1. 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
Stop the Clot ™

2. Topics Hormonal contraception and blood clots
Pregnancy and blood clots
Thrombophilia and pregnancy complications
Hormone replacement and blood clots
Stop the Clot ™

3. “The tendency to develop clots in veins or arteries.”
Thrombophilia
“The tendency to develop clots in veins or arteries.”
Primary/ Inherited
Factor V Leiden Prothrombin mutation
↓ Protein S
↓ Protein C
↓ Antithrombin Hyperhomocysteinemia
Secondary/ Acquired
Pregnancy
Estrogen use
Immobilization
Trauma
Postoperative state
Advancing age
Antiphospholipid syndrome
Stop the Clot ™

4. Estrogen and the Clotting System
Increases procoagulants (proteins that make the blood clot)
Factor VIII
Platelet
vWF
Von Willebrand Factor
(vWF)
Blood vessel wall
Fibrinogen
Stop the Clot ™

5. 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
Stop the Clot ™

6. Premenopausal Women
Stop the Clot ™

7. 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
Stop the Clot ™

8. 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
Stop the Clot ™

9. 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
Stop the Clot ™

10. 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
Stop the Clot ™

11. 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
Stop the Clot ™

12. Should every woman be tested before using hormonal contraception?
Important Question ??
If all estrogen-containing contraception increases
the risk of blood clots.
Should every woman be tested before
using hormonal contraception?
Stop the Clot ™

13. 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:
Antithrombin deficiency - 1:
Stop the Clot ™

14. Cost vs benefit of Universal Screening
Risk of death from a blood clot – 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
Stop the Clot ™

15. 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
Stop the Clot ™

16. Important Question ?? If you have had a prior blood clot OR
If you have a known thrombophilia
What is safe to use?
Stop the Clot ™

17. 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
Stop the Clot ™

18. 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
Stop the Clot ™

19. 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
Stop the Clot ™

20. Pregnancy
Stop the Clot ™

21. Pulmonary embolism is the leading cause of maternal death
Pregnancy and Venous Blood Clots
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
Stop the Clot ™

22. 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
Stop the Clot ™

23. What Anticoagulant Drugs are safe during Pregnancy?
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
Stop the Clot ™

24. 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
Stop the Clot ™

25. 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
Stop the Clot ™

26. Warfarin Crosses the placenta - Birth defects in 4-5%
Especially 1st 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
Stop the Clot ™

27. 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
Stop the Clot ™

28. Pregnancy in Women on Coumadin
Warfarin crosses the placenta
- Birth defects in 4-5%
- Especially 1st 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
Stop the Clot ™

29. 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
Stop the Clot ™

30. 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
Stop the Clot ™

31. 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
Stop the Clot ™

32. Thrombophilia and Pregnancy
Complications
Increased incidence of:
FV Leiden
Prothrombin mutation
Protein S deficiency
Protein C deficiency
Antithrombin deficiency
Antiphospholipid syndrome
In women with obstetric
complications
(especially when severe) .
Stop the Clot ™

33. 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
Stop the Clot ™

34. 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
Stop the Clot ™

35. Menopause
Stop the Clot ™

36. Menopause Ovaries stop producing estrogen Symptoms Hot flashes
Sleep disturbances
Vaginal dryness
Sexual dysfunction
Urinary problems- incontinence and infections
Depression
Osteoporosis
Stop the Clot ™

37. 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
Stop the Clot ™

38. 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
Stop the Clot ™

39. 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
Stop the Clot ™

40. Vaginal Estrogen For genitourinary symptoms of menopause Incontenance
Urinary infections
Vaginal dryness
Minimal exposure of other organs
Risks unknown
Stop the Clot ™

41. 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
Stop the Clot ™

42. How to manage menopause in women at risk of blood clots?
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
Stop the Clot ™

43. at higher risk of blood clots
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
Stop the Clot ™

44. at higher risk of blood clots
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
Stop the Clot ™

45. Thank you
Stop the Clot ™