{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T13:40:25Z","timestamp":1742218825332,"version":"3.38.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"James and Esther King Biomedical Research Program","award":["9JK08","9JK08","9JK08","9JK08","9JK08"],"award-info":[{"award-number":["9JK08","9JK08","9JK08","9JK08","9JK08"]}]},{"name":"Lois Pope Neuroscience Summer Research Scholarship"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharmacol. Rep"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Current therapies to treat excessive bleeding are associated with significant complications, which may outweigh their benefits. Red blood cell-derived microparticles (RMPs) are a promising hemostatic agent. Previous studies demonstrated that they reduce bleeding in animal models, correct coagulation defects in patient blood, and have an excellent safety profile. However, their exact mechanism of action is not known. We investigated the potential role of RMPs on primary and secondary hemostasis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To evaluate the effects of RMPs, prepared using high-pressure extrusion, on primary hemostasis, we employed platelet aggregometry with platelet inhibitors, eptifibatide, and ticagrelor, with and without RMPs. To evaluate their effects on secondary hemostasis, we employed thromboelastography with plasma deficient in factors VII, VIII, IX, XI, and XII with and without RMPs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We found that RMPs significantly increased collagen-induced platelet aggregation. However, there were no significant differences with and without RMP in the presence of the platelet inhibitors, indicating that RMPs may work through these receptors, either directly or indirectly. For secondary hemostasis, RMPs significantly decreased clotting times for plasma deficient in factors VII, VIII, IX, and XI but not in XII.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our results indicate that RMPs enhance primary hemostasis and both pathways of secondary hemostasis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s43440-024-00688-0","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T08:11:02Z","timestamp":1736323862000},"page":"508-516","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Red cell microparticles produced using high-pressure extrusion enhance both primary and secondary hemostasis"],"prefix":"10.1007","volume":"77","author":[{"given":"Snigdha","family":"Sama","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunjoo","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashish K.","family":"Rehni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenche","family":"Jy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0173-5338","authenticated-orcid":false,"given":"Kunjan R.","family":"Dave","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"688_CR1","unstructured":"Donley ER, Munakomi S, Loyd JW, Hemorrhage Control Treasure Island (FL).: StatPearls Publishing; 2023 [updated August 13, 2023. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK535393\/"},{"key":"688_CR2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1757-7241-20-47","volume":"20","author":"PI Johansson","year":"2012","unstructured":"Johansson PI, Stensballe J, Ostrowski SR. Current management of massive hemorrhage in trauma. Scand J Trauma Resusc Emerg Med. 2012;20:47.","journal-title":"Scand J Trauma Resusc Emerg Med"},{"issue":"1","key":"688_CR3","doi-asserted-by":"publisher","first-page":"e000107","DOI":"10.1136\/tsaco-2017-000107","volume":"2","author":"JM Bardes","year":"2017","unstructured":"Bardes JM, Palmer A, Con J, Wilson A, Schaefer G. Antifibrinolytics in a rural trauma state: assessing the opportunities. Trauma Surg Acute Care Open. 2017;2(1):e000107.","journal-title":"Trauma Surg Acute Care Open"},{"issue":"6","key":"688_CR4","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1097\/TA.0000000000000242","volume":"76","author":"EJ Valle","year":"2014","unstructured":"Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76(6):1373\u20138.","journal-title":"J Trauma Acute Care Surg"},{"key":"688_CR5","doi-asserted-by":"publisher","first-page":"599","DOI":"10.3389\/fphar.2018.00599","volume":"9","author":"W Jy","year":"2018","unstructured":"Jy W, Rehni AK, Bidot C Jr., Navarro-Quero H, Haase CR, Koch S, et al. Pharmacokinetics of Human Red Blood Cell Microparticles Prepared Using High-Pressure Extrusion Method. Front Pharmacol. 