Hostname: page-component-7c8c6479df-r7xzm Total loading time: 0 Render date: 2024-03-28T19:31:14.879Z Has data issue: false hasContentIssue false

Effect of Progesterone and Synthetic Progestins on Whole Blood Clot Formation and Erythrocyte Structure

Published online by Cambridge University Press:  08 May 2017

Get access

Abstract

Combined oral contraceptive (COC) use is a risk factor for venous thrombosis (VT) and related to the specific type of progestin used. VT is accompanied by inflammation and pathophysiological clot formation, that includes aberrant erythrocytes and fibrin(ogen) interactions. In this paper, we aim to determine the influence of progesterone and different synthetic progestins found in COCs on the viscoelasticity of whole blood clots, as well as erythrocyte morphology and membrane ultrastructure, in an in vitro laboratory study. Thromboelastography (TEG), light microscopy, and scanning electron microscopy were our chosen methods. Our results point out that progestins influence the rate of whole blood clot formation. Alterations to erythrocyte morphology and membrane ultrastructure suggest the presence of eryptosis. We also note increased rouleaux formation, erythrocyte aggregation, and spontaneous fibrin formation in whole blood which may explain the increased risk of VT associated with COC use. Although not all COC users will experience a thrombotic event, individuals with a thrombotic predisposition, due to inflammatory or hematological illness, should be closely monitored to prevent pathological thrombosis.

Type
Biological Science Applications
Copyright
© Microscopy Society of America 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Adams, P.C. & Barton, J.C. (2007). Haemochromatosis. Lancet 370(9602), 18551860.CrossRefGoogle ScholarPubMed
Ami, R.B., Barshtein, G., Zeltser, D., Goldberg, Y., Shapira, I., Roth, A., Keren, G., Miller, H., Prochorov, V., Eldor, A., Berliner, S. & Yedgar, S. (2001). Parameters of red blood cell aggregation as correlates of the inflammatory state. Am J Physiol Heart Circ Physiol 280(5), H1982H1988.CrossRefGoogle ScholarPubMed
Andrews, D.A. & Low, P.S. (1999). Role of red blood cells in thrombosis. Curr Opin Hematol 6(2), 76.CrossRefGoogle ScholarPubMed
Barshtein, G., Wajnblum, D. & Yedgar, S. (2000). Kinetics of linear rouleaux formation studied by visual monitoring of red cell dynamic organization. Biophys J 78(5), 24702474.CrossRefGoogle ScholarPubMed
Barsoum, M.K., Heit, J.A., Ashrani, A.A., Leibson, C.L., Petterson, T.M. & Bailey, K.R. (2010). Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 126(5), 373378.CrossRefGoogle ScholarPubMed
Baskurt, O., Neu, B. & Meiselman, H. (2012). Red Blood Cell Aggregation. Boca Raton, FL, USA: CRC Press, Taylor and Francis Group.Google Scholar
Benagiano, G., Gabelnick, H. & Brosens, I. (2015). Long-acting hormonal contraception. Women’s Health 11(6), 749757.Google ScholarPubMed
Blanco-Molina, M., Lozano, M., Cano, A., Cristobal, I., Pallardo, L. & Lete, I. (2012). Progestin-only contraception and venous thromboembolism. Thromb Res 129(5), e257e262.CrossRefGoogle ScholarPubMed
Brust, M., Aouane, O., Thiébaud, M., Flormann, D., Verdier, C., Kaestner, L., Laschke, M., Selmi, H., Benyoussef, A. & Podgorski, T. (2014). The plasma protein fibrinogen stabilizes clusters of red blood cells in microcapillary flows. Sci Rep 4, 4348.CrossRefGoogle ScholarPubMed
Buchan, P.C. & Macdonald, H.N. (1980). Altered haemorheology in oral-contraceptive users. BMJ 280(6219), 978979.CrossRefGoogle ScholarPubMed
Burton, J.L. (1967). Effect of oral contraceptives on erythrocyte sedimentation rate in healthy young women. BMJ 3(5559), 214215.CrossRefGoogle ScholarPubMed
