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 ™

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

“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 ™

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 ™

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 ™

Premenopausal Women Stop the Clot ™

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 ™

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 ™

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 ™

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 ™

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 ™

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 ™

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 Stop the Clot ™

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 Stop the Clot ™

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 ™

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 ™

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 ™

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 ™

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 ™

Pregnancy Stop the Clot ™

Pulmonary embolism is the leading cause of maternal death 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 Stop the Clot ™

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 ™

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 ™

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 ™

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 ™

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 Stop the Clot ™

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 ™

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 Stop the Clot ™

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 ™

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 ™

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 ™

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 ™

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 ™

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 ™

Menopause Stop the Clot ™

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

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 ™

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 ™

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 ™

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

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 ™

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 ™

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 ™

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 ™

Thank you Stop the Clot ™