Sex-Related Differences in Platelet Aggregation: A Literature Review Supplemented with Local Data from a Group of Generally Healthy Individuals

Abstract

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A₂ analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment.

Keywords

platelet aggregation - blood coagulation - antiplatelet drug - correlation of data - sex differences

Author Contributions

Study conceptualization and design: A.C., L.J., P.M.; aggregatory experiments: A.C., L.K., J.K., M.H., M.S.P.; bioanalysis: L.J., K.M., L.K.K.; data curation: A.C., P.M., L.J.; patient recruitment: P.S., M.P., F.M., A.Š., V.B.; literature review: A.C., P.M.; manuscript preparation: A.C., P.M.; manuscript revision: A.C., M.H., P.M.; funding acquisition: A.C., L.J., P.M. All authors read and approved the submitted version of the manuscript.

Publikationsverlauf

Artikel online veröffentlicht:
07. Oktober 2022

• References

• 1 Yeung J, Li W, Holinstat M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev 2018; 70 (03) 526-548
• 2 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
• 3 McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol 2018; 15 (03) 181-191
• 4 Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev 2000; 80 (04) 1669-1699
• 5 Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 2002; 30 (5, Suppl): S294-S301
• 6 Mastenbroek TG, van Geffen JP, Heemskerk JW, Cosemans JM. Acute and persistent platelet and coagulant activities in atherothrombosis. J Thromb Haemost 2015; 13 (Suppl 1): S272-S280
• 7 Ranucci M, Aloisio T, Dedda UD, La Rovere MT, De Arroyabe BML, Baryshnikova E. Platelet reactivity in overweight and obese patients undergoing cardiac surgery. Platelets 2019; 30 (05) 608-614
• 8 Elaïb Z, Lopez JJ, Coupaye M. et al. Platelet functions are decreased in obesity and restored after weight loss: evidence for a role of the SERCA3-dependent ADP secretion pathway. Thromb Haemost 2019; 119 (03) 384-396
• 9 Davì G, Averna M, Catalano I. et al. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation 1992; 85 (05) 1792-1798
• 10 Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol 2008; 51 (19) 1829-1843
• 11 Krcmova L, Solichova D, Melichar B. et al. Determination of neopterin, kynurenine, tryptophan and creatinine in human serum by high throughput HPLC. Talanta 2011; 85 (03) 1466-1471
• 12 Stoupel E. The effect of geomagnetic activity on cardiovascular parameters. Biomed Pharmacother 2002; 56 (Suppl 2): 247s-256s
• 13 White J. American Heart Association. AHA statement highlights gender differences in PCI: part II. J Interv Cardiol 2005; 18 (05) 355-356
• 14 Soedamah-Muthu SS, Stehouwer CD. Cardiovascular disease morbidity and mortality in patients with type 1 diabetes mellitus: management strategies. Treat Endocrinol 2005; 4 (02) 75-86
• 15 Hansen JB, Berge LN, Svensson B, Lyngmo V, Nordøy A. Effects of cod liver oil on lipids and platelets in males and females. Eur J Clin Nutr 1993; 47 (02) 123-131
• 16 Frontroth JP, Favaloro EJ. Ristocetin-induced platelet aggregation (RIPA) and RIPA mixing studies. Methods Mol Biol 2017; 1646: 473-494
• 17 Koltai K, Papp J, Kenyeres P. et al. Gender differences in hemorheological parameters and in in vitro platelet aggregation in acetylsalicylic acid and clopidogrel treated vascular patients. Biorheology 2014; 51 (2-3): 197-206
• 18 Phang M, Garg ML, Sinclair AJ. Inhibition of platelet aggregation by omega-3 polyunsaturated fatty acids is gender specific - redefining platelet response to fish oils. Prostaglandins Leukot Essent Fatty Acids 2009; 81 (01) 35-40
• 19 Freed MI, Boike S, Zariffa N, Jorkasky DK. Effect of acetylsalicylic acid on inhibition of ex vivo platelet aggregation and secretion by SKF 107260, a novel GPIIb/IIIa receptor antagonist. Thromb Haemost 1994; 72 (04) 622-626
