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Women’s Issues and Blood Clotting
Colleen T. Morton M.D.
Hematology and Oncology HealthPartners
Regions Hospital and HealthPartners Riverside
Assistant Professor University of Minnesota
No disclosures
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Topics
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Hormonal contraception and blood clots
Pregnancy and blood clots
Thrombophilia and pregnancy
complications
Hormone replacement and blood clots
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Thrombophilia
“The tendency to develop clots in veins or
arteries.”
Primary/ Inherited
Factor V Leiden
Prothrombin mutation
↓ Protein S
↓ Protein C
↓ Antithrombin
Hyperhomocysteinemia
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Secondary/ Acquired
Pregnancy
Estrogen use
Immobilization
Trauma
Postoperative state
Advancing age
Antiphospholipid syndrome
Estrogen and the Clotting System
Increases procoagulants (proteins that make the blood clot)
• Factor VIII
Platelet
vWF
• Von Willebrand Factor
(vWF)
• Fibrinogen
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Blood vessel wall
Estrogen and the Clotting System
Decreases anticoagulant (anti-clotting) mechanisms
• Decreases Protein S
• Acquired Protein C deficiency
• Decreases fibrinolytic activity (clot breakdown)
↑ risk of blood clots
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Premenopausal Women
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Hormonal Contraception and Blood Clots
Any contraception with estrogen increases the risk of blood clots
The risk increases further with:
• Increase in dose of estrogen
• Inherited or acquired thrombophilia
• Obesity
• Smoking
• Age
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Estrogen Containing Oral Contraceptives
(OCs)
• Contain estrogen and progestin
• Doses may vary or stay the same through the cycle
• 3 weeks of active drug and 1 week of placebo
Risk of clots
Risk increases 3 – 4 X normal
Newer, 3rd generation, OCs have a higher risk than 2nd generation
- related to the type of progestin
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Estrogen Containing Oral Contraceptives
(OCs)
Interaction with Thrombophilias
Factor V Leiden
• Factor V leiden - risk of clot 3 – 8 fold higher
• OCs – risk of a clot 3 – 4 fold higher
Factor V Leiden PLUS OCs – risk of a clot 30 fold higher
Prothrombin mutation plus OCs – 7.4 – 60 fold higher
Antithrombin deficiency plus OCs – 100 fold higher
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Transdermal Patch
• Contains estrogen and progestin
• Patch placed on arm, buttock or torso
• Change patch once a week x 3 weeks and 1 week patch free
Risk of clots
These were initially thought to be safer
Newer studies show a 2 fold higher risk compared to OCs
Increased exposure to estrogen
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Contraceptive Vaginal Ring
• Contains estrogen and progestin
• Worn intravaginally for 3 of 4 weeks
• Exposure to estrogen is ½ of that of OCs
Risk of clots
Less activation of the clotting system in trials
Not yet known if this is safer
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Important Question
??
If all estrogen-containing contraception increases
the risk of blood clots.
Should every woman be tested before
using hormonal contraception?
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Should every woman be tested before
using hormonal contraception?
Cost vs benefit of universal screening
Screening the general population:
Factor V Leiden - 1:20
Prothrombin mutation - 1:50
Protein C and S deficiency - 1:300-500
Antithrombin deficiency - 1:500-1000
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Cost vs benefit of Universal Screening
Risk of death from a blood clot - 0.4 – 1%
14-30 deaths per million patients with blood clots
Factor V Leiden
It would cost 2 million dollars to prevent 1 death from
OC/ FV Leiden associated clot
It would cost much more to screen for the more rare thrombophilias
Not cost effective to screen for inherited thrombophilia
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Should every Woman be Tested before
Using Hormonal Contraception?
Who to test?
• Personal history of a clot
• Family history of clots or thrombophilia
• History of poor pregnancy outcomes
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Important Question
??
If you have had a prior blood clot
OR
If you have a known thrombophilia
What is safe to use?
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What can “at risk” Women use?
Progestin – only pill (minipill)
• Taken daily without a pill-free interval
• Higher risk of failure if there is a delay in taking the pill
• More “breakthrough” bleeding
Does not appear to increase the risk of clots
Recommended by many hematologists
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What can “at risk” Women use?
Injectable progestin
• Injection every 3 months
• Reduces bleeding
• Package insert contains a warning for risk of clotting
May not be safe
If on coumadin - reduces bleeding
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What can “at risk” Women use?
Intra Uterine Device ( IUD)
Copper containing IUDs
• Interfere with sperm transport and fertilization
• Effective for 10 years
No thrombosis risk
Progestin – releasing IUD
• Interfere with sperm transport and fertilization
• Partially inhibit ovulation
• Decrease menstrual bleeding
• Effective for 5 years
Probably safe
Great if on coumadin – reduces bleeding
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Pregnancy
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Pregnancy and Venous Blood Clots
6 - 10 fold ↑ risk of clots during pregnancy and
especially in the
6 – 8 weeks postpartum (1/1500 pregnancies)
Pulmonary embolism is the leading
cause of maternal death
in the developed world
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Pregnancy and Venous Blood Clots
Risk is further increased by:
• Cesarean delivery
• Personal history of clots
• Family history of clots
• Inherited or acquired thrombophilia
• Obesity
• Older age
• Higher parity
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Important Question
??
If you are pregnant and need to be on anticoagulant drugs
What Anticoagulant Drugs are safe during Pregnancy?
• Unfractionated heparin
• Low molecular weight heparin ( lovenox)
• Warfarin
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Unfractionated heparin and
Low molecular weigh heparin (LMWH)
Risk to the fetus
• Neither cross the placenta
- no risk of fetal hemorrhage
• No risk of birth defects
• Neither are secreted in breast
milk
- can be used during lactation
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Unfractionated heparin and
Low molecular weigh heparin (LMWH)
Risk to the mother
• Low incidence of complications - 2% incidence of major bleeding
• Osteoporosis - risk lower with LMWH.