Calderon-Salinas, J.V., Munoz-Reyes, E.G., Guerrero-Romero, J.F., Rodriguez-Moran, M., Bracho-Riquelme, R.L., Carrera-Gracia, M.A. & Quintanar-Escorza, M.A. (2011). Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease. Mol Cell Biochem 357(1–2), 171179.CrossRefGoogle ScholarPubMed
Chen, J.T. & Kotani, K. (2012). Oral contraceptive therapy increases oxidative stress in pre-menopausal women. Int J Prev Med 3(12), 893896.CrossRefGoogle ScholarPubMed
Ciavatti, M., Michel, G., Chataing, B. & Jouvenceaux, A. (1974). Preservation of human erythrocyte membrane proteins during cold storage with addition of progesterone. Biochem Med 9(3), 293300.CrossRefGoogle ScholarPubMed
Daniels, K., Daugherty, J. & Jones, J. (2014). Current contraceptive status among women aged 15–44: United States, 2011–2013. NCHS Data Brief 173, 18.Google Scholar
De Groote, D., Perrier d’Hauterive, S., Pintiaux, A., Balteau, B., Gerday, C., Claesen, J. & Foidart, J.M. (2009). Effects of oral contraception with ethinylestradiol and drospirenone on oxidative stress in women 18-35 years old. Contraception 80(2), 187193.CrossRefGoogle ScholarPubMed
Devenuto, F., Ligon, D.F., Friedrichsen, D.H. & Wilson, H.L. (1969). Human erythrocyte membrane uptake of progesterone and chemical alterations. Biochim Biophys Acta 193(1), 3647.CrossRefGoogle ScholarPubMed
de Villiers, S., Swanepoel, A., Bester, J. & Pretorius, E. (2016). Novel diagnostic and monitoring tools in stroke: An individualized patient-centered precision medicine approach. J Atheroscler Thromb 23(5), 493504.CrossRefGoogle ScholarPubMed
Farre, A.L., Modrego, J. & Zamorano-Leon, J.J. (2014). Effects of hormones on platelet aggregation. Horm Mol Biol Clin Investig 18(1), 2736.CrossRefGoogle ScholarPubMed
Fehily, A.M., Dickerson, J.W., Meade, B.W. & Ellis, F.R. (1982). Plasma and erythrocyte membrane fatty acids in oral contraceptive users. Clin Chim Acta 120(1), 4147.CrossRefGoogle ScholarPubMed
Finch, C.A., Bellotti, V., Stray, S, Lipschitz, D.A., Cook, J.D., Pippard, M.J. & Huebers, H.A. (1986). Plasma ferritin determination as a diagnostic tool. West J Med 145(5), 657663.Google ScholarPubMed
Gorton, H.J., Warren, E.R., Simpson, N.A., Lyons, G.R. & Columb, M.O. (2000). Thromboelastography identifies sex-related differences in coagulation. Anesth Analg 91(5), 12791281.Google ScholarPubMed
Gronich, N., Lavi, I. & Rennert, G. (2011). Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: A population-based cohort study. Can Med Assoc J 183(18), E1319E1325.CrossRefGoogle ScholarPubMed
Gyawali, P., Richards, R.S., Bwititi, P.T. & Nwose, E.U. (2015). Association of abnormal erythrocyte morphology with oxidative stress and inflammation in metabolic syndrome. Blood Cells Mol Dis 54(4), 360363.CrossRefGoogle ScholarPubMed
Jacobstein, R. & Polis, C.B. (2014). Progestin-only contraception: Injectables and implants. Best practice & research. Clin Obstet Gynaecol 28(6), 795806.Google Scholar
Jick, S.S. & Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Case-control study using United States claims data. BMJ 342, d2151.CrossRefGoogle ScholarPubMed
Jones, J., Mosher, W. & Daniels, K. (2012). Current contraceptive use in the United States, 2006–2010, and changes in patterns of use since 1995. Natl Health Stat Report 60, 125.Google Scholar
Jones, R.K. (2011). Beyond Birth Control: The Overlooked Benefits of Oral Contraceptive Pills. New York: Alan Guttmacher Institute.Google Scholar
Kaya, H. & Saito, T. (1985). Effect of progesterone and its 17 alpha-hydroxyl derivative on human erythrocyte membrane. Jpn J Pharmacol 39(3), 299306.CrossRefGoogle ScholarPubMed
Kowalska, K. & Milnerowicz, H. (2016). Pro/antioxidant status in young healthy women using oral contraceptives. Environ Toxicol Pharmacol 43, 16.CrossRefGoogle ScholarPubMed
Krintus, M., Sypniewska, G. & Kuligowska-Prusinska, M. (2010). Effect of second and third generation oral contraceptives on C-reactive protein, lipids and apolipoproteins in young, non-obese, non-smoking apparently healthy women. Clin Biochem 43(6), 626628.CrossRefGoogle ScholarPubMed