• 20 Agren JJ, Pekkarinen H, Litmanen H, Hänninen O. Fish diet and physical fitness in relation to membrane and serum lipids, prostanoid metabolism and platelet aggregation in female students. Eur J Appl Physiol Occup Physiol 1991; 63 (05) 393-398
• 21 Kurrelmeyer K, Becker L, Becker D, Yanek L, Goldschmidt-Clermont P, Bray PF. Platelet hyperreactivity in women from families with premature atherosclerosis. J Am Med Womens Assoc 2003; 58 (04) 272-277
• 22 Lee TK, Chen YC, Kuo TL. Comparison of the effect of acetylsalicylic acid on platelet function in male and female patients with ischemic stroke. Thromb Res 1987; 47 (03) 295-304
• 23 Halimeh S, Angelis Gd, Sander A. et al. Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents. Klin Padiatr 2010; 222 (03) 158-163
• 24 Faraday N, Goldschmidt-Clermont PJ, Bray PF. Gender differences in platelet GPIIb-IIIa activation. Thromb Haemost 1997; 77 (04) 748-754
• 25 Leng XH, Hong SY, Larrucea S. et al. Platelets of female mice are intrinsically more sensitive to agonists than are platelets of males. Arterioscler Thromb Vasc Biol 2004; 24 (02) 376-381
• 26 Ajayi AA, Hercule H, Cory J, Hayes BE, Oyekan AO. Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats. Diabetes Res Clin Pract 2003; 59 (01) 11-24
• 27 Torres Duarte AP, Ramwell P, Myers A. Sex differences in mouse platelet aggregation. Thromb Res 1986; 43 (01) 33-39
• 28 Waissi F, Dekker M, Bank IEM. et al. Sex differences in flow cytometry-based platelet reactivity in stable outpatients suspected of myocardial ischemia. Res Pract Thromb Haemost 2020; 4 (05) 879-885
• 29 Verdoia M, Pergolini P, Nardin M. et al; Novara Atherosclerosis Study Group (NAS). Gender differences in platelet reactivity in diabetic patients receiving dual antiplatelet therapy. Cardiovasc Revasc Med 2020; 21 (09) 1144-1149
• 30 Agarwal KC. Modulation of vasopressin actions on human platelets by plasma adenosine and theophylline: gender differences. J Cardiovasc Pharmacol 1993; 21 (06) 1012-1018
• 31 Otahbachi M, Simoni J, Simoni G. et al. Gender differences in platelet aggregation in healthy individuals. J Thromb Thrombolysis 2010; 30 (02) 184-191
• 32 Verdoia M, Pergolini P, Rolla R. et al; Novara Atherosclerosis Study Group (NAS). Gender differences in platelet reactivity in patients receiving dual antiplatelet therapy. Cardiovasc Drugs Ther 2016; 30 (02) 143-150
• 33 Becker DM, Segal J, Vaidya D. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA 2006; 295 (12) 1420-1427
• 34 Samad Z, Boyle S, Ersboll M. et al; REMIT Investigators. Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study. J Am Coll Cardiol 2014; 64 (16) 1669-1678
• 35 Friede KA, Infeld MM, Tan RS. et al. Influence of sex on platelet reactivity in response to aspirin. J Am Heart Assoc 2020; 9 (14) e014726
• 36 Beyan C, Kaptan K, Ifran A, Savaşçi S, Oztürk Y, Okmen B. Effect of sex difference on platelet aggregation using an optical method in healthy subjects. Clin Lab Haematol 2006; 28 (01) 14-16
• 37 Rodriguez BAT, Johnson AD. Platelet measurements and type 2 diabetes: investigations in two population-based cohorts. Front Cardiovasc Med 2020; 7: 118
• 38 Coppe D, Wessinger SJ, Ransil BJ, Harris W, Salzman E. Sex differences in the platelet response to aspirin. Thromb Res 1981; 23 (1-2): 1-21
• 39 Correia CJ, Ricardo da Silva FY, Armstrong R. et al. Sex differences in the coagulation process and microvascular perfusion induced by brain death in rats. Transpl Int 2020; 33 (11) 1541-1550
• 40 Eshel-Green T, Berny MA, Conley RB, McCarty OJ. Effect of sex difference on platelet adhesion, spreading and aggregate formation under flow. Thromb Haemost 2009; 102 (05) 958-965
