{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:34:53Z","timestamp":1760146493416,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103443"],"award-info":[{"award-number":["P20GM103443"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Platelet activation plays an essential role in clot formation to prevent blood loss following vascular damage. In pathologic conditions, platelet activation can lead to obstructive clots, disrupting blood flow and resulting in thrombosis. Native Americans suffer disproportionately from arterial disease and previous research has shown that Blacks are enriched in genetic polymorphisms that correlate with higher platelet reactivity contributing to an increased risk for thrombosis. Therefore, the current study sought to determine phenotypic variations in Native American platelet responses following stimulation with agonists, simulating vascular damage. Several donors from a small cohort of Native Americans showed atypical robust platelet aggregation when stimulated with submaximal concentrations of agonists. Further, when comparing \u03b1-granule secretion, a specific marker of platelet activation, Native Americans were more likely to have elevated responses to multiple agonist conditions of stimulation compared to Whites. Interestingly, there were no noticeable differences in integrin activation between Native Americans and Whites. Our study is the first to observe elevated Native American platelet responses compared to Whites, supporting further mechanistic studies and investigation of treatment approaches for the prevention of thrombosis.<\/jats:p>","DOI":"10.3390\/ijms252211990","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T04:02:54Z","timestamp":1731038574000},"page":"11990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Observational Analyses of Ex Vivo Native American Platelet Responses"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5419-3009","authenticated-orcid":false,"given":"Krista","family":"Goerger","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Biermann","sequence":"additional","affiliation":[{"name":"Biology Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Besh","sequence":"additional","affiliation":[{"name":"Biology Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanner","family":"Flickema","sequence":"additional","affiliation":[{"name":"Biology Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pramit","family":"Patel","sequence":"additional","affiliation":[{"name":"Biology Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla","family":"Abbott","sequence":"additional","affiliation":[{"name":"Nursing Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5100-1933","authenticated-orcid":false,"given":"Michael","family":"Holinstat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark K.","family":"Larson","sequence":"additional","affiliation":[{"name":"Biology Department, Augustana University, Sioux Falls, SD 57197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1161\/CIR.0000000000001123","article-title":"Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association","volume":"147","author":"Tsao","year":"2023","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1016\/j.jacc.2022.11.005","article-title":"The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health","volume":"80","author":"Vaduganathan","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","first-page":"e18","article-title":"Heart disease and stroke statistics\u20142011 update: A report from the American Heart Association","volume":"123","author":"Roger","year":"2011","journal-title":"Circulation"},{"key":"ref_4","first-page":"785","article-title":"Thrombosis and platelets: An update","volume":"38","author":"Koupenova","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1182\/blood-2006-12-027698","article-title":"The growing complexity of platelet aggregation","volume":"109","author":"Jackson","year":"2007","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1055\/s-0038-1657598","article-title":"Mechanisms initiating platelet thrombus formation","volume":"78","author":"Ruggeri","year":"1997","journal-title":"Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1473-0502(03)00044-2","article-title":"Platelets in hemostasis and thrombosis: Role of integrins and their ligands","volume":"28","author":"Ni","year":"2003","journal-title":"Transfus. Apher. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/nm1102-1227","article-title":"Platelets in atherothrombosis","volume":"8","author":"Ruggeri","year":"2002","journal-title":"Nat. Med."},{"key":"ref_9","unstructured":"(2023, July 10). The Top 200 Drugs of 2022. Available online: https:\/\/clincalc.com\/DrugStats\/."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"152","DOI":"10.7861\/clinmedicine.16-2-152","article-title":"Antiplatelet therapy\u2014A summary for general physicians","volume":"16","author":"Thachil","year":"2016","journal-title":"Clin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1016\/j.jtha.2023.09.013","article-title":"Antiplatelet strategies: Past, present, and future","volume":"21","author":"Stanger","year":"2023","journal-title":"J. Thromb. Haemost."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7135","DOI":"10.1038\/s41467-021-27378-2","article-title":"Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19","volume":"12","author":"Nishikawa","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1182\/blood-2005-03-1290","article-title":"Aggregometry detects platelet hyperreactivity in healthy individuals","volume":"106","author":"Yee","year":"2005","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.thromres.2018.12.008","article-title":"Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults","volume":"174","author":"Lindkvist","year":"2019","journal-title":"Thromb. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/nm.3385","article-title":"Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c","volume":"19","author":"Edelstein","year":"2013","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1161\/ATVBAHA.114.304249","article-title":"Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis","volume":"34","author":"Tourdot","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1161\/ATVBAHA.118.311112","article-title":"Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics","volume":"38","author":"Tourdot","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e024159","DOI":"10.1161\/JAHA.121.024159","article-title":"CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings","volume":"11","author":"Beitelshees","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/oxfordjournals.aje.a117632","article-title":"Coronary Heart Diseease Prevalence and Its Relation to Risk Factors in American Indians: The Strong Heart Study. The Strong Heart Study","volume":"142","author":"Howard","year":"1995","journal-title":"Am. J. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/oxfordjournals.aje.a009817","article-title":"Prevanence of peripheral arterial disease and associated risk factors in American Indians: The Strong Heart Study","volume":"149","author":"Fabsitz","year":"1999","journal-title":"Am. J. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Au, N.T., Reyes, M., Boyer, B.B., Hopkins, S.E., Black, J., O\u2019Brien, D., Fohner, A.E., Yracheta, J., Thornton, T., and Austin, M.A. (2017). Dietary and genetic influences on hemostasis in a Yup\u2019ik Alaska Native population. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173616"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1111\/jth.15184","article-title":"DHA 12-LOX-derived oxylipins regulate platelet activation and thrombus formation through a PKA-dependent signaling pathway","volume":"19","author":"Yamaguchi","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"28275","DOI":"10.1073\/pnas.2008921117","article-title":"GPR56\/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force","volume":"117","author":"Yeung","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1160\/TH13-01-0014","article-title":"12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity","volume":"110","author":"Yeung","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1182\/blood-2008-03-145821","article-title":"Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression","volume":"114","author":"Yang","year":"2009","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1161\/CIRCRESAHA.117.310795","article-title":"Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis","volume":"122","author":"Koupenova","year":"2018","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1161\/01.CIR.99.18.2389","article-title":"Rising Tide of cardiovascular disease in American Indians. The Strong Heart Study","volume":"99","author":"Howard","year":"1999","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.1182\/blood-2014-04-572479","article-title":"Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race","volume":"124","author":"Edelstein","year":"2014","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"903","DOI":"10.2217\/bmm-2016-0070","article-title":"Platelet function testing as a biomarker for efficacy of antiplatelet drugs","volume":"10","author":"So","year":"2016","journal-title":"Biomark. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1124\/pr.117.014530","article-title":"Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases","volume":"70","author":"Yeung","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Huskens, D., Sang, Y., Konings, J., van der Vorm, L., de Laat, B., Kelchtermans, H., and Roest, M. (2018). Standardization and reference ranges for whole blood platelet function measurements using a flow cytometric platelet activation test. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192079"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/11990\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:28:30Z","timestamp":1760113710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/22\/11990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":31,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252211990"],"URL":"https:\/\/doi.org\/10.3390\/ijms252211990","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,11,8]]}}}