Reviews
Vol. 3 No. 2 (2024)
Stroke in women: anticoagulation in a complicated puzzle
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 1 May 2024
Accepted: 11 July 2024
Accepted: 11 July 2024
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Stroke is the third leading cause of death and the most important reason for disability. It is worth noting that 60% of all stroke deaths involve women. This review aims to revise the prothrombotic hemostatic alterations in hypertension along with the often-overlooked role of depression and the job strain of the homemakers’ condition proven to be risk factors for stroke. Moreover, the impact of atrial fibrillation and the related oral anticoagulation with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) in women will be discussed. Another point is that women are treated less with anticoagulants than men. Underdosing is also frequent. In our opinion, defensive medicine represents the basic bias, which plays a major role in this contest. The main reasons are the overlooking of the increased cardioembolic risk in women, the fear of an increased bleeding risk, and the wrong concept regarding a hypothetical higher frailty. In conclusion, from a practical point of view, thrombosis centers should consider all these factors when a woman shows a bad quality of anticoagulation with VKA or a poor adherence to DOAC treatment. Underdosing should also be carefully avoided. We hope that the sex gap in terms of inadequate treatment and inclusion in clinical trials will be covered in the future. Lastly, defensive medicine should be strongly discouraged.
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Citations
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38-360.
Persky RW, Turtzo LC, McCullough LD. Stroke in women: disparities and outcomes. Curr Cardiol Rep 2010;12:6-13. DOI: https://doi.org/10.1007/s11886-009-0080-2
Cherian L. Women and Ischemic Stroke: Disparities and Outcomes. Neurol Clin 2023;41:265-81. DOI: https://doi.org/10.1016/j.ncl.2022.10.001
Barcellona D, Grandone E, Marongiu F. Hormones and thrombosis: the dark side of the moon. Blood Transfus 2024;22:46-54.
Reeves MJ, Bushnell CD, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008;7:915-26. DOI: https://doi.org/10.1016/S1474-4422(08)70193-5
Gall SL, Donnan G, Dewey HM, et al. Sex differences in presentation, severity, and management of stroke in a population-based study. Neurology 2010;74:975-81. DOI: https://doi.org/10.1212/WNL.0b013e3181d5a48f
Novella S, Heras M, Hermenegildo C, et al. Effects of estrogen on vascular inflammation: a matter of timing. Arterioscler Thromb Vasc Biol 2012;32:2035-42. DOI: https://doi.org/10.1161/ATVBAHA.112.250308
Cove CL, Albert CM, Andreotti F, et al. Female sex as an independent risk factor for stroke in atrial fibrillation: possible mechanisms. Thromb Haemost 2014;111:385-91. DOI: https://doi.org/10.1160/TH13-04-0347
Wenger NK, Arnold A, Bairey Merz CN, et al. Hypertension across a woman's life cycle. J Am Coll Cardiol 2018;71:1797-813. DOI: https://doi.org/10.1016/j.jacc.2018.02.033
Lodi E, Carollo A, Martinotti V, Modena MG. Hypertension and pharmacological therapy in women. High Blood Press Cardiovasc Prev 2018;25:147-50. DOI: https://doi.org/10.1007/s40292-018-0257-0
Ratajczak J, Wysoczynski M, Hayek F, et al. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006;20:1487-95. DOI: https://doi.org/10.1038/sj.leu.2404296
Cordazzo C, Neri T, Petrini S, et al. Angiotensin II induces the generation of procoagulant microparticles by human mononuclear cells via an angiotensin type 2 receptor-mediated pathway. Thromb Res 2013;13:e168-e174. DOI: https://doi.org/10.1016/j.thromres.2013.01.019
Owens AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011;108:1284-97. DOI: https://doi.org/10.1161/CIRCRESAHA.110.233056
Rafaqat S, Khalid A, Riaz S et al. Irregularities of coagulation in hypertension. Curr Hypertens Rep 2023;25:271-86. DOI: https://doi.org/10.1007/s11906-023-01258-0
Voukalis C, Shantsila E, Lip GYH. Microparticles and cardiovascular diseases. Ann Med 2019;51:193-223. DOI: https://doi.org/10.1080/07853890.2019.1609076
Hirschfeld RM. Major depression, dysthymia and depressive personality disorder. Br J Psychiatry Suppl 1994:23-30. DOI: https://doi.org/10.1192/S0007125000293252
