Hostname: page-component-76fb5796d-wq484 Total loading time: 0 Render date: 2024-04-25T15:51:41.467Z Has data issue: false hasContentIssue false

Mechanical and Physical Behavior of Fibrin Clot Formation and Lysis in Combined Oral Contraceptive Users

Published online by Cambridge University Press:  11 August 2020

Albe Carina Swanepoel*
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia0007, South Africa Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom2520, South Africa
Janette Bester
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia0007, South Africa
Zelda de Lange-Loots
Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom2520, South Africa
*Author for correspondence: Albe Carina Swanepoel, E-mail:
Get access


Combined oral contraceptives (COCs) are commonly prescribed and increase the risk of venous thromboembolism (VTE). We have previously found that two COCs, both containing drospirenone (DRSP) and ethinyl estradiol (EE), cause spontaneous fibrin formation in whole blood. The aim of this study was, therefore, to use platelet-poor plasma (PPP) from the same cohort of DRSP/EE users to determine the impact of these COCs on the fibrin component, specifically the fibrin clot viscoelasticity, turbidimetry, and biophysical traits. PPP from 25 females per test group and a control group (n = 25) were analyzed using thromboelastography (TEG), turbidimetry, and scanning electron microscopy. The results highlight abnormal fibrin clot formation, lysis, and architecture; DRSP/20EE showed the greatest effect. DRSP/EE use increased the fibrin fiber diameter and showed dense matted clots. Only when the influence of COCs on the structural properties and behavior of fibrin fibers during thrombus formation and lysis is better understood are we able to predict and prevent coagulopathies associated with these synthetic hormones. Clinical practitioners should take this into consideration for female patients that either have comorbidities, which could burden the coagulation system, or may be exposed to external factors that could increase their risk for VTE.

Biological Applications
Copyright © Microscopy Society of America 2020

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.)


