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

Thrombophilia Made Simple for Obstetricians

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

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Page 1: Thrombophilia Made Simple for Obstetricians

Thrombophilia Made Simple for Obstetricians

Dr Tan Lay KokMBBS FRCOG MMED(O&G) FAMSDepartment of OBGYN, Singapore General Hospital

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ScopeReview of thrombophiliaRelationship between thrombophilia &

adverse pregnancy outcomes – the evidenceRole of screening

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ThrombophiliaInheritedAntithrombin deficiencyProtein C deficiencyProtein S deficiencyFactor V LeidenProthrombin gene mutationMTHFR and hyperhomocysteinaemia

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ThrombophiliaAcquiredAnti-Phospholipid Syndrome (APS)APCRElevated factor VIIIPregnancyNephrotic syndrome

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Physiological anticoagulants

Thrombophilia made simple

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Prothrombin gene mutation

Thrombophilia made simple

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Prothrombin gene mutation

Antithrombin deficiency

Factor V LeidenAPC Resistance

Thrombophilia made simple

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Prothrombin gene mutation

Antithrombin deficiency

Factor V LeidenAPC Resistance

Protein C deficiencyProtein S deficiency

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Thrombophilia made simple

Towards ANTICOAGULA

TIONTowards CLOT

formation

Factor V

Thrombin

Fibrinogen

Antithrombin III

Protein C

Protein S

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Thrombophilia testingHistory of recurrent, atypical (axillary vein,

CVT) thromboembolismUnprovoked thromboembolism

Provoking factors eg COCP, pregnancy, surgery, trauma

Family history of thromboembolism

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Thrombophilia testingHas increased tremendously in last few

decades in O&GBelief

that thrombophilia underlies and causes bad pregnancy outcomes

that screening for and treatment for thrombophilia improves outcomes

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

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WHAT NOT TO ORDER!

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Thrombophilia but no thrombosisFVL / PT / APSPC / PS / homozygous FVLATCombination

Increasing risk

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Thrombophilia but no thrombosisFVL / PT / APSPC / PS / homozygous FVLATCombination

Increasing risk

Stratify risk & consider other risk factors• Personal history• Family history

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2 QuestionsDo inherited thrombophilias, inherited or acquired, cause pregnancy complications?

Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

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ConclusionsThrombophilias 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!

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

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Thrombophilia and Placenta- Mediated Pregnancy Complications

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Thrombophilia and Placenta- Mediated Pregnancy Complications

Pregnancy loss – recurrent miscarriage, late pregnancy lossIUGRPre-eclampsiaAbruptio

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

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Association between Thrombophilia & Pregnancy complications

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Factor V Leiden and Pregnancy Loss- Weak associationReview: Thrombophilic women and placenta mediated pregnancy complicationsComparison: 04 FVLOutcome: 01 Pregnancy Loss

Study FVL Positive FVL Negative RR (random) Weight RR (random)

or sub-category n/N n/N 95% CI % 95% CI

Clark 2008 1/142 71/3802 6.14 0.38 [0.05, 2.69] Dizon-Townson 2005 8/134 264/4751 20.36 1.07 [0.54, 2.13]

Lindqvist 2006 13/270 73/2210 22.39 1.46 [0.82, 2.59] Rodger 2008 3/133 28/2811 12.51 2.26 [0.70, 7.35]

Karakantza 2008 4/13 47/379 17.19 2.48 [1.05, 5.85] Murphy 2000 3/16 24/572 13.61 4.47 [1.50, 13.33]

Said 2006 2/93 4/1633 7.79 8.78 [1.63, 47.32]

Total (95% CI) 801 16158 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% LossNo FVL: 3.2% Loss

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Review: Thrombophilic women and placenta mediated pregnancy complications (all studies)Comparison: 01 Factor V LeidenOutcome: 01 Pre-eclampsia

Study FVL Positive FVL Negative RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Salomon 2004 1/38 28/605 5.20 0.57 [0.08, 4.07] Said 2006 5/93 98/1633 16.58 0.90 [0.37, 2.15] Rodger 2008 4/128 76/2783 10.49 1.14 [0.43, 3.08] Lindqvist 2006 5/257 34/2137 11.46 1.22 [0.48, 3.10] Dizon-Townson 2005 5/134 141/4751 12.15 1.26 [0.52, 3.02] Clark 2008 3/141 63/3731 7.20 1.26 [0.40, 3.96] Dudding 2008 17/243 204/4206 34.99 1.44 [0.89, 2.33] Murphy 2000 0/13 12/548 0.98 1.57 [0.10, 25.20] Karakantza 2008 0/13 8/379 0.95 1.60 [0.10, 26.30]

Total (95% CI) 1060 20773 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

Factor V Leiden and Pre-Eclampsia - No Association

Exposure:4.9% FVL

Outcome Event Rates:FVL: 3.8% Pre-EclampsiaNo FVL: 3.2% Pre-Eclampsia

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Prothrombin GM and Pre-Eclampsia - No Association