Lang, F., Gulbins, E., Lang, P.A., Zappulla, D. & Föller, M. (2010). Ceramide in suicidal death of erythrocytes. Cell Physiol Biochem 26(1), 2128.CrossRefGoogle ScholarPubMed
Lang, F., Gulbins, E., Lerche, H., Huber, S.M., Kempe, D.S. & Föller, M. (2008). Eryptosis, a window to systemic disease. Cell Physiol Biochem 22(5–6), 373380.CrossRefGoogle ScholarPubMed
Liang, S.-Y., Grossman, D. & Phillips, K.A. (2012). User characteristics and out-of-pocket expenditures for progestin-only versus combined oral contraceptives. Contraception 86(6), 666672.CrossRefGoogle ScholarPubMed
Lidegaard, O. (2014). Hormonal contraception, thrombosis and age. Expert Opin Drug Saf 13(10), 13531360.CrossRefGoogle ScholarPubMed
Lidegaard, Ø., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E. & Løkkegaard, E. (2011). Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423.CrossRefGoogle ScholarPubMed
Lim, H.W.G., Wortis, M. & Mukhopadhyay, R. (2002). Stomatocyte-discocyte-echinocyte sequence of the human red blood cell: Evidence for the bilayer-couple hypothesis from membrane mechanics. Proc Natl Acad Sci U S A 99(26), 1676616769.CrossRefGoogle Scholar
Mackman, N. (2012). New insights into the mechanisms of venous thrombosis. J Clin Invest 122(7), 23312336.CrossRefGoogle ScholarPubMed
Manzoli, L., De Vito, C., Marzuillo, C., Boccia, A. & Villari, P. (2012). Oral contraceptives and venous thromboembolism. Drug Saf 35(3), 191205.Google ScholarPubMed
Moro, L., Reineri, S., Piranda, D., Pietrapiana, D., Lova, P., Bertoni, A., Graziani, A., Defilppi, P., Canobbio, I., Torti, M., Sinigaglia, F. (2005). Nongenomic effects of 17B-estradiol in human platelets: Potentiation of thrombin-induced aggregation through estrogen receptor B and Src kinase. Blood 105(1), 115121.CrossRefGoogle Scholar
Nielsen, V.G. (2008). Beyond cell based models of coagulation: Analyses of coagulation with clot “lifespan” resistance-time relationships. Thromb Res 122(2), 145152.CrossRefGoogle ScholarPubMed
Ogunro, P.S., Bolarinde, A.A., Owa, O.O., Salawu, A.A. & Oshodi, A.A. (2014). Antioxidant status and reproductive hormones in women during reproductive, perimenopausal and postmenopausal phase of life. Afr J Med Med Sci 43(1), 4957.Google ScholarPubMed
Paciorek, J. & Spencer, N. (1980). An association between plasma progesterone and erythrocyte carbonic anhydrase I concentration in women. Clin Sci 58(2), 161164.CrossRefGoogle ScholarPubMed
Parkin, L., Sharples, K., Hernandez, R.K. & Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database. BMJ 342, d2139.CrossRefGoogle ScholarPubMed
Petitti, D.B. (2003). Combination estrogen–progestin oral contraceptives. N Eng J Med 349(15), 14431450.CrossRefGoogle ScholarPubMed
Pincemail, J., Vanbelle, S., Gaspard, U., Collette, G., Haleng, J., Cheramy-Bien, J.P., Charlier, C., Chapelle, J.P., Giet, D., Albert, A., Limet, R. & Defraigne, J.O. (2007). Effect of different contraceptive methods on the oxidative stress status in women aged 40–48 years from the ELAN study in the province of Liège, Belgium. Hum Reprod 22(8), 23352343.CrossRefGoogle ScholarPubMed
Powell, L.W., George, D.K., McDonnell, S.M., & Kowdley, K.V. (1998). Diagnosis of hemochromatosis. Ann Intern Med 129(11), 925931.CrossRefGoogle ScholarPubMed
Pretorius, E., Swanepoel, A.C., Buys, A.V., Vermeulen, N., Duim, W. & Kell, D.B. (2014). Eryptosis as a marker of Parkinson’s disease. Aging (Albany, NY) 6(10), 788.CrossRefGoogle ScholarPubMed
Renner, R.-M. & Edelman, A. (2016). Progestin-only oral contraceptives. In The Handbook of Contraception, Shoupe, D. and Mishell, D.R. (Eds), pp. 7986. Cham, Switzerland: Springer International Publishing.Google Scholar