Goldstein BI, Carnethon MR, Matthews KA, et al. American Heart Association Atherosclerosis; Hypertension and Obesity in Youth Committee of the Council on Cardiovascular disease in the Young. Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2015;132:965-86. DOI: https://doi.org/10.1161/CIR.0000000000000229
Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55:580-92. DOI: https://doi.org/10.1001/archpsyc.55.7.580
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009;71:171-86. DOI: https://doi.org/10.1097/PSY.0b013e3181907c1b
Emerging Risk Factors Collaboration; Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375:132-40. DOI: https://doi.org/10.1016/S0140-6736(09)61717-7
Wassertheil-Smoller S, Shumaker S, Ockene J, et al. Depression and cardiovascular sequelae in postmenopausal women. The Women's Health Initiative (WHI). Arch Intern Med 2004;164:289-98. DOI: https://doi.org/10.1001/archinte.164.3.289
Bucciarelli V, Caterino AL, Bianco F, et al. Depression and cardiovascular disease: The deep blue sea of women's heart. Trends Cardiovasc Med 2020;30:170-6. DOI: https://doi.org/10.1016/j.tcm.2019.05.001
Harshfield EL, Pennells L, Schwartz JE, et al. Emerging risk factors collaboration. association between depressive symptoms and incident cardiovascular diseases. JAMA 2020;324:2396-405. DOI: https://doi.org/10.1001/jama.2020.23068
Thomas Q, Crespy V, Duloquin, et al. Stroke in women: when gender matters. Rev Neurol (Paris) 2021;177:881-9. DOI: https://doi.org/10.1016/j.neurol.2021.01.012
Karasek RA. Job demands, job decision latitude and mental strain: implications for job redesign. Adm Sci Q 1979;24:285-308. DOI: https://doi.org/10.2307/2392498
Flynn N, James JE. Relative effects of demand and control on task-related cardiovascular reactivity, task perceptions, performance accuracy, and mood. Int J Psychophysiol 2009;72:217-27. DOI: https://doi.org/10.1016/j.ijpsycho.2008.12.006
Wang J, Schmitz N, Dewa C, et al. Changes in perceived job strain and the risk of major depression: results from a population-based longitudinal study. Am J Epidemiol 2009;169:1085-91. DOI: https://doi.org/10.1093/aje/kwp037
Huang Y, Xu S, Hua J, et al. Association between job strain and risk of incident stroke: a meta-analysis. Neurology 2015;85:1648-54. DOI: https://doi.org/10.1212/WNL.0000000000002098
Brunner E, Marmot M. Chronic stress at work and the metabolic syndrome: prospective study. BMJ 2006;332:521-5. DOI: https://doi.org/10.1136/bmj.38693.435301.80
Nyberg ST, Fransson EI, Heikkilä K, et al. IPD-Work Consortium. Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women. PLoS One 2013;8:e67323. DOI: https://doi.org/10.1371/journal.pone.0067323
Emeny RT, Zierer A, Lacruz ME, et al. Job strain-associated inflammatory burden and long-term risk of coronary events: findings from the MONICA/KORA Augsburg case-cohort study. Psychosom Med 2013;75:317-25. DOI: https://doi.org/10.1097/PSY.0b013e3182860d63
Madsen IEH, Nyberg ST, Magnusson Hanson LL, et al. Work Consortium. Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data. Psychol Med 2017;47:1342-56. DOI: https://doi.org/10.1017/S003329171600355X
Bolijn R, Kunst AE, Appelman Y, et al. Prospective analysis of gender-related characteristics in relation to cardiovascular disease. Heart 2022;108:1030-38. DOI: https://doi.org/10.1136/heartjnl-2021-320414
Rose KM, Carson AP, Catellier D, et al. Women's employment status and mortality: the atherosclerosis risk in communities study. J Womens Health (Larchmt) 2004;13:1108-18. DOI: https://doi.org/10.1089/jwh.2004.13.1108
Carson AP, Rose KM, Catellier DJ, et al l. Employment status, coronary heart disease, and stroke among women. Ann Epidemiol 2009;19:630-36. DOI: https://doi.org/10.1016/j.annepidem.2009.04.008
Eek F, Axmon A. Gender inequality at home is associated with poorer health for women. Scand J Public Health 2015;43:176-82. DOI: https://doi.org/10.1177/1403494814562598
Floderus B, Hagman M, Aronsson G, et al. Work status, work hours and health in women with and without children. Occup Environ Med 2009;66:704-10. DOI: https://doi.org/10.1136/oem.2008.044883
Collins LG, Swartz K. Caregiver care. Am Fam Physician 2011;83:1309-17.
