Thrombophilia Made Simple for Obstetricians

Thrombophilia Made Simple for Obstetricians

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

ScopeReview of thrombophiliaRelationship between thrombophilia &

adverse pregnancy outcomes – the evidenceRole of screening

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

ThrombophiliaAcquiredAnti-Phospholipid Syndrome (APS)APCRElevated factor VIIIPregnancyNephrotic syndrome

Thrombophilia made simple

Thrombophilia made simple

Physiological anticoagulants

Thrombophilia made simple

Prothrombin gene mutation

Thrombophilia made simple

Prothrombin gene mutation

Antithrombin deficiency

Factor V LeidenAPC Resistance

Thrombophilia made simple

Prothrombin gene mutation

Antithrombin deficiency

Factor V LeidenAPC Resistance

Protein C deficiencyProtein S deficiency

Thrombophilia made simple

Towards ANTICOAGULA

TIONTowards CLOT

formation

Factor V

Thrombin

Fibrinogen

Antithrombin III

Protein C

Protein S

Thrombophilia testingHistory of recurrent, atypical (axillary vein,

CVT) thromboembolismUnprovoked thromboembolism

Provoking factors eg COCP, pregnancy, surgery, trauma

Family history of thromboembolism

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

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

WHAT NOT TO ORDER!

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

Increasing risk

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

Increasing risk

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

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

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

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!

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

Thrombophilia and Placenta- Mediated Pregnancy Complications

Thrombophilia and Placenta- Mediated Pregnancy Complications

Pregnancy loss – recurrent miscarriage, late pregnancy lossIUGRPre-eclampsiaAbruptio

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

Association between Thrombophilia & Pregnancy complications

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

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

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

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)

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)

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)

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

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?

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

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

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?

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

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

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

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

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.

• 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

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

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