1. Venous thromboembolic disease
John C. Stevenson
Editor: Martin Birkhäuser

2. Coagulation and fibrinolysis
Endothelial cells
Activated platelets
XII
TFPI
tPA
PAI-1 IX
Protein C
Protein S
VIII
VII X TF
Plasminogen V AT
Prothrombin
F1+2
Plasmin
Thrombin
FPA
Fibrinogen
Fibrin
D-dimer

3. Venous thromboembolism
Risk of VTE in postmenopausal women: 1 per 10,000 patient-years
2–3 non-fatal VTE per year for every 10,000 women given HRT
Deaths from VTE: 1 per 1,000,000 patient-years

4. Increased VTE risk Age Obesity Malignancy Immobilization
History/family history
Oral estrogen
Specific SERMs

5. Venous thromboembolism
HRT affects vascular endothelium
Oral HRT affects hepatic production and clearance of hemostatic factors

6. Oral HRT and VTE Observational studies
Case-control studies (n = 7) RR 2.1 (CI 1.4–3.0)
Prospective cohort studies (n = 1) RR (CI 1.2–3.8)
Oger and Scarabin. Drugs Aging 1999;14:55–61

7. Oral HRT and VTE Randomized clinical trials
HERS RR 2.9 (CI 1.5–5.6)
WHI (E alone) RR 1.3 (CI 1.0–1.8)
WHI (E + P) RR 2.1 (CI 1.6–2.7)
E + P (age 70–79 years) RR vs. placebo (age 50–59 years)
E + P (age 50–59 years) RR 0.7 vs. placebo (age 70–79 years)
Hulley et al. J Am Med Assoc 1998;280:605–13
Cushman et al. J Am Med Assoc 2004;292:1573–80
Women’s Health Initiative Steering Committee. J Am Med Assoc 2004;291:1701–12

8. ERT/HRT and thromboembolic risk: absolute risk
A per oral HRT increases moderately the thromboembolic risk, in particular in presence of hereditary or acquired thrombophilia, and during the first year after initiation of ERT/HRT
(Age 50–59: 2 additional cases/year per 10,000 women)
Low-dose transdermal HRT seems not to increase the thromboembolic risk
WHI, Cushman M, et al. J Am Med Assoc 2004;292:1573–80

9. Oral HRT and VTE Duration and dose of HRT
Risk of VTE higher in first year of treatment
Risk of VTE dose-dependent
Effect of HRT less than OC in women with other increased VTE risk
<1 year
Duration
>1 year
High
Dose
Low 2 4 6 8
Odds ratio
Oger and Scarabin. Drugs Aging 1999;14:55–61
Waselenko et al. Semin Thromb Hemost 1998;24(Suppl):33–9

10. HRT route and VTE No HRT Transdermal HRT Oral HRT 2 4 6 8 Odds ratio2 4 6 8
Odds ratio
Scarabin, et al. Lancet 2003;362:428–32

11. Risk of VTE: HRT route of administration and progestogens (ESTHER study)
Route/progestagen OR 95% CI
Oral –11.6
Transdermal –2.1
Micronized progesterone –1.9
Pregnanes –2.3
Norpregnanes –10.0
Canonico M, et al. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2007;115:820–2

12. SERMS and VTE Randomized clinical trials
Tamoxifen (n = 5408) RR (CI 1.02–2.63)
Raloxifene (n = 10,101) RR (CI 1.06–1.85)
Decensi, et al. Circulation 2005;111:650–56
Barrett-Connor, et al. N Engl J Med 2006;355:125–37

13. Thrombophilia Established inherited Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Activated protein C resistance (factor V Leiden)
Homocystinuria
Dysfibrinogenemia
Prothrombin gene mutation
Further
Homocystinuria
Factor VIII elevation
Low tissue factor pathway inhibitor (TFPI)

14. Protein C anticoagulant pathwayPC PS Va T PC
APC
VIIIa T PS Va
VIIIa
APC
Thrombomodulin
APC receptor
VIIIa inactive
Va inactive
Dahlback B. Thromb Res 1995;77:1–43

15. HRT route and ETP-APC resistance
152 hysterectomized, postmenopausal women
Aged 45–65 years
Randomized to placebo, transdermal estradiol 50 μg, oral estradiol 1 mg, oral estradiol 1 mg + gestodene 25 μg for 13 cycles
Normalized ETP-APC sensitivity ratios measured * *
*p < vs. placebo
Post, et al. Arterioscler Thromb Vasc Biol 2003;23:1116–21

16. HRT and prothrombotic mutations
235 postmenopausal women with VTE
22% oral E
26% transdermal E
554 postmenopausal controls
7% oral E
31% transdermal E
4.9% prevalence of factor V Leiden
2.5% prevalence of prothrombin G20210A mutation
Straczek, et al. Circulation 2005;112:3495–500

17. Acquired ETP-APC resistance
Antiphospholipid syndrome
Oral contraception
Pregnancy
Oral estrogen (CEE and E2) replacement

18. Thrombophilia screening
Patients with personal history of VTE
Patients with first- or second-degree relative with VTE

19. VTE management Full anti-coagulation
Low-dose warfarin (1 mg/day) lifelong
Low-dose aspirin lifelong
Avoidance of oral HRT (CEE, E2, tamoxifen, raloxifene)

20. HRT and thromboembolism
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
HRT and thromboembolism
The HRT-related risk for serious venous thromboembolic events increases with age (although minimal until age 60) and is also positively associated with obesity and thrombophilia
By avoiding first-pass hepatic metabolism, transdermal estrogen may avert the risk associated with oral HRT
The impact on the risk of a thromboembolic event may also be affected by progestogen, depending on the type
Climacteric 2007;10:181–96

21. HRT and thromboembolism: Misperceptions
The risk of both venous and arterial thromboembolism is increased during HRT
Stroke risk is substantially increased in women receiving HRT
IMS Global Summit Climacteric 2008;11:267–72

22. HRT and thromboembolism: Evidence
The risk of venous thrombosis is approximately two-fold higher with standard doses of oral HRT, but is a rare event in that the background prevalence is extremely low in a healthy woman under 60 years of age. It is also associated with obesity and with thrombophilia
The risk of venous thrombosis is possibly less with transdermal, compared with oral, estrogen therapy
IMS Global Summit Climacteric 2008;11:267–72