Transcript Medical Therapeutics During Pregnancy

Indications for a thrombophilia workup
in Obstetrics
Helen H. Kay, MD
February, 2005
Definition of thrombophilia
A disorder associated with an
increased tendency to thrombosis.
Coagulation pathway
History of Inherited Thrombophilias
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1956 Dysfibrinogenemia described
1965 Antithrombin III
deficiency discovered
1981 Protein C
deficiency
1984 Protein S
deficiency
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1993 APCR/Factor V
Leiden mutation
1996 Prothrombin
G20210A mutation
1990’s MTHFR
mutation
– Mild to moderate
hyperhomocysteinemia
– A more severe form
described in 1985
Pregnancy as a hypercoagulable state
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Virchow’s Triad
– Increase in coagulation factors (fibrinogen, VII, VIII, X,
von Willebrand)
• Also a decrease in coagulation inhibitor Protein S
• Increased resistance to activated protein C (APC)
• Increased levels of plasminogen activator inhibitor 1 and 2 (PAI-1,
PAI-2)
• Increased levels of thrombin activatable fibrinolysis inhibitor
(TAFI)
– Venous stasis
• Due to venocaval obstruction by gravid uterus
• Left greater than right (85%,15%)
– Endothelial damage
• From delivery, infection
Incidence of VTE: Antepartum
0.13-0.85/1000 pregnancies, 0.17-1.0/1000
pregnant-women-years
 This is modestly higher than age-matched
nonpregnant controls (0.2-0.4/1000 personyears)
 Leiden Thrombophilia Study (1995) found 4x
increase risk due to pregnancy
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Incidence of VTE: Postpartum
Risk is greater than during pregnancy
 1.0-6.1/1000 deliveries
 Rates cover only the 4-6 weeks of the
puerperium (compared to 40 wks)
 Rate of VTE is estimated to be 3-8x greater
postpartum than antepartum
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Risk Factors for Venous Thrombosis
Acquired
Inherited
Mixed/Unknown
Pregnancy
Antithrombin Deficiency
Homocysteine
Advancing age
Protein C deficiency
Factor VIII
Prior thrombosis
Protein S deficiency
Immobilization
Factor V Leiden (FVL)
APC resistance in the absence of
FVL
Major surgery
Prothrombin G20210A
Malignancy
Dysfibrinogenemias (rare)
Estrogens (OCP, HRT< SERMs)
Antiphospholipid antibody syndrome
Myeloproliferative disorders, IBD
Heparin-induced thrombocytopenia
Prolonged air travel
Factor IX
Factor XI
TAFI
Free TFPI
PAI-I, PAI-II
Factor V Leiden mutation
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Substitution of adenine for guanine at the 1691 position
Factor V resistant to cleavage by APC
Mutation present in 5.2% of Europeans, rare in Asians and
Africans
Autosomal dominant
Heterozygosity present in 20-40% nonpregnant patients with
thromboembolic disease
Homozygosity rare, risk >100 fold
Prothrombin gene mutation G20210A
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Autosomal dominant
Heterozygosity for mutation in the promoter of prothrombin
gene (G20210)
Present in 2-3% of Europeans, 150-200% increased levels
of prothrombin
Accounts for 17% of thromboembolism in pregnancy
In asymptomatic patients, risk of clotting is 0.5%, 1 in 200
Homozygosity is rare, very high risk of thromboembolism,
>100 fold
Antithrombin III deficiency
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Autosomal dominant, point mutations, deletions, insertions
Most thrombogenic of inherited thrombophilias
Type I and II
70-90% lifetime risk of thromboembolism
Antithrombin inactivates factors Xa, Ixa, VIIa, plasmin
Anticoagulant activity increased 5000 to 40,000 fold by
heparin
Prevalence low, 1% of patients with thromboembolism
Protein C deficiency
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Autosomal dominant
Numerous mutations lead to types I and II
Protein C is a vitamin K-dependent glycoprotein substrate
Activated to APC by thrombin, half-life of 6-8 hours
Inactivates factor Va and VIIIa with protein S and factor V,
decreases thrombin
Prevalence of deficiency is 0.2-0.5%
Risks of thromboembolism in pregnancy is 5-20%
Protein S deficiency
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Autosomal dominant
Vitamin K-dependent glycoprotein
Inactivates factors Va, VIIIa, Xa
Plasma half-life of 42 hours
Multiple mutations, types I, II,III, highly variable procoagulant
sequelae
Prevalence is 0.03-1.3%
16% of maternal thromboembolism
Normal pregnancy is associated with decreased levels of PS
activity, in the 30 range
Protein Z deficiency
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Autosomal dominant
Vitamin K-dependent plasma protein
Cofactor for a PZ-dependent protease inhibitor of
factor Xa.
