1. Thrombophilia Made Simple for Obstetricians
Dr Tan Lay Kok
MBBS FRCOG MMED(O&G) FAMS
Department of OBGYN, Singapore General Hospital

2. Scope Review of thrombophilia
Relationship between thrombophilia & adverse pregnancy outcomes – the evidence
Role of screening

3. Thrombophilia Inherited Antithrombin deficiency Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin gene mutation
MTHFR and hyperhomocysteinaemia

4. Thrombophilia Acquired Anti-Phospholipid Syndrome (APS) APCR
Elevated factor VIII
Pregnancy
Nephrotic syndrome

6. Thrombophilia made simple

7. Thrombophilia made simple

8. Thrombophilia made simple
Physiological anticoagulants

9. Thrombophilia made simple
Prothrombin gene mutation

10. Thrombophilia made simple
Antithrombin deficiency
Prothrombin gene mutation
Factor V Leiden
APC Resistance

11. Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Prothrombin gene mutation
Factor V Leiden
APC Resistance

12. Thrombophilia made simple
Towards ANTICOAGULATION
Antithrombin III
Protein C
Protein S
Towards CLOT formation
Factor V
Thrombin
Fibrinogen

13. Thrombophilia testing
History of recurrent, atypical (axillary vein, CVT) thromboembolism
Unprovoked thromboembolism
Provoking factors eg COCP, pregnancy, surgery, trauma
Family history of thromboembolism

14. Thrombophilia testing
Has increased tremendously in last few decades in O&G
Belief
that thrombophilia underlies and causes bad pregnancy outcomes
that screening for and treatment for thrombophilia improves outcomes

16. Seminars in Reproductive Medicine 2006 Feb; 24 (1) : 54-66.

18. WHAT NOT TO ORDER!

19. Thrombophilia but no thrombosis
FVL / PT / APS
PC / PS / homozygous FVL AT
Combination
Increasing risk

20. Thrombophilia but no thrombosis
FVL / PT / APS
PC / PS / homozygous FVL AT
Combination
Increasing risk
Stratify risk & consider other risk factors
Personal history
Family history

21. 2 Questions
Do inherited thrombophilias, inherited or acquired, cause pregnancy complications?
Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

22. Conclusions
Thrombophilias likely a weak cause of early and “later” pregnancy loss; likely don’t contribute to pre-eclampsia and SGA; unknown if associated with abruption
No proven preventative measures in thrombophilic pregnancies- LMWH is not candy!

23. Thrombophilias predispose to development of thrombosis
in slow flow circulation of the placenta

24. Thrombophilia and Placenta- Mediated Pregnancy Complications

25. Thrombophilia and Placenta- Mediated Pregnancy Complications
Pregnancy loss – recurrent miscarriage, late pregnancy loss
IUGR
Pre-eclampsia
Abruptio

28. Current Opinion in Obstetrics & Gynecology 2012 Aug; 24 (4) : 229-34.

30. Association between Thrombophilia & Pregnancy complications

31. Factor V Leiden and Pregnancy Loss- Weak association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
04 FVL
Outcome:
01 Pregnancy Loss
Study
FVL Positive
FVL Negative
RR (random)
Weight
or sub-category
n/N
95% CI %
Clark 2008
1/ /3802
6.14
0.38 [0.05, 2.69]
Dizon-Townson 2005
8/ /4751
20.36
1.07 [0.54, 2.13]
Lindqvist 2006
13/ /2210
22.39
1.46 [0.82, 2.59]
Rodger 2008
3/ /2811
12.51
2.26 [0.70, 7.35]
Karakantza 2008
4/ /379
17.19
2.48 [1.05, 5.85]
Murphy 2000
3/ /572
13.61
4.47 [1.50, 13.33]
Said 2006
2/ /1633
7.79
8.78 [1.63, 47.32]
Total (95% CI)
100.00
1.96
[1.13,3.38]
Total events: 34 (FVL Positive), 511 (FVL Negative)
Test for heterogeneity: Chi² = 12.77, df = 6 (P = 0.05), I² = 53.0%
Test for overall effect: Z = 2.40 (P = 0.02)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
4.7% FVL
Outcome Event Rates:
FVL: 4.2% Loss
No FVL: 3.2% Loss