2018;9:599.","journal-title":"Front Pharmacol"},{"issue":"7","key":"688_CR6","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1111\/j.1538-7836.2012.04758.x","volume":"10","author":"PE Van Der Meijden","year":"2012","unstructured":"Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renne T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost. 2012;10(7):1355\u201362.","journal-title":"J Thromb Haemost"},{"issue":"1","key":"688_CR7","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s00441-008-0710-9","volume":"335","author":"GN Chironi","year":"2009","unstructured":"Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A. Endothelial microparticles in diseases. Cell Tissue Res. 2009;335(1):143\u201351.","journal-title":"Cell Tissue Res"},{"issue":"1","key":"688_CR8","doi-asserted-by":"publisher","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","volume":"7","author":"C Thery","year":"2018","unstructured":"Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.","journal-title":"J Extracell Vesicles"},{"issue":"5","key":"688_CR9","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1177\/1074248419838512","volume":"24","author":"AK Rehni","year":"2019","unstructured":"Rehni AK, Shukla V, Navarro Quero H, Bidot C Jr., Haase CR, Crane EAA, et al. Preclinical Evaluation of Safety and Biodistribution of Red Cell Microparticles: A Novel Hemostatic Agent. J Cardiovasc Pharmacol Ther. 2019;24(5):474\u201383.","journal-title":"J Cardiovasc Pharmacol Ther"},{"issue":"10","key":"688_CR10","doi-asserted-by":"publisher","first-page":"3182","DOI":"10.1161\/STROKEAHA.122.039641","volume":"53","author":"AK Rehni","year":"2022","unstructured":"Rehni AK, Cho S, Quero HN, Shukla V, Zhang Z, Dong C, et al. Red Blood Cell Microparticles Limit Hematoma Growth in Intracerebral Hemorrhage. Stroke. 2022;53(10):3182\u201391.","journal-title":"Stroke"},{"issue":"12","key":"688_CR11","doi-asserted-by":"publisher","first-page":"5242","DOI":"10.1182\/blood-2006-06-030619","volume":"109","author":"O Panes","year":"2007","unstructured":"Panes O, Matus V, Saez CG, Quiroga T, Pereira J, Mezzano D. Human platelets synthesize and express functional tissue factor. Blood. 2007;109(12):5242\u201350.","journal-title":"Blood"},{"issue":"4","key":"688_CR12","first-page":"751","volume":"110","author":"W Jy","year":"2013","unstructured":"Jy W, Johansen ME, Bidot C Jr., Horstman LL, Ahn YS. Red cell-derived microparticles (RMP) as haemostatic agent. Thromb Haemost. 2013;110(4):751\u201360.","journal-title":"Thromb Haemost"},{"issue":"1","key":"688_CR13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/vox.12014","volume":"105","author":"Y Gao","year":"2013","unstructured":"Gao Y, Lv L, Liu S, Ma G, Su Y. Elevated levels of thrombin-generating microparticles in stored red blood cells. Vox Sang. 2013;105(1):11\u20137.","journal-title":"Vox Sang"},{"issue":"8","key":"688_CR14","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1111\/trf.12008","volume":"53","author":"O Rubin","year":"2013","unstructured":"Rubin O, Delobel J, Prudent M, Lion N, Kohl K, Tucker EI, et al. Red blood cell-derived microparticles isolated from blood units initiate and propagate thrombin generation. Transfusion. 2013;53(8):1744\u201354.","journal-title":"Transfusion"},{"key":"688_CR15","doi-asserted-by":"crossref","unstructured":"Rehni AK, Cho S, Zhang Z, Khushal P, Raval AP, Koch S et al. Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats. Int J Mol Sci. 2022;23(23).","DOI":"10.3390\/ijms232315167"},{"issue":"4","key":"688_CR16","doi-asserted-by":"publisher","first-page":"e152","DOI":"10.1161\/STROKEAHA.122.042152","volume":"54","author":"AK Rehni","year":"2023","unstructured":"Rehni AK, Cho S, Navarro Quero H, Zhang Z, Dong C, Zhao W, et al. Red Blood Cell Microparticles Limit Hemorrhage Following Intracerebral Hemorrhage in Spontaneously Hypertensive Rats. Stroke. 2023;54(4):e152\u20134.","journal-title":"Stroke"},{"issue":"4","key":"688_CR17","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nm0410-347","volume":"16","author":"Mechanism matters","year":"2010","unstructured":"Mechanism matters. Nat Med. 2010;16(4):347.","journal-title":"Nat Med"},{"issue":"2","key":"688_CR18","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1053\/j.seminhematol.2010.01.011","volume":"47","author":"GJ Weiner","year":"2010","unstructured":"Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115\u201323.","journal-title":"Semin Hematol"},{"key":"688_CR19","unstructured":"Shaydakov ME, Sigmon DF, Blebea J. Thromboelastography Treasure Island (FL): StatPearls Publishing; 2023 [updated April 10, 2023. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30725746"},{"issue":"10","key":"688_CR20","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1182\/blood.2019001643","volume":"135","author":"DF Noubouossie","year":"2020","unstructured":"Noubouossie DF, Henderson MW, Mooberry M, Ilich A, Ellsworth P, Piegore M, et al. Red blood cell microvesicles activate the contact system, leading to factor IX activation via 2 independent pathways. Blood. 