Archives of Gynecology and Obstetrics

, Volume 285, Issue 4, pp 1035–1041 | Cite as

Hormone replacement therapy leads to increased plasma levels of platelet derived microparticles in postmenopausal women

  • Andreas Rank
  • Rienk Nieuwland
  • Katharina Nikolajek
  • Sabine Rösner
  • Lisa-Maria Wallwiener
  • Erhard Hiller
  • Bettina Toth
General Gynecology

Abstract

Background

Whereas prevention of cardiovascular diseases by hormonal replacement therapy is still part of an ongoing debate, well-defined data are available relating hormonal replacement therapy to an elevated risk of venous thrombosis and embolism. Although it seems that venous thrombosis in patients treated with hormonal replacement therapy is linked to changes in plasmatic coagulation, less is known about the role of platelet-derived microparticles, as well as endothelial cell-derived microparticles.

Patients and methods

In this prospective case–control study, levels of microparticles were investigated in postmenopausal women receiving hormone replacement therapy (n = 15) and compared to age-matched controls (n = 15).

Results

Total count of microparticles and the subgroup of microparticles derived from endothelial cells did not differ in the investigated groups. In contrast, median levels of microparticles derived from platelet/megacaryocyte were higher in women taking hormonal replacement therapy (5,244 × 106/l) than in controls (2,803 × 106/l; p = 0.040). Furthermore, hormonal replacement therapy led to a higher plasma level of microparticles derived from activated platelets, exposing P-selectin (136 × 106/l vs. 58 × 106/l; p = 0.011), or exposing CD63 (171 × 106 vs. 91 × 106/l; p = 0.011) compared to the control group.

Conclusion

Higher concentrations of microparticles derived from (activated) platelets/megacaryocytes were present in postmenopausal women taking hormonal replacement therapy. This finding indicates a procoagulant state in these women and might play a role in the development of venous side effects. In contrast, levels of endothelial cell-derived microparticles did not differ.