Aleman, MM, Walton, BL, Byrnes, JR & Wolberg, AS (2014). Fibrinogen and red blood cells in venous thrombosis. Thromb Res 133(Suppl 1), S38S40.CrossRefGoogle ScholarPubMed
Amatayakul, K, Laokuldilok, T, Koottathep, S, Dejsarai, W, Prapamontol, T, Srirak, N, Tansuhaj, A & Uttaravichai, C (1994). The effect of oral contraceptives on protein metabolism. J Med Assoc Thai 77(10), 509516.Google ScholarPubMed
Barsoum, MK, Heit, JA, Ashrani, AA, Leibson, CL, Petterson, TM & Bailey, KR (2010). Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 126(5), 373378.CrossRefGoogle ScholarPubMed
Bateson, D, Butcher, B, Donovan, C, Farrell, L, Kovacs, G, Mezzini, T, Raynes-Greenow, C, Pecoraro, G, Read, C & Baber, R (2016). Risk of venous thromboembolism in women taking the combined oral contraceptive: A systematic review and meta-analysis. Aust Fam Physician 45, 5964.Google ScholarPubMed
Becatti, M, Marcucci, R, Bruschi, G, Taddei, N, Bani, D, Gori, AM, Giusti, B, Gensini, GF, Abbate, R & Fiorillo, C (2014). Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol 34(7), 13551361.CrossRefGoogle ScholarPubMed
Bird, ST, Delaney, JA, Etminan, M, Brophy, JM & Hartzema, AG (2013). Drospirenone and non-fatal venous thromboembolism: Is there a risk difference by dosage of ethinyl-estradiol? J Thromb Haemost 11(6), 10591068.CrossRefGoogle Scholar
Caserta, D, Ralli, E, Matteucci, E, Bordi, G, Mallozzi, M & Moscarini, M (2014). Combined oral contraceptives: Health benefits beyond contraception. Panminerva Med 56(3), 233244.Google ScholarPubMed
Collet, J, Park, D, Lesty, C, Soria, J, Soria, C, Montalescot, G & Weisel, J (2000). Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 20(5), 13541361.CrossRefGoogle ScholarPubMed
Collet, J-P, Lesty, C, Montalescot, G & Weisel, JW (2003). Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots. J Biol Chem 278(24), 2133121335.CrossRefGoogle ScholarPubMed
Cooper, DB & Mahdy, H (2020). Oral contraceptive pills. In StatPearls. Treasure Island, FL: StatPearls Publishing LLC.Google ScholarPubMed
De Vries, JJ, Snoek, CJM, Rijken, DC & De Maat, MPM (2020). Effects of post-translational modifications of fibrinogen on clot formation, clot structure, and fibrinolysis: A systematic review. Arterioscler Thromb Vasc Biol 40(3), 554569.CrossRefGoogle ScholarPubMed
Dragoman, MV (2014). The combined oral contraceptive pill – Recent developments, risks and benefits. Best Pract Res Clin Obstet Gynaecol 28(6), 825834.CrossRefGoogle ScholarPubMed
Emmerson, O, Bester, J, Lindeque, BG & Swanepoel, AC (2018). The impact of two combined oral contraceptives containing ethinyl estradiol and drospirenone on whole blood clot viscoelasticity and the biophysical and biochemical characteristics of erythrocytes. Microsc Microanal 24(6), 713728.CrossRefGoogle ScholarPubMed
Falvo, MR, Gorkun, OV & Lord, ST (2010). The molecular origins of the mechanical properties of fibrin. Biophys Chem 152(1), 1520.CrossRefGoogle ScholarPubMed
Fuchs, TA, Brill, A & Wagner, DD (2012). Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 32(8), 17771783.CrossRefGoogle ScholarPubMed
Gomes, MP & Deitcher, SR (2004). Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: A clinical review. Arch Intern Med 164(18), 19651976.CrossRefGoogle ScholarPubMed
Gronich, N, Lavi, I & Rennert, G (2011). Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: A population-based cohort study. CMAJ 183(18), E1319E1325.CrossRefGoogle ScholarPubMed
Heit, JA (2008). The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 28(3), 370372.CrossRefGoogle Scholar
Krysiak, R, Gilowska, M & Okopien, B (2017). The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels. Pharmacol Rep 69(1), 4549.CrossRefGoogle ScholarPubMed
Larivee, N, Suissa, S, Khosrow-Khavar, F, Tagalakis, V & Filion, KB (2017). Drospirenone-containing oral contraceptive pills and the risk of venous thromboembolism: A systematic review of observational studies. BJOG 124(10), 14901499.CrossRefGoogle ScholarPubMed
Li, W, Sigley, J, Pieters, M, Helms, CC, Nagaswami, C, Weisel, JW & Guthold, M (2016). Fibrin fiber stiffness is strongly affected by fiber diameter, but not by fibrinogen glycation. Biophys J 110(6), 14001410.CrossRefGoogle Scholar
Lidegaard, O, Lokkegaard, E, Svendsen, AL & Agger, C (2009). Hormonal contraception and risk of venous thromboembolism: National follow-up study. BMJ 339, b2890.CrossRefGoogle ScholarPubMed
Lidegaard, O, Nielsen, LH, Skovlund, CW, Skjeldestad, FE & Lokkegaard, 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
Lisman, T, De Groot, PG, Meijers, JC & Rosendaal, FR (2005). Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 105(3), 11021105.CrossRefGoogle ScholarPubMed
