Estrogen and Thrombosis• Key principles – Estrogen in any dose causes thrombosis – Drugs that act like or oppose estrogen causes thrombosis – Hypercoagulable states synergize with estrogen effect – Age is a hypercoagulable state – The past predicts the future
Women’s Deaths from VTE vs Age Age Death/Million 15-24 0.3 24-34 3.4 35-44 9.9
Estrogen Containing Contraception• Most common medication in young woman – 12 million users• First associated with DVT in 1961• Despite reduction in estrogen, risk remains
Overall Risk• Overall risk of thrombosis is increase 3 fold with use of oral contraception – 1-3:10,000 to 3-6:10,000• Risk higher with 1st and 3rd generation pills – 1st – huge estrogen doses – 3rd- progestin component
Hypercoagulable States• Dramatic interactions with hypercoagulable states• RR range from 10-99!• Highest in OCP that contain desogestrel or gestodene (3rd generation)• ABSOLUTE risk is still 28-50/10,000
FVL and OCPFVL OCP RR CI - - 1 - + 3.7 2-6 + - 6.9 2-28 + + 34.7 7-224Lancet. 1995 Dec 16;346(8990):1593-6
Should Woman be Screened for Hypercoagulable States?• No utility in screening!• Will deny contraception to > 60 women to prevent one DVT
OCP Recommendations: Hypercoagulable State• No general screening• + Hypercoagulable state but NO thrombosis – Controversial – If strong need for OCP - ok – If strong family history - no
OCP Recommendations: History of Thrombosis• If not anticoagulated - no estrogen containing OCP – Progesterone ok – LNG IUS ok• If anticoagulated estrogen containing OCP ok – Unclear if any increase thrombotic risk – Unplanned pregnancy while anticoagulated difficult
Rings and Patches• Patches have same to higher risk as pills• Rings unknown but probably similar to patches/pills• Same precautions apply as OCP
HRT• Overall risk with combined therapy is RR of 2• However baseline risk is 1:1000 – Absolute risk is 1:500• Estrogen only replacement RR is 1.33
Hypercoagulable States• Marked synergy with HRT and hypercoagulable states• RR 6.7-17• Absolute risk is higher due to age effect
Estrogen Related Thrombosis and Risk of Future Thrombosis• Data from Prevent trial – With non-hormone-related thrombosis • Recurrence rate 15.0% – With hormone-related thrombosis • Recurrence rate 5.0% – With hormone-related thrombosis • 58% lower risk than men (HR 0.42) – With hormone-related thrombosis • 46% lower recurrence risk than other women (HR 0.54)
Estrogen Related Thrombosisand Risk of Future Thrombosis• Women who have a DVT due to “estrogen” have very low rates of recurrence• Not influenced by most genetic hypercoagulable states
Estrogen like Drugs• All drugs that interfere with estrogen appear to be prothrombotic• Tamoxifen raised DVT rates 3 fold• Raloxifene doubles risk• Aromatase inhibitors also slightly increase risk
Assisted Reproduction• Increasing reports of DVT with ART – Mainly upper extremity – Appears to be associated with hyperstimulation syndrome• Should treat for at least 6 weeks – Longer if pregnancy successful• Unclear prophylaxis is useful in at risk women
Pregnancy• Multiple factors lead to hypercoagulable state – Estrogens – Venous stasis due to anatomical changes – Bed rest
Pregnancy• Multiple issues – Risk of DVT – Use of anticoagulants – Hypercoagulable states and adverse pregnancy outcomes
Modifiers of Risk: Age• Overall risk is 1:1000 – 50% post-partum• Risk rises with age• Major concern as women are having children at older age
Rates of VTE by Age (DVT/1000 Pregnancies) 3 2.752.5 2.13 2 1.67 1.731.5 1.58 1.47 10.5 0 <20 20-24 25-29 30-34 35-39 >40
Age and Death from VTEAge Death/Million No-OCP OCP Pregnancy15-24 0.3 6.0 5.024-34 3.4 7.9 7.735-44 9.9 13.4 19.2
Risk Modifiers: History of DVT• Women with history if DVT at higher risk of recurrence – Risk is 2-8%• Higher if idiopathic DVT
Risk Modifiers: Bed rest• > 3 days of bed rest increase rate from 0.8/1000 to 15.6/1000• Venous stasis vs hypercoagulable state• Prophylaxis?