Maeda E, Nomura K, Hiraike O, et al. Domestic work stress and self-rated psychological health among women: a cross-sectional study in Japan. Environ Health Prev Med 2019;24:75. DOI: https://doi.org/10.1186/s12199-019-0833-5
Lip G, Freedman B, De Caterina R, et al. Stroke prevention in atrial fibrillation: Past, present and future. Comparing the guidelines and practical decision-making. Thromb Haemost 2017;117:1230-9. DOI: https://doi.org/10.1160/TH16-11-0876
Friberg L, Benson L, Rosenqvist M, et al. Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study. BMJ 2012;344:e3522. DOI: https://doi.org/10.1136/bmj.e3522
Mikkelsen AP, Lindhardsen J, Lip GY, et al. Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study. J Thromb Haemost 2012;10:1745-51. DOI: https://doi.org/10.1111/j.1538-7836.2012.04853.x
Wagstaff A, Overvad TF, Lip GY, et al. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. QJM 2014;107:955-67. DOI: https://doi.org/10.1093/qjmed/hcu054
Nielsen PB, Skjøth F, Overvad TF, et al. Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation: should we use a CHA2DS2-VA score rather than CHA2DS2-VASc? Circulation 2018;137:832-40. DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.029081
Nielsen PB, Overvad TF. Female sex as a risk modifier for stroke risk in atrial fibrillation: using CHA2DS2-VASc versus CHA2DS2-VA for stroke risk stratification in atrial fibrillation: a note of caution. Thromb Haemost 2020;120:894-8. DOI: https://doi.org/10.1055/s-0040-1710014
Brieger D, Amerena J, Attia J, et al; NHFA CSANZ Atrial Fibrillation Guideline Working Group. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018. Heart Lung Circ 2018;27:1209-66. DOI: https://doi.org/10.1016/j.hlc.2018.06.1043
Overvad TF, Potpara TS, Nielsen PB. Stroke risk stratification: CHA2DS2-VA or CHA2DS2-VASc? Heart Lung Circ 2019;2:e14-e15. DOI: https://doi.org/10.1016/j.hlc.2018.08.012
Linde C, Bongiorni MG, Birgersdotter-Green U, et al. ESC Scientific Document Group. Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society. Europace 2018;20:1565-65ao. DOI: https://doi.org/10.1093/europace/euy067
Tse HF, Oral H, Pelosi F, et al. Effect of gender on atrial electrophysiologic changes induced by rapid atrial pacing and elevation of atrial pressure. J Cardiovasc Electrophysiol 2001;12:986-9. DOI: https://doi.org/10.1046/j.1540-8167.2001.00986.x
Li Z, Wang Z, Yin Z, et al. Gender differences in fibrosis remodelling in patients with long-standing persistent atrial fibrillation. Oncotarget 2017;8:53714-29. DOI: https://doi.org/10.18632/oncotarget.16342
Marzona I, Proietti M, Farcomeni A, et al. Sex differences in stroke and major adverse clinical events in patients with atrial fibrillation: A systematic review and meta-analysis of 993,600 patients. Int J Cardiol 2018;269:182-91. DOI: https://doi.org/10.1016/j.ijcard.2018.07.044
Pancholy SB, Sharma PS, Pancholy DS, et al. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol 2014;113:485-90. DOI: https://doi.org/10.1016/j.amjcard.2013.10.035
Barcellona D, Contu P, Marongiu F. Patient education and oral anticoagulant therapy. Haematologica 2002;87:1081-6.