• 41 Siess W, Lapetina EG. Platelet aggregation induced by alpha 2-adrenoceptor and protein kinase C activation. A novel synergism. Biochem J 1989; 263 (02) 377-385
• 42 Patti G, De Caterina R, Abbate R. et al; Working Group on Thrombosis of the Italian Society of Cardiology. Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A ‘state-of-the-art’ paper. Eur Heart J 2014; 35 (33) 2213-2223b
• 43 Segal JB, Moliterno AR. Platelet counts differ by sex, ethnicity, and age in the United States. Ann Epidemiol 2006; 16 (02) 123-130
• 44 Di Giosia P, Passacquale G, Petrarca M, Giorgini P, Marra AM, Ferro A. Gender differences in cardiovascular prophylaxis: focus on antiplatelet treatment. Pharmacol Res 2017; 119: 36-47
• 45 Petronio AS, De Carlo M, Misuraca L. Does percutaneous coronary intervention in women provide the same results as in men?. [Article in Italian] G Ital Cardiol (Rome) 2012; 13 (06) 414-418
• 46 Cho L, Topol EJ, Balog C. et al. Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the prevention of ischemic complications. Evaluation in percutaneous transluminal coronary angioplasty to improve long-term outcome with abciximab GP IIb/IIIa blockade. Evaluation of platelet IIb/IIIa Inhibitor for stent. J Am Coll Cardiol 2000; 36 (02) 381-386
• 47 Falsetti L, Viticchi G, Buratti L, Balucani C, Marra AM, Silvestrini M. From head to toe: sex and gender differences in the treatment of ischemic cerebral disease. Pharmacol Res 2017; 121: 240-250
• 48 Eindhoven DC, Hilt AD, Zwaan TC, Schalij MJ, Borleffs CJW. Age and gender differences in medical adherence after myocardial infarction: women do not receive optimal treatment - the Netherlands claims database. Eur J Prev Cardiol 2018; 25 (02) 181-189
• 49 Nohria A, Vaccarino V, Krumholz HM. Gender differences in mortality after myocardial infarction. Why women fare worse than men. Cardiol Clin 1998; 16 (01) 45-57
• 50 Marcucci R, Cioni G, Giusti B. et al. Gender and anti-thrombotic therapy: from biology to clinical implications. J Cardiovasc Transl Res 2014; 7 (01) 72-81
• 51 Guo L, Lv H, Zhong L. et al. Gender differences in long-term outcomes of medical therapy and successful percutaneous coronary intervention for coronary chronic total occlusions. J Interv Cardiol 2019; 2019: 2017958
• 52 Baker-Groberg SM, Lattimore S, Recht M, McCarty OJ, Haley KM. Assessment of neonatal platelet adhesion, activation, and aggregation. J Thromb Haemost 2016; 14 (04) 815-827
• 53 Winter MP, Schneeweiss T, Cremer R. et al. Platelet reactivity patterns in patients treated with dual antiplatelet therapy. Eur J Clin Invest 2019; e13102: e13102
• 54 Zuern CS, Lindemann S, Gawaz M. Platelet function and response to aspirin: gender-specific features and implications for female thrombotic risk and management. Semin Thromb Hemost 2009; 35 (03) 295-306
• 55 Shaw LJ, Shaw RE, Merz CN. et al; American College of Cardiology-National Cardiovascular Data Registry Investigators. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation 2008; 117 (14) 1787-1801
• 56 Ho SJ, Gemmell R, Brighton TA. Platelet function testing in uraemic patients. Hematology 2008; 13 (01) 49-58
• 57 Schoos MM, Mehran R, Dangas GD. et al. Gender differences in associations between intraprocedural thrombotic events during percutaneous coronary intervention and adverse outcomes. Am J Cardiol 2016; 118 (11) 1661-1668
• 58 Verdoia M, Suryapranata H, Damen S. et al. Gender differences with short-term vs 12 months dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: 2-years follow-up results of the REDUCE trial. J Thromb Thrombolysis 2021; 52 (03) 797-807
• 59 Wijnbergen I, Tijssen J, van 't Veer M, Michels R, Pijls NH. Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2013; 82 (03) 379-384
