1. The Woman at Risk for Blood Clots:
Guidelines for Screening & Management
Tom DeLoughery, MD FACP FAWM
Oregon Health and Sciences University

2. DISCLOSURE
Relevant Financial Relationship(s)
Speaker Bureau - None
Consultant – Amgen
Grants - Alexion

3. 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

4. Women’s Deaths from VTE vs Age
Age Death/Million
15-24 0.3
24-34 3.4
35-44 9.9

5. Estrogen Containing
Contraception
• Most common medication in young
woman
– 12 million users
• First associated with DVT in 1961
• Despite reduction in estrogen, risk
remains

6. 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

7. Overall Risk
Lewis MA Human Reproduction 1999

8. Overall Risk 2nd vs 3rd
Kemmeren, et al BMJ 2001

9. 3 Generation Pills
rd
• Desogestrel, gestodene, and
norgestimate
• Reduced androgenic side effects
• RR over 2nd generation pills 1.7-2.6
– 1-2 extra DVT/10,000 users

10. Drospirenone
• Progestin with antimineralocorticoid
and antiandrogen effect
• Risk varies in studies but appears
double of 2nd generation pills
– FDA ~ 1.5

11. Progestin Only
• Pills (northethisterone, desogestrel)
– No increased risk
• Injectable
– 2.2-3.6 increase risk
– Patient selection?

12. Levonorgestrel IUD
• No increase risk of thrombosis
• Decrease menstruation can be an
advantage in women on
anticoagulation

13. 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

14. Age of Patient
• Risk higher in older patients
– Additive effect with thrombophilia of
aging

15. Risk of DVT vs Age
BMJ 2011:343:d6423

16. 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

17. 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

18. Should Woman be Screened for
Hypercoagulable States?
• No utility in screening!
• Will deny contraception to > 60
women to prevent one DVT

19. OCP Recommendations:
Hypercoagulable State
• No general screening
• + Hypercoagulable state but NO
thrombosis
– Controversial
– If strong need for OCP - ok
– If strong family history - no

20. 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

21. Rings and Patches
• Patches have same to higher risk as
pills
• Rings unknown but probably similar
to patches/pills
• Same precautions apply as OCP

23. 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

24. Hypercoagulable States
• Marked synergy with HRT and
hypercoagulable states
• RR 6.7-17
• Absolute risk is higher due to age
effect

25. 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

26. RCT: HRT and Prior Thrombosis
• 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

27. 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

28. Recommendations: HRT
• History of DVT: no HRT unless
anticoagulated
• + Hypercoagulable state: No
– Patch - ???
• On anticoagulation: Yes

30. 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

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

32. 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)

33. 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

34. 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

35. 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

37. Pregnancy
• Multiple factors lead to
hypercoagulable state
– Estrogens
– Venous stasis due to anatomical
changes
– Bed rest

38. Pregnancy
• Multiple issues
– Risk of DVT
– Use of anticoagulants
– Hypercoagulable states and adverse
pregnancy outcomes

39. 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

40. Rates of VTE by Age
(DVT/1000 Pregnancies)
3
2.75
2.5
2.13
2
1.67 1.73
1.5 1.58
1.47
1
0.5
0
<20 20-24 25-29 30-34 35-39 >40

41. 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

42. Risk Modifiers: History of DVT
• Women with history if DVT at higher
risk of recurrence
– Risk is 2-8%
• Higher if idiopathic DVT

43. 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?

44. Hypercoagulable States
• Again a profound influence
• RR 57 in meta-analysis
• Most women with DVT during
pregnancy have hypercoagulable
state

45. Therapy
• Warfarin: No!
• New drugs: No!
• Heparin
• Low molecular weight heparin
• (Fondaparinux)

46. Warfarin
• Teratogenic
– Bone development
– Increased incidence of CNS defects?
– Highest risk 9-12 weeks
– Greatest with dose > 5 mg/day

47. 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

48. Low Molecular Weight Heparin
• Safe and effective in pregnancy
– Abundant use
• Does not cross placenta
• Predicable dosing
• Lesser risk of osteoporosis

49. 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

50. 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

51. 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

52. 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

53. What to Evaluate
• Antithrombin III
• Protein C
• Protein S
• Factor V Leiden
• Prothrombin gene mutation
• Antiphospholipid antibodies
– Lupus inhibitor
– Anticardiolipin antibodies
• MTHFR – NO!

54. 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

55. Patient on Warfarin Planning
Pregnancy
• Frequent pregnancy checks
• Change to LMWH when test is
positive
• Alternative is to change to LMWH

57. Are Pregnancy Complications
Thrombotic?
• Placental ischemia results in:
– Decreased fetal growth
– Fetal death
– Pregnancy induced hypertension

58. 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.

59. Overall Risk
• Miscarriages 16:100
– 2-3 trimester 1-2:100
• Preeclampsia 2-4:1000
• How dose hypercoagulable states
influence this risk?

60. 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 5-14
Am J Obstet Gynecol. 2004 Aug;191(2):412-24.

61. 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

62. LMWH Prophylaxis
• Antiphospholipid syndrome – Yes
• Unselected women with 2 or more losses
– 2 RCT say No
• Definite Thrombophilia - ?
• Multiple last losses - ?

63. 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

64. Summary
• Risk of thrombosis with estrogen is
dependent on
– Age
– Thrombophilia
– History of thrombosis