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Venous thromboembolic disease

Explore the risks and factors related to venous thromboembolism in postmenopausal women, including the impact of HRT, oral estrogen, and specific SERMs.

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Venous thromboembolic disease

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

  2. Coagulation and fibrinolysis Endothelial cells Activated platelets XII TFPI tPA PAI-1 IX VIII Protein C Protein S VII X TF Plasminogen V AT Prothrombin F1+2 Thrombin Plasmin 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 VTEObservational studies • Case-control studies (n = 7) RR 2.1 (CI 1.4–3.0) • Prospective cohort studies (n = 1) RR 2.1 (CI 1.2–3.8) Oger and Scarabin. Drugs Aging 1999;14:55–61

  7. Oral HRT and VTERandomized 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 7.5 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 VTEDuration 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 0 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 0 2 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 4.2 1.5–11.6 Transdermal 0.9 0.4–2.1 Micronized progesterone 0.7 0.3–1.9 Pregnanes 0.9 0.4–2.3 Norpregnanes 3.9 1.5–10.0 Canonico M, et al. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2007;115:820–2

  12. SERMS and VTERandomized clinical trials • Tamoxifen (n = 5408) RR 1.63 (CI 1.02–2.63) • Raloxifene (n = 10,101) RR 1.44 (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 pathway PC PS Va T PC APC VIIIa T PS Va VIIIa APC APC receptor Thrombomodulin 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 < 0.001 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: 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 2008. Climacteric 2008;11:267–72

  21. 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 2008. Climacteric 2008;11:267–72

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