Thrombophilias of questionable
significance
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MTHFRm 667/C-T
11% among Europeans
Results in mild to moderate hyperhomocysteinemia
Homozygosity for the 4G/4G mutation in the PAI-1 gene
Results in a 3-5 fold increased level of circulating PAI-1
Polymorphisms of the thrombomodulin gene associated with
increased risk of thrombosis
Oral Contraceptives and
Thrombophilias
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OCP users have 4x risk of VTE compared with nonusers
Carriers of FVL or PT mutation have 3-10x risk of
VTE over those without mutation
If both OCP use and thrombophilia risk of VTE is
30x
Most data find 3rd generation OCP’s double risk of
VTE over other OCP’s
Prevalence of thrombophilias
Thrombotic effect
Hereditary
Antithrombin III deficiency
++++
Prevalence
0.02%
Autosomal dominant
Factor V Leiden
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5-15% in Caucasians
++
approximately 3%
Autosomal dominant
Prothrombin mutation
Autosomal dominant
Protein C deficiency
in Caucasians
++
0.5%
+
0.5%
Autosomal dominant
Protein S deficiency
Autosomal dominant
Acquired
Antiphospholipid antibody syndrome
Varied
<15%
Mixed/Unknown
Mild hyperhomocysteinemia
Dependant on level
11%
Due primarily to MTHFR
mutation, Autosomal
recessive
of homocysteine
Increase in risk of VTE to thrombophilias
(nonpregnant)
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Coagulation inhibitor deficiencies
10x
– Protein S, C or Antithrombin
– Rare, so risk estimates difficult to assess and
vary widely; ATIII is most severe
Factor V Leiden
5-8x
PT G20210A
2-3x
MTHFR mutation
1-2x
Increased F VIII (>20 umol/L)
3-4x
Increase in risk of VTE due to thrombophilias
(pregnant)
Type
RR (95% CI)
Antithrombin
6.2 (2.2-17.3)
Protein C
2.3 (0.8-6.6)
Protein S
3.2 (1.3-8.0)
Factor VL
9.0 (4.7-17.4)
PT G20210A
10.8 (2.9-40.3)
MTHFR mutation
2.1 (1.0-4.5)
Grandone, AJOG 1998 and Gerhardt, NEJM 2000
Pregnancy complications due to inherited
thrombophilias
Spontaneous abortion/fetal loss/IUFD
 Severe preeclampsia
 Placental abruption
 Intrauterine growth restriction
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Fetal loss in thrombophilias
Type
RR (95% CI) for
RR (95% CI) for
1st trim sab
IUFD
Antithrombin
1.7 (1.0-2.8)
5.2 (1.5-18.1)
Protein C
1.4 (0.9-2.2)
2.3 (0.6-8.3)
Protein S
1.2 (0.7-1.9)
3.3 (1.0-11.3)
Factor V
0.9 (0.5-1.5)
3.2 (1.0-10.9)
PT G20210A
--
3.3 (1.1-10.3)
MTHFR
--
0.8 (0.5-1.2)
Combined (2)
0.8 (0.2-3.6)
14.3 (2.4-86.0)
Preston, Lancet, 1996 and Martinelli, NEJM 2000
Increased risk of preeclampsia in
thrombophilias
Type
RR
Factor VL
4.9-5.3
MTHFR mutation
1.8-2.9
PT G20210A
2.2
Kupferminc, NEJM 1999 and Grandone, Thromb Haemost 1997
Severe preeclampsia and high frequency of
thrombophilia
Thrombophilia
Odds ratio
Factor V
4.6 (1.8, 11.6)
MTHFR
3.0 (1.3, 6.8)
Prothrombin
2.6 (0.7, 10.2)
All mutations
5.3 (2.7, 10.3)
Protein S
10.7 (1.2, 94.3)
Protein C
NA
Antithrombin III
NA
Anticardiolipin antibodies
NA
All thrombophilias
8.0 (4.1, 15.9)
Kupferminc, Obstet Gynecol, 2000
Increased risk of placental abruption in
thrombophilias
Type
RR (95% CI)
Factor VL
4.9 (1.4-17.4)
MTHFR mutation
2.0 (0.5-8.1)
PT G20210A
8.9 (1.8-43.6)
Kupferminc, NEJM 1999
Increased risk of IUGR in thrombophilias
Type
RR (95% CI)
RR (95% CI)
Factor VL
1.9 (0.6-6.3)
1.18 (0.54-2.55)
MTHFR mutation
4.2 (1.6-10.9)
