Bob Silver, MD

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Thrombophilias in Obstetrics

• Bob Silver, MD
• University of Utah Health Sciences

Modified from a presentation to the Society of
Maternal Fetal Medicine by
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Thrombophilias

• A heterogeneous group of conditions that
  predispose individuals to (venous)
  thromboembolism

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Why we care

• Thromboembolism
• 1 killer in pregnancy
• Common obstetric problems
• Stillbirth
• Severe IUGR
• Severe preeclampsia
• Abruption

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Initiation of Hemostasis
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Limitation of Hemostasis
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Procoagulant
Anticoagulant
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Procoagulant
Anticoagulant
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Components of Hemostasis

• Factor IX
• Factor VIII
• Factor X
• Factor V
• Factor II
• Factor XIII
• Factor VII

• Protein C
• Protein S
• Antithrombin III
• Fibrinolysis
• PAI-1

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Pregnancy enhances clotting

• Increase 20-200
• Factor II
• Factor VII
• Factor VIII
• Factor X
• Factor XII
• Decrease in Protein S
• Increase in PAI-1 300
• Resistance to APC
• Impaired fibrinolysis

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Hereditary Thrombophilias

• Protein C pathway
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
• Prothrombin G20210A mutation
• Antithrombin III deficiency
• Hyperhomocystinemia
• C677T MTHFR mutation

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Factor V Leiden Mutation

• Mutation in Factor V
• Protein C/S complex
• Impaired anticoagulation
• 5-11 of white Europeans
• Heterozygous
• Autosomal dominant
• Homozygous rare

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Prothrombin G20210A mutation

• Mutation in promotor
• 150-200 ? in prothrombin levels
• 2-3 of Europeans
• Heterozygous
• autosomal dominant
• Homozygous similar to Factor V

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Protein C / Protein S Deficiencies

• Protein C deficiency
• Type I ? number and activity
• Type II ? activity
• Protein S deficiency
• Type I ? total and free forms
• Type II ? cofactor activity
• Type III - ? free only
• Autosomal dominant
• 0.2-0.5, 0.8 prevalence

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AT III Deficiency

• Multiple mutations
• Most thrombogenic disorder
• Type I
• Levels and activity
• Type II
• Activity

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Hyperhomocysteinemia

• Atherosclerosis, NTD, thromboembolism
• Severe homozygous
• 1 in 200,000-355,000
• Cystathionine ? -synthase
• Mild to moderate
• Heterozygotes for C?S mutation
• Homozygous for 667C-T MTHFR (11)

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Prevalence in Populations
Gen Pop
Thrombosis
Prevalence lower in African, Latin, and Asian
Americans
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Lifetime Prevalence of Thromboembolism
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Thromboembolism in Pregnancy

• 0.70 1.0 per 1,000 pregnancies
• Presence of Thrombophilias
• 8 fold increase in risk (overall)
• Dramatic increase in risk ifgt 1 thrombophilia

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Thrombophilias and VTE in Pregnancy

• Case-control study
• 119 with prior VTE in pregnancy
• 233 age-matched controls
• Tested
• inherited thrombophilias
• APS

Gerhardt et al, N Engl J Med 2000 342374
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Prothrombin and Factor V Mutations in Women with
VTE in Pregnancy
Cases (119)
Controls (233)
Thrombophilia
Gerhardt, NEJM 2000 342374
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Risk of VTE Associated with Hereditary
Thrombophilias
RR
Factor V
6.9
PT G20210
9.5
PC def.
2.2
AT III def.
10.4
1
66
0
5
10
50
20
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Estimated Probability of Thromboembolism
Gerhardt, NEJM 2000 342374
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Thrombophilias and Pregnancy Complications

• Preeclampsia
• Pregnancy loss
• Fetal growth restriction
• Placental abruption

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Pathophysiology of Thrombophilia in Pregnancy

• Thrombosis in uteroplacental circulation causes
  infarction
• Abnormal placentation
• Insufficiency
• Abruption
• Pregnancy loss
• preeclampsia

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Villous Infarction
Normal Villi
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Factor V Leiden Mutation
50
N 24
40
30
Percent
20
10
N 372
0


lt 10 Infarction
gt 10 Infarction
Dizon-Townson, AJOG 1997177402
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Thrombophilias and Pregnancy Complications

• Case control study
• 110 women with severe preeclampsia, IUGR,
  stillbirth, or abruption
• Inherited thrombophilias and APS
• 65 cases positive (18 controls)
• 52 mutation
• 13 acquired/inherited
• OR for thrombophilia 8.2, 4.4-15.3

Kupferminc, NEJM 19993409
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Thrombophilias and Pregnancy Complications
Preeclampsia
Abruption
IUGR
Stillbirth
Kupferminc, NEJM 19993409
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Thrombophilias and Pregnancy Loss

• Case control study
• 67 women
• 1st fetal death ? 20 wks
• no prior thrombosis
• 232 fertile controls
• Postpartum tests for 3 mutations