Hypercoagulable States• Again a profound influence• RR 57 in meta-analysis• Most women with DVT during pregnancy have hypercoagulable state
Warfarin• Teratogenic – Bone development – Increased incidence of CNS defects? – Highest risk 9-12 weeks – Greatest with dose > 5 mg/day
Standard Heparin in Pregnancy• aPTT unreliable in pregnancy• Must use “heparin levels” (anti-Xa) even with prophylaxis – PK of UFH changed in pregnancy• Leads to osteoporosis in 36% of women – Not dose dependent!• Inconvenient dosing
Low Molecular Weight Heparin• Safe and effective in pregnancy – Abundant use• Does not cross placenta• Predicable dosing• Lesser risk of osteoporosis
LMWH in Pregnancy• Prophylaxis – Enoxaparin 40mg/day – Dalteparin 7500q day or 5000 q12 – No need to check levels• Therapy – Usual dose • Enoxaparin 1mg/kg q12hours – Check levels qmonth • 4 hours after dose • 0.7-1.1 anti-Xa units
Duration of Therapy• 3 months or 6 weeks after delivery for first thrombosis• 2 DVTs: life long• “Strong” hypercoagulable state: lifelong – True APLA, MPS, PNH, cancer• “Weak” hypercoagulable state: does not effect duration• Note: warfarin is NOT a contraindication to breast feeding
History of DVT• Women with history of DVT needs prophylaxis• LMWH--->warfarin/LMWH for 6 weeks – Provoked DVT just post-partum• Hypercoagulable state but no DVT history – Controversial! – 1-10% rate with factor V Leiden – Post-partum prophylaxis
Hypercoagulable States• Controversial if all women with thrombosis during pregnancy need evaluation – Establish duration of therapy – Establish type of therapy – Family studies and interventions• Etiologies may be found in up to 60% of women
What to Evaluate• Antithrombin III• Protein C• Protein S• Factor V Leiden• Prothrombin gene mutation• Antiphospholipid antibodies – Lupus inhibitor – Anticardiolipin antibodies• MTHFR – NO!
When to Evaluate• During pregnancy – Antiphospholipid assays – Antithrombin levels – Factor V Leiden – Prothrombin gene defect• 3 month post-partum – Protein C – Protein S • Note: Protein S can drop to very low levels during pregnancy
Patient on Warfarin Planning Pregnancy• Frequent pregnancy checks• Change to LMWH when test is positive• Alternative is to change to LMWH
Are Pregnancy Complications Thrombotic?• Placental ischemia results in: – Decreased fetal growth – Fetal death – Pregnancy induced hypertension
Frequent Miscarriages• Placenta becomes blood supply to fetus 8-9 weeks• Early losses due to many factors• Strong association with hypercoagulable states if miscarriage after 10 weeks.
Overall Risk• Miscarriages 16:100 – 2-3 trimester 1-2:100• Preeclampsia 2-4:1000• How dose hypercoagulable states influence this risk?
Risk of Pregnancy Loss with Thrombophilia Disorder OR for Preg Loss Factor V Leiden 2-5 Prothrombin Gene 2-9 Mutation Protein C Deficiency 2-3 Protein S Deficiency 2-40 Combined 5-14Am J Obstet Gynecol. 2004 Aug;191(2):412-24.
Who Should Be Evaluated?• No use in screening• + Family history• + Thrombosis• Pregnancy complications (HELLP,PIH,....)• 1 or more fetal death after 10 weeks• 1 or more premature birth due to PIH or FUGR• 3 or more miscarriages before week 10
LMWH Prophylaxis• Antiphospholipid syndrome – Yes• Unselected women with 2 or more losses – 2 RCT say No• Definite Thrombophilia - ?• Multiple last losses - ?
Recommendations: Therapy• Consider prophylaxis with one or more unexplained loss and hypercoagulable state• Difficulty is in woman with no identifiable hypercoagulable state – Consider therapy if multiple early losses, late losses, or evidence of placental thrombosis
Summary• Risk of thrombosis with estrogen is dependent on – Age – Thrombophilia – History of thrombosis