Litvinov, RI & Weisel, JW (2017). Fibrin mechanical properties and their structural origins. Matrix Biol 60–61, 110123.CrossRefGoogle ScholarPubMed
Mathur, R, Levin, O & Azziz, R (2008). Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther Clin Risk Manag 4(2), 487492.CrossRefGoogle ScholarPubMed
Moore, P & Streeton, C (2017). Oral hormonal contraception in special circumstances. Aust Fam Physician 46, 728732.Google ScholarPubMed
Plu-Bureau, G, Maitrot-Mantelet, L, Hugon-Rodin, J & Canonico, M (2013). Hormonal contraceptives and venous thromboembolism: An epidemiological update. Best Pract Res Clin Endocrinol Metab 27(1), 2534.CrossRefGoogle Scholar
Reif, S, Snelder, N & Blode, H (2013). Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: Population pharmacokinetic analysis from a randomised Phase III study. J Fam Plann Reprod Health Care 39(2), e1e13.CrossRefGoogle ScholarPubMed
Rosendaal, FR (2016). Causes of venous thrombosis. Thromb J 14(Suppl 1), 2424.CrossRefGoogle Scholar
Schindler, AE (2013). Non-contraceptive benefits of oral hormonal contraceptives. InternatiInt J Endocrinol Metab 11(1), 4147.Google ScholarPubMed
Shacter, E, Williams, JA, Lim, M & Levine, RL (1994). Differential susceptibility of plasma proteins to oxidative modification: Examination by western blot immunoassay. Free Rad Biol Med 17(5), 429437.CrossRefGoogle ScholarPubMed
Sidney, S, Cheetham, TC, Connell, FA, Ouellet-Hellstrom, R, Graham, DJ, Davis, D, Sorel, M, Quesenberry, CP Jr, Cooper, WO (2013). Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 87(1), 93100.CrossRefGoogle ScholarPubMed
Stocco, B, Fumagalli, HF, Franceschini, SA, Martinez, EZ, Marzocchi-Machado, CM, De Sa, MF & Toloi, MR (2015). Comparative study of the effects of combined oral contraceptives in hemostatic variables: An observational preliminary study. Medicine (Baltimore) 94(4), e385.CrossRefGoogle ScholarPubMed
Swanepoel, AC (2016). Clinical relevance of fibrin fiber diameter during different phases of pregnancy. Microsc Res Tech 79(10), 959965.CrossRefGoogle ScholarPubMed
Swanepoel, AC, Bester, J, Emmerson, O, Soma, P, Beukes, D, Van Reenen, M, Loots, DT & Du Preez, I (2020). Serum metabolome changes in relation to prothrombotic state induced by combined oral contraceptives with drospirenone and ethinylestradiol. Omics 24(7), 404414.CrossRefGoogle ScholarPubMed
Swanepoel, AC, Lindeque, BG, Swart, PJ, Abdool, Z & Pretorius, E (2014 a). Estrogen causes ultrastructural changes of fibrin networks during the menstrual cycle: A qualitative investigation. Microsc Res Tech 77(8), 594601.CrossRefGoogle ScholarPubMed
Swanepoel, AC, Lindeque, BG, Swart, PJ, Abdool, Z & Pretorius, E (2014 b). Part 2: Ultrastructural changes of fibrin networks during three phases of pregnancy: A qualitative investigation. Microsc Res Tech 77(8), 602608.CrossRefGoogle ScholarPubMed
Swanepoel, AC, Visagie, A, De Lange, Z, Emmerson, O, Nielsen, VG & Pretorius, E (2016 a). The clinical relevance of altered fibrinogen packaging in the presence of 17β-estradiol and progesterone. Thromb Res 146, 2334.CrossRefGoogle ScholarPubMed
Swanepoel, AC, Visagie, A & Pretorius, E (2016 b). Synthetic hormones and clot formation. Microsc Microanal 22(4), 878886.CrossRefGoogle ScholarPubMed
Undas, A (2014). Fibrin clot properties and their modulation in thrombotic disorders. Thromb Haemost 112(1), 3242.Google ScholarPubMed
Undas, A & Ariëns, RA (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
Von Bruhl, ML, Stark, K, Steinhart, A, Chandraratne, S, Konrad, I, Lorenz, M, Khandoga, A, Tirniceriu, A, Coletti, R, Kollnberger, M, Byrne, RA, Laitinen, I, Walch, A, Brill, A, Pfeiler, S, Manukyan, D, Braun, S, Lange, P, Riegger, J, Ware, J, Eckart, A, Haidari, S, Rudelius, M, Schulz, C, Echtler, K, Brinkmann, V, Schwaiger, M, Preissner, KT, Wagner, DD, Mackman, N, Engelmann, B & Massberg, S (2012). Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209(4), 819835.CrossRefGoogle ScholarPubMed
Wang, Q, Wurtz, P, Auro, K, Morin-Papunen, L, Kangas, AJ, Soininen, P, Tiainen, M, Tynkkynen, T, Joensuu, A, Havulinna, AS, Aalto, K, Salmi, M, Blankenberg, S, Zeller, T, Viikari, J, Kahonen, M, Lehtimaki, T, Salomaa, V, Jalkanen, S, Jarvelin, MR, Perola, M, Raitakari, OT, Lawlor, DA, Kettunen, J & Ala-Korpela, M (2016). Effects of hormonal contraception on systemic metabolism: Cross-sectional and longitudinal evidence. Int J Epidemiol 45(5), 14451457.CrossRefGoogle ScholarPubMed
Weisel, JW (2004). The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem 112(2–3 SPEC. ISS.), 267276.CrossRefGoogle ScholarPubMed
Ziller, M, Ziller, V, Haas, G, Rex, J & Kostev, K (2014). Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: A patient database analysis. Arch Gynecol Obstet 289(2), 413419.CrossRefGoogle ScholarPubMed