Martinelli, NEJM 20003431015
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Thrombophilias and Pregnancy Loss
Fetal Death (N67)
Fertile Controls (N20)
OR (95CI)
Martinelli, N Engl J Med 20003431015
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Thrombophilias and Recurrent Miscarriage

• Case-Control study
• 50 women with 3 or more 1st trimester SAB
• 50 healthy women
• Tested for three mutations plus IgG
  anticardiolipin

Kutteh, Fertil Steril 2000711048-53
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Thrombophilias and Recurrent Miscarriage
RR
Factor V
0.5
PT G20210
1.0
MTHFR /
2.1
APS
6
1
0
2
5
30
Kutteh, Fertil Steril 2000711048-53
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Thrombophilias and Pregnancy Loss Meta-analysis

• Medline 1975 2002
• 31 studies
• Mostly retrospective
• Moderate-high quality

Rey et al., Lancet 2003361901
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Thrombophilias and Pregnancy Loss
Meta-analysis (RR 95 CI)

• Factor V Leiden
• Early recurrent loss 2.0 (1.1 3.6)
• Late recurrent loss 7.8 (2.8 21.7)
• Late sporadic loss 3.3 (1.8 5.8)
• Increased effect if other pathologies excluded

Rey et al., Lancet 2003361901
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Thrombophilias and Pregnancy Loss
Meta-analysis (RR 95 CI)

• Prothrombin gene mutation
• Early recurrent loss 2.6 (1.0 6.3)
• Late sporadic loss 2.3 (1.1 4.9)
• Protein S deficiency
• Recurrent loss 14.7 (1.0 218.0)
• Late sporadic loss 7.4 (1.3 42.6)

Rey et al., Lancet 2003361901
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Thrombophilias and Pregnancy Loss
Meta-analysis (RR 95 CI)

• Protein C deficiency
• ATIII deficiency
• MTHFR homozygosity
• No association with fetal loss

Rey et al., Lancet 2003361901
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Thrombophilias and IUGR

• Case-control study
• 493 IUGR pregnancies (lt10)
• 472 normal pregnancies
• Tested newborns and mothers
• Three mutations

Infante-Rivard, NEJM 200234757-9
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Thrombophilias and IUGR
RR
Factor V
1.2
PT G20210
0.92
MTHFR /-
0.98
MTHFR /
1.6
0
2
3
1
Infante-Rivard, NEJM 200234757-9
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Thrombophilias and Preeclampsia
RR
Preeclampsia
1.2
HELLP
1.7
IUGR
2.4
0
2
3
20
1
Livingston, AJOG 2001185153-7
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Thrombophilias andAdverse Pregnancy Outcomes

• Fetal death
• Consistent (not uniform) association (Not MTHFR)
• Spontaneous abortion
• Some association with APS
• Others? Mostly No
• Other complications Mixed results
• Preeclampsia?
• IUGR?
• Abruption?

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Factor V LeidenProspective Obstetric Outcome

• Prospective cohort
• 2,480 women in early pregnancy
• Factor V Leiden 270 (11)
• 8 fold increase in VTE
• Less intrapartum blood loss

Lindqvist, Thromb Haemost 199981532-7
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Obstetric Outcome
Controls
Factor V Leiden
Percent
Abruptio
Sab
FD
PIH
IUGR
Lindqvist, Thromb Haemost 199981532-7
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Factor V LeidenProspective Obstetric Outcome

• Prospective cohort - MFMU
• 5,188 women in early pregnancy
• Factor V Leiden 134 (2.7)
• No increase in VTE!
• 4 VTE all testing negative

Dizon-Townson, AJOG 2002187S159 (SFMFM)
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Factor V LeidenProspective Obstetric Outcome
Dizon-Townson, AJOG 2002187S159 (SMFM)
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Thrombophilias andAdverse Pregnancy Outcomes

• Apparently conflicting results
• Retrospective vs. prospective
• Most women with thrombophilias
• Normal pregnancy outcome
• Two-hit hypothesis
• Thrombophilia and fetal death (or thrombosis) is
  different than thrombophilia alone

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Thrombophilias Who Should we Test?
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Venous thrombosis or embolism
Factor V Leiden
Factor V Leiden Prothrombin G20210A
Prothrombin G20210A
Antiphospholipid Antibodies (LA and aCL)
Consider other (PC def, PS def, AT-III def)
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Family History of Venous thrombosis or
thrombophilia
??????
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What About Obstetric Complications?
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Postnatal Screening for Thrombophilias

• Case control
• 102 women with complications
• 44 healthy women
• 10 weeks postpartum
• Tested for all thrombophilias
• 53 of cases positive
• 39 of controls positive

Alfirevic, OBGYN 200197753
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Postnatal Screening for Thrombophilias
Factor V
PTG20210
MTHFR (/)
Preeclampsia
Abruption
IUGR
Stillbirth
Alfirevic, OBGYN 200197753
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Thrombophilias andAdverse Pregnancy Outcomes

• Statistically significant
• ? Clinically significant
• Most women with thrombophilias
• Normal pregnancy outcome
• Ability to predict which subset of women with
  thrombophilia will have adverse outcomes
• Poor history better than labs

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Who Should we Test?