• 60 Williams JE, Chimowitz MI, Cotsonis GA, Lynn MJ, Waddy SP. WASID Investigators. Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 2007; 38 (07) 2055-2062
• 61 Sam C, Massaro JM, D'Agostino Sr RB. et al; Framingham Heart Study. Warfarin and aspirin use and the predictors of major bleeding complications in atrial fibrillation (the Framingham Heart Study). Am J Cardiol 2004; 94 (07) 947-951
• 62 Holm A, Swahn E, Lawesson SS. et al. Sex differences in platelet reactivity in patients with myocardial infarction treated with triple antiplatelet therapy - results from assessing platelet activity in coronary heart disease (APACHE). Platelets 2021; 32 (04) 524-532
• 63 Batić-Mujanović O, Zildzić M, Beganlić A. Secondary prevention of coronary heart disease in primary health care. Bosn J Basic Med Sci 2006; 6 (02) 37-41
• 64 DeWilde S, Carey IM, Richards N, Whincup PH, Cook DG. Trends in secondary prevention of ischaemic heart disease in the UK 1994 2005: use of individual and combination treatment. Heart 2008; 94 (01) 83-88
• 65 Kim BS, Chan N, Hsu G. et al. Sex differences in coronary arterial calcification in symptomatic patients. Am J Cardiol 2021; 149: 16-20
• 66 Opotowsky AR, McWilliams JM, Cannon CP. Gender differences in aspirin use among adults with coronary heart disease in the United States. J Gen Intern Med 2007; 22 (01) 55-61
• 67 Fisher M, Zipser R. Increased excretion of immunoreactive thromboxane B2 in cerebral ischemia. Stroke 1985; 16 (01) 10-14
• 68 Jang IK, Baron SJ, Hursting MJ, Anglade E. Argatroban therapy in women with heparin-induced thrombocytopenia. J Womens Health (Larchmt) 2007; 16 (06) 895-901
• 69 Birkemeyer R, Schneider H, Rillig A. et al. Do gender differences in primary PCI mortality represent a different adherence to guideline recommended therapy? a multicenter observation. BMC Cardiovasc Disord 2014; 14: 71
• 70 Iakovou I, Dangas G, Mehran R. et al. Gender differences in clinical outcome after coronary artery stenting with use of glycoprotein IIb/IIIa inhibitors. Am J Cardiol 2002; 89 (08) 976-979
• 71 Zheng X, Dreyer RP, Hu S. et al; China PEACE Collaborative Group. Age-specific gender differences in early mortality following ST-segment elevation myocardial infarction in China. Heart 2015; 101 (05) 349-355
• 72 Okunrintemi V, Valero-Elizondo J, Patrick B. et al. Gender differences in patient-reported outcomes among adults with atherosclerotic cardiovascular disease. J Am Heart Assoc 2018; 7 (24) e010498
• 73 Ruiz-Pizarro V, Ferrera C, Gómez-Polo JC. et al. Sex differences in treatment and prognosis of acute coronary syndrome with interventional management. Cardiovasc Revasc Med 2019; 20 (03) 183-186
• 74 Nilsson G, Strender LE. Management of heart failure in primary health care. A retrospective study on electronic patient records in a registered population. Scand J Prim Health Care 2002; 20 (03) 161-165
• 75 Doyle F, De La Harpe D, McGee H, Shelley E, Conroy R. Gender differences in the presentation and management of acute coronary syndromes: a national sample of 1365 admissions. Eur J Cardiovasc Prev Rehabil 2005; 12 (04) 376-379
• 76 Ravn-Fischer A, Perers E, Karlsson T, Caidahl K, Hartford M. Seventeen-year mortality following the acute coronary syndrome: gender-specific baseline variables and impact on outcome. Cardiology 2019; 143 (01) 22-31
• 77 Bobbert P, Stellbaum C, Steffens D. et al. Postmenopausal women have an increased maximal platelet reactivity compared to men despite dual antiplatelet therapy. Blood Coagul Fibrinolysis 2012; 23 (08) 723-728
• 78 Reading HW, Rosie R. Age and sex differences related to platelet aggregation. [Proceedings] Biochem Soc Trans 1980; 8 (02) 180-181