Rickli, E.E., Ghazanfar, S., Gibbons, B.H. & Edsall, J.T. (1964). Carbonic anhydrases from human erythrocytes preparation and properties of two enzymes. J Biol Chem 239(4), 10651078.CrossRefGoogle ScholarPubMed
Rott, H. (2013). Contraception, venous thrombosis and biological plausability. Minerva Med 104(2), 161167.Google ScholarPubMed
Sheetz, M.P. & Singer, S.J. (1974). Biological membranes as bilayer couples. A molecular mechanism of drug-erythrocyte interactions. Proc Natl Acad Sci U S A 71(11), 44574461.CrossRefGoogle ScholarPubMed
Sørensen, C.J., Pedersen, O.B., Petersen, M.S., Sørensen, E., Kotzé, S., Thørner, L.W., Hjalgrim, H., Rigas, A.S., Møller, B., Rostgaard, K., Riiskjær, M., Ullum, H. & Erikstrup, C. (2014). Combined oral contraception and obesity are strong predictors of low-grade inflammation in healthy individuals: Results from the Danish Blood Donor Study (DBDS). PLoS ONE 9(2), e88196.CrossRefGoogle ScholarPubMed
Stegeman, B.H., de Bastos, M., Rosendaal, F.R., van Hylckama Vlieg, A., Helmerhorst, F.M., Stijnen, T. & Dekkers, O.M. (2013). Different combined oral contraceptives and the risk of venous thrombosis: Systematic review and network meta-analysis. BMJ 347, f5298.CrossRefGoogle ScholarPubMed
Stegeman, B.H.B. (2013). Hormonal contraceptives and venous thrombosis. Department of Thrombosis and Hemostasis, Faculty of Medicine, Leiden University Library (LUMC), Leiden University, Leiden, The Netherlands.Google Scholar
Straat, M., van Bruggen, R., de Korte, D. & Juffermans, N.P. (2012). Red blood cell clearance in inflammation. Transfus Med Hemother 39(5), 353361.Google Scholar
Swanepoel, A., Nielsen, V. & Pretorius, E. (2015). Viscoelasticity and ultrastructure in coagulation and inflammation: Two diverse techniques, one conclusion. Inflammation 38(4), 17071726.CrossRefGoogle ScholarPubMed
Swanepoel, A.C., Lindeque, B.G., Swart, P.J., Abdool, Z. & Pretorius, E. (2014). Estrogen causes ultrastructural changes of fibrin networks during the menstrual cycle: A qualitative investigation. Microsc Res Tech 77, 594601.CrossRefGoogle ScholarPubMed
Swanepoel, A.C., Visagie, A., de Lange, Z., Emmerson, O., Nielsen, V.G. & Pretorius, E. (2016a). The clinical relevance of altered fibrinogen packaging in the presence of 17beta-estradiol and progesterone. Thromb Res 146, 2334.CrossRefGoogle Scholar
Swanepoel, A.C., Visagie, A. & Pretorius, E. (2016b). Synthetic hormones and clot formation. Microsc Microanal 22(4), 878886.CrossRefGoogle ScholarPubMed
Tripatara, A., Srichana, N., Lamool, P., Amnuaykan, S., Hongart, P. & Jetsrisuparb, A. (2012). Relationship between Plasma Ferritin Level and Siderocyte Number in Splenectomized beta-Thalassemia/HbE Patients. Anemia 2012, 890471.CrossRefGoogle ScholarPubMed
Tsuda, K., Kinoshita, Y. & Nishio, I. (2002). Synergistic role of progesterone and nitric oxide in the regulation of membrane fluidity of erythrocytes in humans: An electron paramagnetic resonance investigation. Am J Hypertens 15(8), 702708.Google Scholar
Undas, A. & Ariëns, R.A. (2011). Fibrin clot structure and function: A role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 31(12), e88e99.CrossRefGoogle ScholarPubMed
van Hylckama Vlieg, A., Helmerhorst, F., Vandenbroucke, J., Doggen, C. & Rosendaal, F. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339, b2921.CrossRefGoogle ScholarPubMed
van Hylckama Vlieg, A., Helmerhorst, F.M. & Rosendaal, F.R. (2010). The risk of deep venous thrombosis associated with injectable depot–medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol 30(11), 2297.CrossRefGoogle ScholarPubMed
Wakefield, T.W., Myers, D.D. & Henke, P.K. (2008). Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 28(3), 387391.CrossRefGoogle ScholarPubMed
Wolberg, A.S. (2010). Plasma and cellular contributions to fibrin network formation, structure and stability. Haemophilia 16(Suppl 3), 712.CrossRefGoogle ScholarPubMed