• With LMWH – drug lasts longer, need to plan for the delivery
LMWH = drug of choice
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Warfarin
Crosses the placenta
- Birth defects in 4-5%
- Especially 1st 6-12 weeks of pregnancy
- Brain abnormalities can occur in any trimester
- Avoid after 36 weeks - due to excessive bleeding risks for both
mother and fetus in the peripartum period
Breast Feeding
- not present in clinically significant amounts in breast milk
- safe to use during lactation
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Management of Women at higher risk of
Blood Clots During pregnancy
Women with a history of blood clots
Women with thrombophilia
Must be seen by a hematologist to evaluate the risk
• May need prophylactic (low-dose) heparin or LMWH during pregnancy
- All with a prior estrogen-related clot will need treatment
- Decide on an individual basis
• All should have anticoagulation for 6 weeks postpartum
- LMWH (prophylactic doses)
OR
- coumadin
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Pregnancy in Women on Coumadin
Warfarin crosses the placenta
- Birth defects in 4-5%
- Especially 1st 6-12 weeks – so not want exposure during this time
Choices are:
• Change to LMWH when trying to get pregnant
BUT – this may take a while
• Change to LMWH as soon as pregnant - Recommended
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Thrombophilia and Pregnancy
Complications
The placenta is a vascular organ after 10 weeks of pregnancy.
The thrombophilias can cause clots in the placenta
Placental vascular complications
• Fetal loss (miscarriage)
• Preeclampsia
• Intra uterine growth retardation
• Placental abruption
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Thrombophilia and Pregnancy
Complications
Fetal Loss
15% of pregnancies fail
Recurrent pregnancy loss (3 consecutive miscarriages) - affects
1-2% of women.
Etiologies include:
• Chromosomal abnormalities
• Uterine abnormalities.
• Hormonal abnormalities
• Autoimmune disorders
• Thrombophilia – inherited and the antiphospholipid syndrome
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Thrombophilia and Pregnancy
Complications
Preeclampsia
• Pregnancy induced or aggravated hypertension,
• Excess protein in the urine
• Leg edema (swelling)
Needs immediate delivery of the baby
Intrauterine growth retardation (IUGR)
A fetus small for gestational age ( < 10th percentile)
Placental Abruption
Premature separation of the placenta prior to delivery
Life-threatening for mother and child
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Thrombophilia and Pregnancy
Complications
Increased incidence of:
• FV Leiden
• Prothrombin mutation
• Protein S deficiency
• Protein C deficiency
• Antithrombin deficiency
• Antiphospholipid syndrome
.
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In women with obstetric
complications
(especially when severe)
Who should be tested for thrombophilia?
Test if:
• 3 or more pregnancy losses < 10 weeks
• Pregnancy loss >10 weeks
• Severe or recurrent IUGR, pre-eclampsia and placental abruption
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Management of Thrombophilia and
Pregnancy Complications
• Low dose LMWH daily throughout pregnancy
• Add in aspirin 81 mg daily for those with antiphospholipid syndrome
• All with a thrombophilia should have post partum anticoagulation
Best data in fetal loss and antiphospholipid syndrome
Rest of the data is less reliable
NEED CLINICAL TRIALS
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Menopause
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Menopause
Ovaries stop producing estrogen
Symptoms
• Hot flashes
• Sleep disturbances
• Vaginal dryness
• Sexual dysfunction
• Urinary problems- incontinence and infections
• Depression
• Osteoporosis
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Hormone Replacement (HRT)
and Blood Clots
• Most HRT contain estrogen and progestin
• Estrogen alone - if have had a hysterectomy
Risks:
• Breast cancer
• Coronary artery disease
• Stroke
• Venous blood clots
Use for as little time as possible
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Oral Hormone Replacement (HRT)
Most estrogen in these drugs is from pregnant mare’s urine
Plant-derived estrogen has the same risks
Risk of venous blood clots is increased 2 fold
Risk increased further with:
• Higher doses of estrogen
• Obesity
• Age > 60 yrs
• In the 1st 6 – 12 months of therapy
• Thrombophilia
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Transdermal Patch
Combination estrogen and progestin patches
Estrogen only patches – post hysterectomy
Risk of venous blood clots
• Lower risk of clots than oral HRT
• Less activation of the clotting system
Unclear if safe in women at risk for clots
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Vaginal Estrogen
For genitourinary symptoms of menopause
• Incontenance
• Urinary infections
• Vaginal dryness
Minimal exposure of other organs
Risks unknown
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Bio-identical Hormone Therapy
Chemically made and identical to natural hormones
Each women gets an individualized dose of hormones
• Hormone levels tested in blood and saliva
• Prescriber selects the type and dose of hormones
No evidence that they are better or safer than regular HRT
FDA – action against compounding pharmacies
No credible scientific evidence
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Important Question
??
How to manage menopause in women
at risk of blood clots?
Manage the symptoms
• Vitamin E
• Antidepressants
• Blood pressure medications - clonidine
• Other drugs - neurontin
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Conclusions for women
at higher risk of blood clots
Estrogen increases the risk of blood clots
Premenopausal women
• If you have had a clot or have a family history of blood clots
you should be tested for inherited thrombophilia before starting
estrogen-based contraception
• Progestin–only contraception and IUDs are the best
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Conclusions for women
at higher risk of blood clots
Pregnancy
• Lovenox and heparin are safe
• Anticoagulation can prevent blood clots
• Anticoagulation can prevent pregnancy complications
• All at risk should have post partum anticoagulation
Menopause
• Avoid estrogen replacement
• Symptom management
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Thank you
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