1.55 (0.83-2.90)
PT G20210A
4.6 (1.0-20.0)
0.92 (0.36-2.35)
Kupferminc, 2000
Infante-Rivard, 2002
Thrombophilia among women with obstetric
complications
Type
RR (95% CI)
Factor VL
3.7 (1.5-9.0)
MTHFR mutation
3.1 (1.4-7.1)
PT G20210A
3.9 (1.1-14.6)
Deficiency of Protein S,
Protein C, Antithrombin
9.7 (1.2-78.0)
Anticardiolipin ab’s
2.0 (1.7-2.3)
Kupferminc, NEJM 1999
Historical screen for thrombophilia
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Personal history of a thrombosis
Family history of DVT or pulmonary embolism
Family history of strokes <60 years of age or MI <60 years
in women
Personal history of abruption, severe IUGR, severe or early
preeclampsia <32 weeks
Family history of
– Three pregnancy losses <10 weeks
– Two losses >10 weeks, <20 weeks
– Any unexplained loss >20 weeks
Screening for thrombophilia in patients with
adverse pregnancy outcomes
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Protein C (functional assay)
Protein S (functional or free level)
Antithrombin III (functional assay)
Factor V Leiden mutation (PCR)
Prothrombin 20210A mutation (PCR)
Anticardiolipin antibodies, IgG, IgM,
Lupus anticoagulant (APTT, DRVVT)
Platelet count
Supplemental screening for thrombophilia in
patients with adverse pregnancy outcomes
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Homocysteine
APC resistance
Other Factor V mutations
Thrombomodulin gene variants
Protein Z levels
PAI-1 activity levels
PAI-1 4G/4G polymorphisms
MTHFR C677T mutation
Factor evaluation for VII, VIII, IX, XI
Prophylactic heparin to prevent recurrent
adverse pregnancy outcomes
Kupferminc, 2001 - women with history of
severe preeclampsia, abruption, IUGR or
fetal demise, and known thrombophilia
 Started at 8-12 weeks until 6 weeks
postpartum
 Treated patients had higher birth weight and
gestational age at delivery
 No fetal losses or severe preeclampsia
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Prophylactic heparin to prevent recurrence of
adverse pregnancy outcomes
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Paidas et al, 2004
Cohort of patients carrying either FVL or
prothrombin gene mutation with at least one prior
adverse pregnancy outcome
41 heparin-treated pregnancies compared with
remaining 158 pregnancies
Antenatal heparin administration associated with
80% reduction in adverse pregnancy outcome
Low risk
Pregnancy with transient risk factors:
prolonged bedrest, surgery, obesity
 Family history of thromboembolism
 History of adverse pregnancy outcome
without thrombophilia
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Moderate risk
History of adverse pregnancy outcome with
one thrombophilic condition
 History of thromboembolism with transient
risk factors
 Thrombophilia with family history of
thromboembolism
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High risk
History of idiopathic thromboembolism
outside of pregnancy
 History of thromboembolism with
thrombophilia
 History of antiphospholipid antibody
syndrome
 Two or more thrombophilic disorders but no
personal thromboembolism
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Highest risk
History of antiphospholipid antibody
syndrome
 Active arterial or venous thromboembolism
 Two or more thrombophilic disorders and
adverse pregnancy outcome
 Antithrombin III deficiency
 Homozygous for Factor V Leiden,
prothrombin mutation