• Thromboembolism YES
• Family history of VTE YES
• AT III, protein C, protein S
• Obstetric complications
• Unexplained fetal death Maybe
• Recurrent 1st trimester losses NO
• Severe preeclampsia ?
• Severe IUGR, abruption ?
• Recurrent cases yes

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Which Tests Should We Use?
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Standard Thrombophilias

• Factor V Leiden
• Prothrombin G20210A
• Antithrombin III deficiency
• Protein C deficiency
• Protein S deficiency
• Antiphospholipid antibodies
• Anticardiolipin and lupus anticoagulant

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Caution

• Experimental (at best)
• MTHFR
• Other antiphospholipid antibodies
• Some tests affected by
• Anticoagulation
• Acute thrombosis
• Pregnancy!

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Thrombophilias Laboratory Issues

• DNA tests (Factor V Leiden Prothrombin G20210A)
  - anytime
• Antithrombin functional assay altered by
• Acute thrombosis
• Heparin
• Protein C functional assay altered by
• Pregnancy and OCPs
• Warfarin wait 2 wks
• Acute thrombosis

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ThrombophiliasLaboratory Aspects

• Free Protein S functional assay altered by
• Pregnancy and OCPs
• Warfarin wait 2 wks
• Acute thrombosis
• Inflammatory states always repeat!

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What to do with a Positive result?
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ThrombophiliasTreatment (Problems)

• Lack of data from RCTs
• Retrospective studies
• Selection bias
• Increased relative risk
• Low absolute risk
• Theoretical risk versus risk / cost of
  interventions

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Thrombophilias Treatment Recommendations
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Thrombophilias Treatment Recommendations

• Personal history
• Thrombosis
• Obstetric complications
• Family history
• Thrombophilia

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ACOG Recommendations Thrombophilias

• Full anticoagulation for pregnant women with
• AT III deficiency
• Homozygous for factor V Leiden or prothrombin
  G20210A or double heterozygotes
• APS and previous thrombosis

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ACOG Recommendations Thrombophilias

• Full anticoagulation OR thromboprophylaxis for
  pregnant women with prior thrombosis and
• PC or PS deficiency
• Heterozygous for factor V Leiden or prothrombin
  G20210A mutations
• MTHFR and hyperhomocysteinemia ?

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ACOG Recommendations Thrombophilias

• Thromboprophylaxis OR no treatment for pregnant
  women with NO personal history of thrombosis,
  but
• An inherited thrombophilia and a strong family
  history of thrombosis
• Consider postpartum anticoagulation
• (I do NOT treat these women)

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ACOG Recommendations Thrombophilias

• Dont know what to do with women with NO personal
  or family history of VTE and
• Heterozygous for factor V Leiden or prothrombin
  G20210A mutations
• PC or PS deficiency
• MTHFR and hyperhomocysteinemia

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ACOG Recommendations Thrombophilias

• All women at risk for thrombosis should receive
  postpartum anticoagulation for 6 weeks
• (No data)
• Consider prophylaxis for cesarean delivery in
  high risk cases

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ACOG Recommendations Thrombophilias

• What about asymptomatic women with a prior Ob
  complication(s) and a thrombophilia?

There are few good data upon which to base
management, and expert opinion varies! Treatment
is experimental Consider recurrent cases
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Thrombophilias and Pregnancy Loss Thromboprophylax
is

• Multicenter RCT
• One prior loss gt 10 weeks
• Thrombophilia
• Factor V Leiden
• Prothrombin
• Protein S deficiency

Gris et al., Blood 20041033695
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Thrombophilias and Pregnancy LossThromboprophylax
is

• 5 mg folic acid preconception
• Randomization
• Low dose aspirin (100 mg QD)
• N 80
• Enoxiparin (40 mg QD at 8 weeks)
• N 80

Gris et al., Blood 20041033695
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Thrombophilias and Pregnancy LossThromboprophylax
is
Gris et al., Blood 20041033695
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Thrombophilias and Pregnancy LossThromboprophylax
is

• LMWH - OR for live birth
• 15.5 (7 34)
• Similar results for each thrombophilia
• Protein Z deficiency associated with worse
  outcomes
• Lower birth weight in LDA group

Gris et al., Blood 20041033695
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Thrombophilias and Pregnancy LossThromboprophylax
is

• Similar data from uncontrolled trials
• Caution
• One study not confirmed
• Many Obstetricians in USA are not aware of the
  results
• Studies needed
• window of opportunity

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Thrombophilias and Obstetric ComplicationsWill
everyone end up on heparin?

• Not yet!
• Available data supports
• Heparin for thrombophilia and
• Unexplained fetal death
• Adverse effects / cost of treatment
• Prevalence in normal people
• Consider other causes especially RSAB
• Be on the lookout for new data