32. Factor V Leiden and Pre-Eclampsia - No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications (all studies)
Comparison:
01 Factor V Leiden
Outcome:
01 Pre-eclampsia
Study
FVL Positive
FVL Negative
RR (fixed)
Weight
or sub-category
n/N
95% CI %
Salomon 2004
1/ /605
5.20
0.57 [0.08, 4.07]
Said 2006
5/ /1633
16.58
0.90 [0.37, 2.15]
Rodger 2008
4/ /2783
10.49
1.14 [0.43, 3.08]
Lindqvist 2006
5/ /2137
11.46
1.22 [0.48, 3.10]
Dizon-Townson 2005
5/ /4751
12.15
1.26 [0.52, 3.02]
Clark 2008
3/ /3731
7.20
1.26 [0.40, 3.96]
Dudding 2008
17/ /4206
34.99
1.44 [0.89, 2.33]
Murphy 2000
0/ /548
0.98
1.57 [0.10, 25.20]
Karakantza 2008
0/ /379
0.95
1.60 [0.10, 26.30]
Total (95% CI)
100.00
1.22
[0.89,1.66]
Total events: 40 (FVL Positice), 664 (FVL Negative)
Test for heterogeneity: Chi² = 1.62, df = 8 (P = 0.99), I² = 0%
Test for overall effect: Z = 1.24 (P = 0.21)
0.1
0.2
0.5 1 2 5 10
Increases Risk
Decreases Risk
Exposure:
4.9% FVL
Outcome Event Rates:
FVL: 3.8% Pre-Eclampsia
No FVL: 3.2% Pre-Eclampsia

33. Prothrombin GM and Pre-Eclampsia - No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
01 PGM
Outcome:
02 Pre-eclampsia
Study
PGV Positive
PGV Negative
RR (fixed)
Weight
or sub-category
n/N
95% CI %
Dudding 2008
5/ /4176
44.16
1.03 [0.42, 2.51]
Said 2006
3/ /1685
22.80
1.23 [0.41, 3.73]
Rodger 2008
2/ /2851
14.83
1.27 [0.32, 5.04]
Karakantza 2008
0/ /380
2.69
1.72 [0.11, 28.30]
Salomon 2004
3/ /603
15.52
1.74 [0.55, 5.50]
Total (95% CI)
100.00
1.24
[0.72,2.12]
Total events: 13 (PGV Positive), 294 (PGV Negative)
Test for heterogeneity: Chi² = 0.56, df = 4 (P = 0.97), I² = 0%
Test for overall effect: Z = 0.78 (P = 0.43)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
3.9% PGM
Outcome Event Rates:
PGM: 3.3% Pre-Eclampsia
No PGM: 3.0% Pre-Eclampsia

34. Factor V Leiden and SGA<10th Percentile - No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
02 FVL
Outcome:
01 IUGR (Birthweight <10th Percentile)
Study
FVL Positive
FVL Negative
RR (fixed)
Weight
or sub-category
n/N
95% CI %
Lindqvist 2006
23/ /2137
28.25
0.87 [0.57, 1.30]
Dizon-Townson 2005
10/ /4428
13.07
0.89 [0.49, 1.62]
Said 2006
10/ /1633
11.49
0.98 [0.54, 1.79]
Rodger 2008
9/ /2783
9.84
1.04 [0.55, 1.98]
Dudding 2008
33/ /7282
32.69
1.11 [0.79, 1.57]
Salomon 2004
5/ /603
4.38
1.28 [0.55, 2.99]
Murphy 2000
0/ /548
0.28
2.06 [0.13, 33.73]
Total (95% CI)
100.00
1.00
[0.82,1.23]
Total events: 90 (FVL Positive), 1430 (FVL Negative)
Test for heterogeneity: Chi² = 1.60, df = 6 (P = 0.95), I² = 0%
Test for overall effect: Z = 0.01 (P = 0.99)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
6.0% FVL
Outcome Event Rates:
FVL: 7.2% SGA(10th%ile)
No FVL: 7.3% SGA(10th%ile)

35. Prothrombin GM and SGA<10th Percentile- No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
02 Intaruterine Growth Restriction
Outcome:
02 PGM and IUGR (Birthweight < 10th percentile)
Study
PGV Positive
PGV Negative
RR (fixed)
Weight
or sub-category
n/N
95% CI %
Said 2006
5/ /1685
18.01
1.12 [0.49, 2.57]
Dudding 2008
16/ /7251
50.31
1.21 [0.73, 2.01]
Salomon 2004
5/ /602
15.54
1.24 [0.53, 2.92]
Rodger 2008
5/ /2851
16.14
1.25 [0.53, 2.93]
Total (95% CI)
100.00
1.21
[0.85,1.71]
Total events: 31 (Treatment), 598 (Control)
Test for heterogeneity: Chi² = 0.05, df = 3 (P = 1.00), I² = 0%
Test for overall effect: Z = 1.04 (P = 0.30)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
5.6% PGM
Outcome Event Rates:
PGM: 4.2% SGA(10th%ile)
No PGM: 4.8% SGA(10th%ile)