Keywords

Hormone replacement therapy Microparticle Venous thrombosis 

References

  1. 1.
    Hickey M, Davis SR, Sturdee DW (2005) Treatment of menopausal symptoms: what shall we do now? Lancet 366:409–421PubMedCrossRefGoogle Scholar
  2. 2.
    Bagger YZ, Tanko LB, Alexandersen P, Hansen HB, Mollgaard A, Ravn P, Qvist P, Kanis JA, Christiansen C (2004) Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 34:728–735PubMedCrossRefGoogle Scholar
  3. 3.
    (1997) Collaborative Group on Hormonal Factors in Breast Cancer: breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047–1059Google Scholar
  4. 4.
    Bath P, Gray LJ (2005) Association between hormone replacement therapy and subsequent stroke: a meta analysis. BMJ 330:342PubMedCrossRefGoogle Scholar
  5. 5.
    Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY (2008) Hormone replacement therapy and risk for venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 336(7655):1227–1231PubMedCrossRefGoogle Scholar
  6. 6.
    Sandset PM, Høibraaten E, Eilertsen AL, Dahm A (2009) Mechanisms of thrombosis related to hormone therapy. Thromb Res 123(Suppl 2):S70–S73PubMedCrossRefGoogle Scholar
  7. 7.
    Scarabin PY, Oger E, Plu-Bureau G, Estrogen and Thromboembolism Risk Study Group (2003) Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362(9382):428–432PubMedCrossRefGoogle Scholar
  8. 8.
    Høibraaten E, Mowinckel MC, de Ronde H, Bertina RM, Sandset PM (2001) Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 115(2):415–420PubMedCrossRefGoogle Scholar
  9. 9.
    Rosano GM, Vitale C, Fini M (2006) Hormone replacement therapy and cardioprotection: what is good and what is bad for the cardiovascular system? Ann N Y Acad Sci 1092:341–348PubMedCrossRefGoogle Scholar
  10. 10.
    Arnal JF, Douin-Echinard V, Tremollières F (2007) Understanding the controversy about hormonal replacement therapy: insights from estrogen effects on experimental and clinical atherosclerosis. Arch Mal Coeur Vaiss 100:554–562PubMedGoogle Scholar
  11. 11.
    Stevenson J (2009) HRT and cardiovascular disease. Best Pract Res Clin Obstet Gynaecol 23(1):109–120PubMedCrossRefGoogle Scholar
  12. 12.
    Gokkusu C, Tata G, Ademoğlu E, Tamer S (2010) The benefits of hormone replacement therapy on plasma and platelet antioxidant status and fatty acid composition in healthy postmenopausal women. Platelets 21(6):439–444PubMedCrossRefGoogle Scholar
  13. 13.
    Signorelli SS, Sciacchitano S, Di Pino L, Costa MP, Pennisi G, Caschetto S (2001) Effects of long-term hormone replacement therapy on arterial wall thickness, lipids and lipoproteins, fibrinogen and antithrombin III. Gynecol Endocrinol 15(5):367–372PubMedGoogle Scholar
  14. 14.
    Schindler TH, Campisi R, Dorsey D (2009) Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors. Eur Heart J 30(8):978–986PubMedCrossRefGoogle Scholar
  15. 15.
    Iwamoto S, Kawasaki T, Kambayashi J, Ariyoshi H, Shinoki N, Sakon M, Ikeda Y, Monden M (1997) The release mechanism of platelet-activating factor during shear-stress induced platelet aggregation. Biochem Biophys Res Commun 239(1):101–105PubMedCrossRefGoogle Scholar
  16. 16.
    Cramer EM, Norol F, Guichard J, Breton-Gorius J, Vainchenker W, Massé JM, Debili N (1997) Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 89:2336–2346PubMedGoogle Scholar
  17. 17.
    Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, Maquelin KN, Roozendaal KJ, Jansen PG, ten Have K, Eijsman L, Hack CE, Sturk A (1997) Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 96:3534–3541PubMedGoogle Scholar
  18. 18.
    Sims PJ, Faioni EM, Wiedmer T, Shattil SJ (1988) Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 263:18205–18212PubMedGoogle Scholar
  19. 19.
    Biró E, Sturk-Maquelin KN, Vogel GM, Meuleman DG, Smit MJ, Hack CE, Sturk A, Nieuwland R (2003) Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 1(12):2561–2568PubMedCrossRefGoogle Scholar
  20. 20.
    Sinauridze EI, Kireev DA, Popenko NY, Pichugin AV, Panteleev MA, Krymskaya OV, Ataullakhanov FI (2007) Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 97(3):425–434PubMedGoogle Scholar
  21. 21.
    Gemmell CH, Sefton MV, Yeo EL (1993) Platelet-derived microparticle formation involves glycoprotein IIb–IIIa. Inhibition by RGDS and a Glanzmann’s thrombasthenia defect. J Biol Chem atherothrombotic disease. J Biol Chem 268(20):14586–14589PubMedGoogle Scholar
  22. 22.
    Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ (1988) Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 264(29):17049–17057Google Scholar
  23. 23.
    Kuriyama N, Nagakane Y, Hosomi A, Ohara T, Kasai T, Harada S, Takeda K, Yamada K, Ozasa K, Tokuda T, Watanabe Y, Mizuno T, Nakagawa M (2010) Evaluation of factors associated with elevated levels of platelet-derived microparticles in the acute phase of cerebral infarction. Clin Appl Thromb Hemost 16(1):26–32PubMedCrossRefGoogle Scholar
  24. 24.
    Li X, Cong H (2009) Platelet-derived microparticles and the potential of glycoprotein IIb/IIIa antagonists in treating acute coronary syndrome. Tex Heart Inst J 36(2):134–139PubMedGoogle Scholar
  25. 25.
    Joop K, Berckmans RJ, Nieuwland R, Berkhout J, Romijn FP, Hack CE, Sturk A (2001) Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost 85(5):810–820PubMedGoogle Scholar
  26. 26.
    Kelton JG (2002) Heparin-induced thrombocytopenia: an overview. Blood Rev 16(1):77–80PubMedCrossRefGoogle Scholar
  27. 27.
    Myers DD, Hawley AE, Farris DM, Wrobleski SK, Thanaporn P, Schaub RG, Wagner DD, Kumar A, Wakefield TW (2003) P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 38(5):1075–1089PubMedCrossRefGoogle Scholar
