic acid and vit B6
• LMWH + aspirin

37. Inherited Thrombophilia
• A 2014 Cochrane review including nine trials
(n = 1228 women) concluded there was no
evidence of an increased frequency of live
birth among women with unexplained
recurrent miscarriage and inherited
thrombophilia treated with anticoagulants
(ASA , heparin, LMWH or combinations of
these drugs)

44. low molecular weight heparin
(LMWH)

45. Autoimmune
• Systemic lupus erythematosis - Risk for loss is
20%,mostly in 2nd and 3rd trimester of pregnancy
and associated with antiphospholipid antibodies
• Antiphospholipid syndrome (APA) -5%of women with
RPL may have APA.
• APA induces microthrombi at placentation site.
Altered vascularity affects developing embryo and
induces abortion.

46. Anti-Phospholipid syndrome
• The most treatable cause of RPL which is well accepted and
evidence based.
• Up to 15–20% of women with recurrent pregnancy loss
have antiphospholipid antibodies (aPL).
• In 5% second or third trimester losses occur.
• About 5-10% of all pregnancies are complicated by pre-
eclampsia or fetal growth restriction and up to 75% into
preterm births.

47. Antiphospholipid Syndrome Criteria
(Sydney revision of Sapporo criteria -2006)
CLINICAL CRITERIA
 Vascular Thrombosis-arterial or
venous
 Pregnancy Morbidity:
a) 1 or more death of normal
fetus at > 10 wks
b)1or more premature birth at
< 34 wks due to severe
preeclampsia or placental
insufficiency
c) >3 consecutive abortions
at <10wks with other causes
being ruled out
LABORATORY CRITERA
 Anti-Cardiolipin IgG and IgM
 Lupus anticoagulant (LAC)
 Anti β2-glycoprotein1 IgG and
IgM
medium - high titer(40 GPL or
MPL or higher than 99th
percentile) at least 12 wks apart
Positive test should be repeated at
least 12 apart
Definite APS: 1 Clinical + 1 Lab criteria

52. Treatment Options
Antiphospholipid Antibody Syndrome
None 33/166 20%
Aspirin (80mg/d) 39/81 48%
Prednisone + Asp 82/145 57%
IV Immunoglobulin 91/141 64%
UF Heparin + Asp 114/151 75%
Treatment # Treated Liveborn
ASRM Guidelines: Unfractionated heparin recommended as comparable efficacy low molecular
weight heparin had not be established.

53. Who do we screen?
• Studies suggests that all patients with: a history
of prior venous thrombotic events and those with
adverse pregnancy events such as;
– Fetal loss
– Abortions
– RIF
– Severe intrauterine growth restriction
– Early onset severe preeclampsia
should be evaluated for thrombophilias.

54. Candidate for thrombophilia evaluation

55. Currently, many clinicians
• Treat RPL—either associated with all types of
thrombophilia or unexplained—with low-
molecular-weight heparin combined with low-
dose aspirin.
• This treatment became popular in the late
1990s,after Sanson et al. reported that
thrombophilia is associated with the high risk of
fetal loss in early and late pregnancy.
Thrombophilia is either inherited, acquired or a
combination of both.

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

57. Akthar MA. Cochrane Database Syst Rev 2013

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

59. Empson MB. Cochrane Database Syst Rev 2012
13 Studies (849 participants)
Unfractionated heparin + ASA reduce fetal loss 54 %
ASA alone no significant benefit
Prednisone + ASA increase prematurity and gestational diabetes
Intravenous inmunoglobulin +/- heparin or ASA increase prematurity, PL

60. Clinical utility
Since hypercoagulability might results in RPL,
anticoagulant agents could potentially increase 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

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

62. 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?

64. Recommendations
European Society of Human Reproduction and Embryology
('ESHRE')
• For women with RPL, we suggest not to screen
for hereditary thrombophilia unless in the
context of research, or in women with additional
risk factors for thrombophilia.
• For women with RPL we recommend screening
for antiphospholipid antibodies (LA and ACA [IgG
and IgM]), after two pregnancy losses.
• For women with RPL screening for aβ2GPI can be
considered after two pregnancy losses.

65. Recommendations
European Society of Human Reproduction and Embryology
('ESHRE')
• Measurement of homocysteine plasma levels is
not routinely recommended in women with RPL
• For women with hereditary thrombophilia and a
history of RPL, we suggest not to use
antithrombotic prophylaxis unless in the context
of research, or if indicated for VTE prevention.
• RPL associated with Inh.Throm., LMWH therapy
has been shown to improve live birth rates

66. Royal College of
Obstetricians and Gynaecologists