• 79 Beisiegel B, Treese N, Hafner G, Meyer J, Darius H. Increase in endogenous fibrinolysis and platelet activity during exercise in young volunteers. Agents Actions Suppl 1992; 37: 183-189
• 80 Lawrence JB, Leifer DW, Moura GL. et al. Sex differences in platelet adherence to subendothelium: relationship to platelet function tests and hematologic variables. Am J Med Sci 1995; 309 (04) 201-207
• 81 Yamashita T, Sato A, Ikarugi H. et al. Significantly reduced spontaneous thrombolytic activity in older men: a possible explanation for the gender differences in risk of acute coronary syndromes. Thromb Res 2005; 116 (02) 127-131
• 82 Schmeling JW, Foegh M, Ramey E, Ramwell PW. Reevaluation of sex differences in platelet aggregation in a physiologic system. Prog Lipid Res 1981; 20: 811-814
• 83 Dangas G, Smith DA, Badimon JJ. et al. Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin. Am J Cardiol 1999; 84 (06) 639-643
• 84 Ogunlade OA, Fasanmade AA. Abnormalities in thrombogenic and rheologic factors in Nigerian hypertensive patients. Afr J Med Med Sci 2001; 30 (04) 291-294
• 85 Gremmel T, Kopp CW, Eichelberger B, Koppensteiner R, Panzer S. Sex differences of leukocyte-platelet interactions and on-treatment platelet reactivity in patients with atherosclerosis. Atherosclerosis 2014; 237 (02) 692-695
• 86 González-Correa JA, Arrebola MM, Muñoz-Marín J. et al. Gender differences in the effect of aspirin on retinal ischemia, prostanoid synthesis and nitric oxide production in experimental type 1-like diabetes. Vascul Pharmacol 2007; 47 (2-3): 83-89
• 87 Giani E, Masi I, Colombo C, Galli C. Sex differences in platelet thromboxane and arterial prostacyclin production in control and n-6 fatty acid supplemented rats. Prostaglandins 1984; 28 (04) 573-586
• 88 Kojima T, Inoue M, Morikawa M, Horiguchi Y. Contribution of plasmin to sex differences in platelet aggregation in the rat. Res Commun Chem Pathol Pharmacol 1993; 82 (03) 351-356
• 89 Friedrich V, Bederson JB, Sehba FA. Gender influences the initial impact of subarachnoid hemorrhage: an experimental investigation. PLoS One 2013; 8 (11) e80101
• 90 Lee SJ, Kwon JA, Cho SA, Jarrar YB, Shin JG. Effects of testosterone and 17β-oestradiol on expression of the G protein-coupled receptor P2Y12 in megakaryocytic DAMI cells. Platelets 2012; 23 (08) 579-585
• 91 Alfredsson J, Swahn E. Management of acute coronary syndromes from a gender perspective. Fundam Clin Pharmacol 2010; 24 (06) 719-728
• 92 Mallidi J, Lata K. Role of gender in dual antiplatelet therapy after acute coronary syndrome. Curr Atheroscler Rep 2019; 21 (09) 34
• 93 Lee KH, Jeong MH, Ahn Y, Cho MC, Kim CJ, Kim YJ. New horizons of acute myocardial infarction: from the Korea Acute Myocardial Infarction Registry. J Korean Med Sci 2013; 28 (02) 173-180
• 94 Gutiérrez-Chico JL, Mehilli J. Gender differences in cardiovascular therapy: focus on antithrombotic therapy and percutaneous coronary intervention. Drugs 2013; 73 (17) 1921-1933
• 95 Grines C, Cho L. Atherothrombotic disease and the role of antiplatelet therapy in women. J Womens Health (Larchmt) 2008; 17 (01) 35-46
• 96 Rauch U. Gender differences in anticoagulation and antithrombotic therapy. Handb Exp Pharmacol 2012; (214) 523-542
• 97 Clyne CA. Antithrombotic therapy in the primary and secondary prevention of coronary-related death and infarction: focus on gender differences. Cardiology 1990; 77 (Suppl 2): 99-109
• 98 Sacco S, Cerone D, Carolei A. Gender and stroke: acute phase treatment and prevention. Funct Neurol 2009; 24 (01) 45-52
• 99 Raparelli V, Morano S, Franconi F, Lenzi A, Basili S. Sex differences in type-2 diabetes: implications for cardiovascular risk management. Curr Pharm Des 2017; 23 (10) 1471-1476