Review: Thrombophilic women and placenta mediated pregnancy complicationsComparison: 01 PGMOutcome: 02 Pre-eclampsia

Study PGV Positive PGV Negative RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Dudding 2008 5/239 85/4176 44.16 1.03 [0.42, 2.51]

Said 2006 3/41 100/1685 22.80 1.23 [0.41, 3.73]

Rodger 2008 2/60 75/2851 14.83 1.27 [0.32, 5.04]

Karakantza 2008 0/12 8/380 2.69 1.72 [0.11, 28.30]

Salomon 2004 3/40 26/603 15.52 1.74 [0.55, 5.50]

Total (95% CI) 392 9695 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-EclampsiaNo PGM: 3.0% Pre-Eclampsia

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Factor V Leiden and SGA<10th Percentile - No Association

Review: Thrombophilic women and placenta mediated pregnancy complicationsComparison: 02 FVL Outcome: 01 IUGR (Birthweight <10th Percentile)

Study FVL Positive FVL Negative RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Lindqvist 2006 23/257 221/2137 28.25 0.87 [0.57, 1.30] Dizon-Townson 2005 10/124 403/4428 13.07 0.89 [0.49, 1.62] Said 2006 10/93 179/1633 11.49 0.98 [0.54, 1.79] Rodger 2008 9/128 188/2783 9.84 1.04 [0.55, 1.98] Dudding 2008 33/587 368/7282 32.69 1.11 [0.79, 1.57] Salomon 2004 5/38 62/603 4.38 1.28 [0.55, 2.99] Murphy 2000 0/13 9/548 0.28 2.06 [0.13, 33.73]

Total (95% CI) 1240 19414 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)

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Prothrombin GM and SGA<10th Percentile- No Association

Review: Thrombophilic women and placenta mediated pregnancy complicationsComparison:02 Intaruterine Growth Restriction Outcome:02 PGM and IUGR (Birthweight < 10th percentile)

Study PGV Positive PGV Negative RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Said 2006 5/41 184/1685 18.01 1.12 [0.49, 2.57] Dudding 2008 16/591 162/7251 50.31 1.21 [0.73, 2.01] Salomon 2004 5/39 62/602 15.54 1.24 [0.53, 2.92] Rodger 2008 5/60 190/2851 16.14 1.25 [0.53, 2.93]

Total (95% CI) 731 12389 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)

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Factor V Leiden and SGA 5th Percentile - No Association

Review: Thrombophilic women and placenta mediated pregnancy complicationsComparison: 02 FVLOutcome: 04 IUGR (birth weight < 5th percentile)

Study FVL positive FVL negative RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Said 2006 3/93 90/1633 29.62 0.59 [0.19, 1.81]

Karakantza 2008 0/13 19/379 4.23 0.70 [0.04, 10.95]

Clark 2008 6/141 168/3731 37.37 0.95 [0.43, 2.10]

Dizon-Townson 2005 6/124 173/4428 28.78 1.24 [0.56, 2.74]

Total (95% CI) 371 10171 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)

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Factor V Leiden and Abruption- No Association

Review: Thrombophilic women and placenta mediated pregnancy complicationsComparison: 03 FVLOutcome: 01 Placenta Abruption (all studies)

Study FVL Positive FVL Negative RR (random) Weight RR (random)or sub-category n/N n/N 95% CI % 95% CI

Dizon-Townson 2005 0/134 31/4751 9.01 0.56 [0.03, 9.08]

Said 2006 0/93 6/1726 8.58 1.41 [0.08, 24.90]

Lindqvist 2006 2/257 11/2137 22.44 1.51 [0.34, 6.78]

Rodger 2008 3/128 39/2783 29.70 1.67 [0.52, 5.34]

Karakantza 2008 3/13 12/379 30.27 7.29 [2.34, 22.74]

Total (95% CI) 625 11776 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% AbruptionNo FVL: 0.8% Abruption

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2 QuestionsDo inherited thrombophilias cause placenta-mediated pregnancy complications?No - SGA, Pre-eclampsiaWeakly - Pregnancy loss

Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

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British Journal of Haematology 2008 Nov; 143 (3) : 321-35

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Does knowledge about thrombophilia status alter management?No!Except:

Asymptomatic fertile women + family history of VTE + thrombophilic defect

APS with venous /arterial thrombosis and well defined pregnancy complications

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2 QuestionsDo inherited thrombophilias cause placenta-

mediated pregnancy complications?No - SGA, Pre-eclampsiaWeakly - Pregnancy loss

Do anticoagulants, specifically Low Molecular Weight Heparin (LMWH), prevent these complications in thrombophilic women?

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

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

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

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List of completed RCTS of interventions vs control to prevent pregnancy loss in thrombophilic women– up to 2010

Gris, Blood, 2004Laskin, J Rheumatology, 2009Rey, J Thromb Haemost, 2009

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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.

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• 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

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

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ConclusionAssociation is not causationEvidence supporting thrombophilia screening

is weakNot cost effectiveUnnecessary indiscriminate testing can be

harmfulAntiphospholipid syndrome is the only

thrombophilia justified for screening in defined situations