The Woman at Risk for Blood Clots: Guidelines for Screening & Management

Tom DeLoughery, MD FACP FAWM

Oregon Health and Sciences University

DISCLOSURE

Relevant Financial Relationship(s)

Speaker Bureau - None

Consultant – Amgen

Grants - Alexion

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

Overall Risk

Lewis MA Human Reproduction 1999

Overall Risk 2nd vs 3rd

Kemmeren, et al BMJ 2001

3rd Generation Pills

• Desogestrel, gestodene, and norgestimate

• Reduced androgenic side effects

• RR over 2nd generation pills 1.7-2.6– 1-2 extra DVT/10,000 users

Drospirenone

• Progestin with antimineralocorticoid and antiandrogen effect

• Risk varies in studies but appears double of 2nd generation pills– FDA ~ 1.5

Progestin Only

• Pills (northethisterone, desogestrel)– No increased risk

• Injectable – 2.2-3.6 increase risk

– Patient selection?

Levonorgestrel IUD

• No increase risk of thrombosis

• Decrease menstruation can be an advantage in women on anticoagulation

Modifiers of Risk• Timing: increased in first three

months of use– RR as high as 12 reported

• Risk does persist throughout time of use

• With stopping OCP, risk disappears after three months

Age of Patient

• Risk higher in older patients– Additive effect with thrombophilia of

aging

Risk of DVT vs Age

BMJ 2011:343:d6423

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 OCP

FVL OCP RR CI

- - 1

- + 3.7 2-6

+ - 6.9 2-28

+ + 34.7 7-224

Lancet. 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

FVL and HRT

FVL HRT RR CI

- - 1

- + 3.2 2-6

+ - 3.9 1.3-11.2

+ + 15.5 3-76

Br J Haematol. 2002 Mar;116(4):851-4

• 71 vs 60 women with history of DVT randomized to HRT

• HRT: 10% DVT (3 PE, 1 CVT)– 8.5%/year

• Placebo: 2.2%– 1%/year

• Trial terminated early

RCT: HRT and Prior Thrombosis

HRT Patch

• Unlike contraceptive patch, the risk of thrombosis appears to be lower with HRT patch

• Several studies show no activation of coagulation

• Needs to be prospective studied

Recommendations: HRT

• History of DVT: no HRT unless anticoagulated

• + Hypercoagulable state: No– Patch - ???

• On anticoagulation: Yes

Estrogen Related Thrombosis and Risk of Future Thrombosis

• “Estrogen” is most common risk factor for provoked DVT in woman

• Increasing data on risk of future DVT

JAMA. 2005 May 18;293(19):2352-61

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 Thrombosis and 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)

1.471.58 1.67 1.73

2.13

2.75

0

0.5

1

1.5

2

2.5

3

<20 20-24 25-29 30-34 35-39 >40

Age and Death from VTE

Age Death/Million

No-OCP OCP Pregnancy

15-24 0.3 6.0 5.0

24-34 3.4 7.9 7.7

35-44 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

Therapy

• Warfarin: No!

• New drugs: No!

• Heparin

• Low molecular weight heparin

• (Fondaparinux)

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 Mutation

2-9

Protein C Deficiency 2-3

Protein S Deficiency 2-40

Combined 5-14

Am 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