Avarello I, Bianchi S, Toschi V, et al. Time in therapeutic range is lower in women than in men and is not explained by differences in age or comorbidity. Thromb Res 2021;203:18-21. DOI: https://doi.org/10.1016/j.thromres.2021.04.011
Barcellona D, Schirru P, Mameli A, et al. Over-anticoagulation by vitamin K antagonists and gender differences. Int J Cardiol 2022;362:147-51. DOI: https://doi.org/10.1016/j.ijcard.2022.05.003
Barcellona D, Vannini ML, Fenu L et al. Warfarin or acenocoumarol: which is better in the management of oral anticoagulants? Thromb Haemost 1998;80:899-902. DOI: https://doi.org/10.1055/s-0037-1615385
Thompson LE, Maddox TM, Lei L, et al. Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the national cardiovascular data registry (NCDR®) PINNACLE Registry. J Am Heart Assoc 2017;6:e005801. DOI: https://doi.org/10.1161/JAHA.117.005801
Giner-Soriano M, Prat-Vallverdú O, Ouchi D, et al. Sex and gender differences in the use of oral anticoagulants for non-valvular atrial fibrillation: a population-based cohort study in primary health care in Catalonia. Front Pharmacol 2023;14:1110036. DOI: https://doi.org/10.3389/fphar.2023.1110036
Piepoli MF, Hoes AW, Agewall S, et al. ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81. DOI: https://doi.org/10.1093/eurheartj/ehw106
US Congress Office of Technology Assessment Defensive medicine and medical malpractice. Publication OTA-H-602. Washington, DC:US Government Printing Office 1994.
Berlin L. Medical errors, malpractice, and defensive medicine: an ill-fated triad. Diagnosis (Berl) 2017;4:133-9. DOI: https://doi.org/10.1515/dx-2017-0007
Garattini L, Padula A, Mannucci PM. Defensive medicine: Everything and its opposite. Eur J Intern Med 2020;74:117-8. DOI: https://doi.org/10.1016/j.ejim.2020.01.015
Toraldo DM, Vergari U, Toraldo M. Medical malpractice, defensive medicine and role of the "media" in Italy. Multidiscip Respir Med 2015;10:12. DOI: https://doi.org/10.4081/mrm.2015.285
Daitch V, Turjeman A, Poran I, et al. Underrepresentation of women in randomized controlled trials: a systematic review and meta-analysis. Trials 2022;23:1038. DOI: https://doi.org/10.1186/s13063-022-07004-2
Liu KA, Mager NA. Women's involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada) 2016;14:708. DOI: https://doi.org/10.18549/PharmPract.2016.01.708
National Institutes of Health, Office of Research on Women’s Health. Report of the Advisory Committee on Research on Women’s Health: fiscal years 2011-2012: Office of Research on Women’s Health and NIH Support for Research on Women’s Health. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; 2013. NIH Publication No.: 13-7995.
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1.
Marongiu F, Grandone E, Marongiu S, Mameli A, Barcellona D. Stroke in women: anticoagulation in a complicated puzzle. Bleeding Thromb Vasc Biol [Internet]. 2024 Aug. 26 [cited 2026 Apr. 24];3(2). Available from: https://www.btvb.org/btvb/article/view/137
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