36. Factor V Leiden and SGA 5th Percentile - No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
02 FVL
Outcome:
04 IUGR (birth weight < 5th percentile)
Study
FVL positive
FVL negative
RR (fixed)
Weight
or sub-category
n/N
95% CI %
Said 2006
3/ /1633
29.62
0.59 [0.19, 1.81]
Karakantza 2008
0/ /379
4.23
0.70 [0.04, 10.95]
Clark 2008
6/ /3731
37.37
0.95 [0.43, 2.10]
Dizon-Townson 2005
6/ /4428
28.78
1.24 [0.56, 2.74]
Total (95% CI)
100.00
0.91
[0.56,1.50]
Total events: 15 (FVL positive), 450 (FVL negative)
Test for heterogeneity: Chi² = 1.21, df = 3 (P = 0.75), I² = 0%
Test for overall effect: Z = 0.36 (P = 0.72)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
3.7% FVL
Outcome Event Rates:
FVL: 4.0% SGA (5th%ile)
No FVL: 4.4% SGA (5th%ile)

37. Factor V Leiden and Abruption - No Association
Review:
Thrombophilic women and placenta mediated pregnancy complications
Comparison:
03 FVL
Outcome:
01 Placenta Abruption (all studies)
Study
FVL Positive
FVL Negative
RR (random)
Weight
or sub-category
n/N
95% CI %
Dizon-Townson 2005
0/ /4751
9.01
0.56 [0.03, 9.08]
Said 2006
0/ /1726
8.58
1.41 [0.08, 24.90]
Lindqvist 2006
2/ /2137
22.44
1.51 [0.34, 6.78]
Rodger 2008
3/ /2783
29.70
1.67 [0.52, 5.34]
Karakantza 2008
3/ /379
30.27
7.29 [2.34, 22.74]
Total (95% CI)
100.00
2.28
[0.92, 5.67]
Total events: 8 (FVL Positive), 99 (FVL Negative)
Test for heterogeneity: Chi² = 6.30, df = 4 (P = 0.18), I² = 36.5%
Test for overall effect: Z = 1.77 (P = 0.08)
0.1
0.2
0.5 1 2 5 10
Decreases Risk
Increases Risk
Exposure:
5.1% FVL
Outcome Event Rates:
FVL: 1.3% Abruption
No FVL: 0.8% Abruption

43. 2 Questions
Do inherited thrombophilias cause placenta-mediated pregnancy complications?
No - SGA, Pre-eclampsia
Weakly - Pregnancy loss
Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

45. 2011 says not justified

46. British Journal of Haematology 2008 Nov; 143 (3) : 321-35
No difference from earlier statement in 2008

47. 2008
Need for RCT

49. Does knowledge about thrombophilia status alter management?
Except:
Asymptomatic fertile women + family history of VTE + thrombophilic defect
APS with venous /arterial thrombosis and well defined pregnancy complications

50. 2 Questions
Do inherited thrombophilias cause placenta-mediated pregnancy complications?
No - SGA, Pre-eclampsia
Weakly - Pregnancy loss
Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

51. List of completed RCTs of interventions vs control to prevent pre-eclampsia in thrombophilic women – up to 2010

52. List of completed RCTs of interventions vs control to prevent small for gestational age babies in thrombophilic women – up to 2010

53. List of completed RCTs of interventions vs control to prevent placental abruption in thrombophilic women – up to 2010

54. List of completed RCTS of interventions vs control to prevent pregnancy loss in thrombophilic women – up to 2010
Gris, Blood, 2004
Laskin, J Rheumatology, 2009
Rey, J Thromb Haemost, 2009

65. In conclusion, antepartum prophylactic dose dalteparin in women with thrombophilia at increased risk of pregnancy loss, placenta-mediated pregnancy
complications, or venous thrombosis does not reduce the occurrence of these complications.
Further research is needed to establish whether low-molecular-weight heparin reduces the risk of recurrent severe pre-eclampsia, severely small-for-gestational-age infants (birthweight <5th percentile), or placental abruption.

66. Universal screening of women with previous poor obstetric history for inherited thrombophilia is inappropriate
Use of LMWH in women with inherited thrombophilia with recurrent pregnancy loss is not indicated

67. We mustnt forget cost

68. difference translates into a number needed to treat of six—
This 16% absolute
difference translates into a number needed to treat of six—
ie, six women would need to inject up to 400 needles per
pregnancy at a drug cost of more than US$8000 per
pregnancy to prevent one outcome.
TIPPS Study 2014

70. Conclusion Association is not causation
Evidence supporting thrombophilia screening is weak
Not cost effective
Unnecessary indiscriminate testing can be harmful
Antiphospholipid syndrome is the only thrombophilia justified for screening in defined situations