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Treatment strategy for thrombophilia: no personal
history of thromboembolism but a family history and
positive work-up
Katz, 2002
Treatment strategy for thrombophilia: history of
thromboembolic disease with risk factors
Katz, 2002
Treatment strategy for thrombophilia: pregnant with a
personal history of adverse pregnancy outcomes, and
a positive thrombophilia workup
Katz, 2002
Treatment regimens
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Full therapeutic regimens
– Unfractionated heparin
• Standard dosing, to attain PTT 1.5-2.5
– LMWH
• Dalteparin 200 U/kg qd or 100 U/kg q12 hours
• Enoxaparin 1 mg/kg q12 hours
• Anti-Xa level 4 hrs after dosing =0.8-1.0 U/ml, and repeat qmonth
– Warfarin
• Postpartum
• Adjust dosage to attain INR 2.0-3.0
Treatment regimens
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Prophylactic regimens
– Unfractionated heparin
• 5000 U sc bid; increase to 7500-10000 U bid in latter
half of pregnancy
– LMWH
• Dalteparin 2500 U bid or 5000-7500 U qd
• Enoxaparin 30 mg bid (0.5 mg/kg/q12 h) or 40 mg qd
– For obese patients may check anti-Xa level and target 0.40.6 3-4 hours after morning dose, repeat qtrimester
Adverse reactions to heparin
Hemorrhage
 Osteoporosis with risk of fracture
 Heparin-induced thrombocytopenia, 5%
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– thromboembolism
Treatment for MTHFR mutation
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Heterozygous
– No treatment
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Homozygous
– Folic acid 1 mg/d
– B6 25 mg
– B12 250 mcg
Anticoagulant management at delivery
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Vaginal delivery
– Unfractionated heparin – stop in labor
– LMWH – change to unfractionated heparin at 36-38
weeks
– Warfarin – change to unfractionated heparin at 36-38
weeks
– Resume 6-8 hours after delivery, give warfarin with
heparin until appropriate anticoagulation
– Treat for a minimum of 6 weeks
Anticoagulant management at delivery
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Elective cesarean delivery
– Unfractionated heparin – stop after last evening dose
– LMWH – stop at least 24 hours before surgery
– Warfarin – change to unfractionated heparin at 36-38
weeks
– Resume anticoagulation 6-8 hours after surgery, give
warfarin with heparin until appropriate anticoagulation
– Treat for a minimum of 6 weeks
Conclusions
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Presence of thrombophilia adds to
hypercoagulability of pregnancy
– Postpartum period is highest risk time
Major “vascular” obstetric complications are
increased in thrombophilias
Women with prior hx VTE, strong FHx, or hx
obstetric complications should be screened
Screening for history of adverse
pregnancy outcome
3 or more first trimester losses
 2 or more second trimester losses
 IUFD
 Early and severe preeclampsia
 Severe IUGR
 Abruption
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Conclusions
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Screening should include, possibly in stepwise
fashion…
– Deficiencies for Protein S, C or antithrombin
activity; FVL, PT G20210A; anticardiolipin ab’s,
lupus anticoagulant; platelets
Treatment depends on type of defect, prior history
Routine screening for all pregnant women or those
seeking OCP’s is not recommended at this time