2020;135(10):755\u201365.","journal-title":"Blood"},{"issue":"4","key":"688_CR21","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1002\/JLB.3A0821-451RR","volume":"112","author":"Y Gao","year":"2022","unstructured":"Gao Y, Jin H, Tan H, Cai X, Sun Y. Erythrocyte-derived extracellular vesicles aggravate inflammation by promoting the proinflammatory macrophage phenotype through TLR4-MyD88-NF-kappaB-MAPK pathway. J Leukoc Biol. 2022;112(4):693\u2013706.","journal-title":"J Leukoc Biol"},{"issue":"2","key":"688_CR22","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.transci.2015.10.012","volume":"53","author":"M Prudent","year":"2015","unstructured":"Prudent M, Crettaz D, Delobel J, Seghatchian J, Tissot JD, Lion N. Differences between calcium-stimulated and storage-induced erythrocyte-derived microvesicles. Transfus Apher Sci. 2015;53(2):153\u20138.","journal-title":"Transfus Apher Sci"},{"issue":"22","key":"688_CR23","first-page":"3770","volume":"128","author":"S Cho","year":"2016","unstructured":"Cho S, Jy W, Horstman LL, Bidot C Jr, Yaniz M, Ahn YS. Functional Heterogeneity of Red Cell-Derived Microparticles from Different Sources: Calcium Ionophore Vs. Storage Vs Extrusion Blood. 2016;128(22):3770.","journal-title":"Storage Vs Extrusion Blood"},{"issue":"11","key":"688_CR24","doi-asserted-by":"publisher","first-page":"2701","DOI":"10.1111\/trf.14268","volume":"57","author":"D Fischer","year":"2017","unstructured":"Fischer D, Bussow J, Meybohm P, Weber CF, Zacharowski K, Urbschat A, et al. Microparticles from stored red blood cells enhance procoagulant and proinflammatory activity. Transfusion. 2017;57(11):2701\u201311.","journal-title":"Transfusion"},{"issue":"4","key":"688_CR25","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1016\/j.bbrc.2016.05.008","volume":"474","author":"M Aleshnick","year":"2016","unstructured":"Aleshnick M, Foley JH, Keating FK, Butenas S. Procoagulant activity in stored units of red blood cells. Biochem Biophys Res Commun. 2016;474(4):680\u20135.","journal-title":"Biochem Biophys Res Commun"},{"issue":"8","key":"688_CR26","doi-asserted-by":"publisher","first-page":"e104200","DOI":"10.1371\/journal.pone.0104200","volume":"9","author":"RL Koshiar","year":"2014","unstructured":"Koshiar RL, Somajo S, Norstrom E, Dahlback B. Erythrocyte-derived microparticles supporting activated protein C-mediated regulation of blood coagulation. PLoS ONE. 2014;9(8):e104200.","journal-title":"PLoS ONE"},{"issue":"6","key":"688_CR27","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1097\/00001721-200209000-00003","volume":"13","author":"H Iwata","year":"2002","unstructured":"Iwata H, Kaibara M. Activation of factor IX by erythrocyte membranes causes intrinsic coagulation. Blood Coagul Fibrinolysis. 2002;13(6):489\u201396.","journal-title":"Blood Coagul Fibrinolysis"},{"issue":"3","key":"688_CR28","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1055\/s-0035-1564835","volume":"42","author":"T Gremmel","year":"2016","unstructured":"Gremmel T, Frelinger AL 3rd, Michelson AD. Platelet Physiology. Semin Thromb Hemost. 2016;42(3):191\u2013204.","journal-title":"Semin Thromb Hemost"},{"issue":"5","key":"688_CR29","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/0049-3848(92)90012-Y","volume":"67","author":"PV Vrzheshch","year":"1992","unstructured":"Vrzheshch PV, Tatarintsev AV, Orlova EV, Yershov DE, Varfolomeyev SD. Kinetics of merthiolate-induced aggregation of human platelets. Thromb Res. 1992;67(5):505\u201316.","journal-title":"Thromb Res"}],"container-title":["Pharmacological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43440-024-00688-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43440-024-00688-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43440-024-00688-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T13:01:58Z","timestamp":1742216518000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43440-024-00688-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,8]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["688"],"URL":"https:\/\/doi.org\/10.1007\/s43440-024-00688-0","relation":{},"ISSN":["1734-1140","2299-5684"],"issn-type":[{"type":"print","value":"1734-1140"},{"type":"electronic","value":"2299-5684"}],"subject":[],"published":{"date-parts":[[2025,1,8]]},"assertion":[{"value":"4 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"SC, AKR, WJ, and KRD received a salary from the University of Miami. RxMP Therapeutics provided the testing material for the study. WJ and the University of Miami have partial ownership in RxMP Therapeutics and may receive royalties for future commercialization of the intellectual property used in this study. WJ is the inventor of two US patents related to red cell microparticles. WJ received grant support from RxMP Therapeutics. WJ is serving as a scientific advisor\/consultant to RxMP Therapeutics.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}