  28. 28.
    Jimenez JJ, Jy W, Mauro LM, Soderland C, Horstman LL, Ahn YS (2003) Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res 109(4):175–180PubMedCrossRefGoogle Scholar
  29. 29.
    Abid Hussein MN, Meesters EW, Osmanovic N, Romijn FP, Nieuwland R, Sturk A (2003) Antigenic characterization of endothelial cell-derived microparticles and their detection ex vivo. J Thromb Haemost 1(11):2434–2443PubMedCrossRefGoogle Scholar
  30. 30.
    Berckmans RJ, Nieuwland R, Böing AN, Romijn FP, Hack CE, Sturk A (2001) Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 83:639–646Google Scholar
  31. 31.
    Bal L, Ederhy S, Di Angelantonio E, Toti F, Zobairi F, Dufaitre G, Meuleman C, Mallat Z, Boccara F, Tedgui A, Freyssinet JM, Cohen A (2010) Factors influencing the level of circulating procoagulant microparticles in acute pulmonary embolism. Arch Cardiovasc Dis 103(6–7):394–403PubMedCrossRefGoogle Scholar
  32. 32.
    Rectenwald JE, Myers DD Jr, Hawley AE, Longo C, Henke PK, Guire KE, Schmaier AH, Wakefield TW (2005) D-dimer, P-selectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 94(6):1312–1317PubMedGoogle Scholar
  33. 33.
    Ramacciotti E, Hawley AE, Farris DM, Ballard NE, Wrobleski SK, Myers DD Jr, Henke PK, Wakefield TW (2009) Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 101(4):748–754PubMedGoogle Scholar
  34. 34.
    Rank A, Nieuwland R, Crispin A, Gr Tzner S, Iberer M, Toth B, Pihusch R (2011) Clearance of platelet microparticles in vivo. Platelets 22(2):111–116PubMedCrossRefGoogle Scholar
  35. 35.
    Warren BA, Vales O (1972) The release of vesicles from platelets following adhesion to vessel walls in vitro. Br J Exp Pathol 53:206–215PubMedGoogle Scholar
  36. 36.
    Miyazaki Y, Nomura S, Miyake T, Kagawa H, Kitada C, Taniguchi H, Komiyama Y, Fujimura Y, Ikeda Y, Fukuhara S (1996) High shear stress can initiate both platelet aggregation and shedding of procoagulant containing microparticles. Blood 88:3456–3464PubMedGoogle Scholar
  37. 37.
    Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3799PubMedGoogle Scholar
  38. 38.
    van der Zee PM, Biró E, Ko Y, de Winter RJ, Hack CE, Sturk A, Nieuwland R (2006) P-selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction. Clin Chem 52(4):657–664PubMedCrossRefGoogle Scholar
  39. 39.
    Tan KT, Tayebjee MH, Lynd C, Blann AD, Lip GY (2005) Platelet microparticles and soluble P selectin in peripheral artery disease: relationship to extent of disease and platelet activation markers. Ann Med 37(1):61–66PubMedCrossRefGoogle Scholar
  40. 40.
    Travlos GS (2006) Normal structure, function, and histology of the bone marrow. Toxicol Pathol 34:548–565PubMedCrossRefGoogle Scholar
  41. 41.
    Flaumenhaft R, Dilks JR, Richardson J, Alden E, Patel-Hett SR, Battinelli E, Klement GL, Sola-Visner M, Italiano JE Jr (2009) Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood 113:1112–1121PubMedCrossRefGoogle Scholar
  42. 42.
    Rank A, Nieuwland R, Delker R, Köhler A, Toth B, Pihusch V, Wilkowski R, Pihusch R (2010) Cellular origin of platelet-derived microparticles in vivo. Thromb Res 126(4):255–259CrossRefGoogle Scholar
  43. 43.
    Tarantino MD, Kunicki TJ, Nugent DJ (1994) The estrogen receptor is present in human megakaryocytes. Ann N Y Acad Sci 714:293–296PubMedCrossRefGoogle Scholar
  44. 44.
    Nagata Y, Yoshikawa J, Hashimoto A, Yamamoto M, Payne AH, Todokoro K (2003) Proplatelet formation of megakaryocytes is triggered by autocrine-synthesized estradiol. Genes Dev 17(23):2864–2869PubMedCrossRefGoogle Scholar
  45. 45.
    Stevens RF, Alexander MK (1977) A sex difference in the platelet count. Br J Haematol 37(2):295–300PubMedCrossRefGoogle Scholar
  46. 46.
    Toth B, Nikolajek K, Rank A, Nieuwland R, Lohse P, Pihusch V, Friese K, Thaler CJ (2007) Gender-specific and menstrual cycle dependent differences in circulating microparticles. Platelets 18(7):515–521PubMedCrossRefGoogle Scholar
  47. 47.
    Corada M, Liao F, Lindgren M, Lampugnani MG, Breviario F, Frank R, Muller WA, Hicklin DJ, Bohlen P, Dejana E (2001) Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood 97(6):1679–1684PubMedCrossRefGoogle Scholar
  48. 48.
    Simak J, Holada K, Risitano AM, Zivny JH, Young NS, Vostal JG (2004) Elevated circulating endothelial membrane microparticles in paroxysmal nocturnal haemoglobinuria. Brit J Haematol 125(6):804–813CrossRefGoogle Scholar
  49. 49.
    Koga H, Sugiyama S, Kugiyama K, Watanabe K, Fukushima H, Tanaka T, Sakamoto T, Yoshimura M, Jinnouchi H, Ogawa H (2005) Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 45:1622–1630PubMedCrossRefGoogle Scholar
  50. 50.
    Wakefield TW, Henke PK (2005) The role of inflammation in early and late venous thrombosis: are there clinical implications? Semin Vasc Surg 18(3):118–129PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Andreas Rank
    • 1
  • Rienk Nieuwland
    • 2
  • Katharina Nikolajek
    • 3
  • Sabine Rösner
    • 4
  • Lisa-Maria Wallwiener
    • 4
  • Erhard Hiller
    • 5
  • Bettina Toth
    • 4
  1. 1.2. Medizinische Klinik, Klinikum AugsburgAugsburgGermany
  2. 2.Department of Clinical ChemistryAcademic Medical CenterAmsterdamThe Netherlands
  3. 3.Department of Radiotherapy and RadiooncologyKlinikum der Ludwig Maximilians-Universität MünchenMunichGermany
  4. 4.Department of Gynecological Endocrinology and Fertility DisordersRuprecht-Karls UniversityHeidelbergGermany
  5. 5.Medizinische Klinik IIIKlinikum der Ludwig Maximilians-Universität MünchenMunichGermany

Personalised recommendations