{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T08:15:37Z","timestamp":1758442537941,"version":"3.44.0"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"Supplement_2","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100021538","name":"DARPA BTO","doi-asserted-by":"publisher","award":["HR0011-16-C-0067"],"award-info":[{"award-number":["HR0011-16-C-0067"]}],"id":[{"id":"10.13039\/100021538","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Army SBIR","award":["#W81XWH-20-C-0003"],"award-info":[{"award-number":["#W81XWH-20-C-0003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Noncompressible hemorrhage accounts for up to 90% of potentially survivable combat deaths. Hypothermia, acidosis, and resuscitative hemodilution (\u201cthe lethal triad\u201d) contribute significantly to coagulation dysfunction after trauma and are sequelae of trauma-induced coagulopathy. The polyphosphate (polyP)-silica nanoparticle (SNP) (polyP-SNP) complex is a synthetic biomimetic of platelet-length polyP. It is under development as a prohemostatic therapeutic for noncompressible hemorrhage. In this study, we assessed the polyP-SNP complex\u2019s ability to restore hemostasis under conditions mimicking the lethal triad in human-pooled normal plasma (hPNP).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>Lethal triad conditions were simulated using hPNP by dilution with isotonic saline (hemodilution: 100-10% hPNP), chilling (hypothermia: 37-30\u2009\u00b0C), or adding lactic acid (metabolic acidosis: 0-10\u2009mM). Thrombin generation assay was performed in a 96-well fluorogenic assay format. The reaction was initiated by adding CaCl2\/phospholipid to citrated hPNP with equal concentrations of the polyP-SNP complex or SNP (0.25\u2009mg\/mL). Thromboelastography (TEG) was performed using TEG5000 analyzer. The reactions were initiated by adding CaCl2 to hPNP with equal concentrations of the polyP-SNP complex or SNP. Lipidated tissue factor (0.5\u2009ng\/mL) was used as positive control for both assays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The polyP-SNP complex improved thrombin generation at all diluted hPNP levels with Time-to-Peak \u22642\u2009min at \u226533% hPNP. Lipidated tissue factor -control failed to generate thrombin at \u226433% PNP. PolyP-SNP improved thrombin generation assay Time-to-Peak by 10\u00d7 under hypothermic conditions (32\u2009\u00b0C) and 50% under conditions of severe acidosis, respectively. Across all conditions, polyP-SNP also improved TEG parameters.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The results demonstrate the potential of the polyP-SNP complex as a prohemostatic therapeutic for noncompressible hemorrhage, including under lethal triad conditions.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/milmed\/usaf176","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T07:43:35Z","timestamp":1744962215000},"page":"297-303","source":"Crossref","is-referenced-by-count":0,"title":["A Synthetic Short-Chain Polyphosphate Complexed With Silica Nanoparticle, Corrects Coagulopathy Under Hemodilute, Hypothermic, or Acidotic Conditions as Assessed by <i>In Vitro<\/i> Coagulation Assays"],"prefix":"10.1093","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-9596","authenticated-orcid":false,"given":"Damien","family":"Kudela","sequence":"first","affiliation":[{"name":"Cayuga Biotech Inc. , New York, NY 10018,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genmin","family":"Lu","sequence":"additional","affiliation":[{"name":"Cayuga Biotech Inc. , New York, NY 10018,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B S","family":"Andrea Ashford-Hicks","sequence":"additional","affiliation":[{"name":"Cayuga Biotech Inc. , New York, NY 10018,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"issue":"4","key":"2025092002194250000_R1","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1056\/NEJMra1705649","article-title":"Hemorrhagic shock","volume":"378","author":"Cannon","year":"2018","journal-title":"N Engl J Med"},{"issue":"S2","key":"2025092002194250000_R2","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1111\/trf.15161","article-title":"Outcomes of traumatic hemorrhagic shock and the epidemiology of preventable death from injury","volume":"59","author":"Eastridge","year":"2019","journal-title":"Transfusion"},{"issue":"5","key":"2025092002194250000_R3","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1097\/00005373-199705000-00016","article-title":"Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited","volume":"42","author":"Cosgriff","year":"1997","journal-title":"J Trauma"},{"article-title":"Hemorrhagic Shock","volume-title":"StatPearls","author":"Hooper","key":"2025092002194250000_R4"},{"issue":"3","key":"2025092002194250000_R5","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1111\/j.1537-2995.2009.02458.x","article-title":"Hemostatic resuscitation for massive bleeding: the paradigm of plasma and platelets-a review of the current literature","volume":"50","author":"Johansson","year":"2010","journal-title":"Transfusion"},{"issue":"5","key":"2025092002194250000_R6","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1097\/ALN.0b013e3181f22b5a","article-title":"Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution","volume":"113","author":"Bolliger","year":"2010","journal-title":"Anesthesiology"},{"issue":"1","key":"2025092002194250000_R7","doi-asserted-by":"publisher","DOI":"10.1186\/s12959-014-0031-z","article-title":"Hypothermia: effects on platelet function and hemostasis","volume":"12","author":"Van Poucke","year":"2014","journal-title":"Thromb J"},{"issue":"6","key":"2025092002194250000_R8","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1097\/MBC.0b013e32832dc327","article-title":"Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser","volume":"20","author":"Ramaker","year":"2009","journal-title":"Blood Coagul Fibrinol"},{"issue":"5","key":"2025092002194250000_R9","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1097\/01.TA.0000156246.53383.9F","article-title":"Independent contributions of hypothermia and acidosis to coagulopathy in swine","volume":"58","author":"Martini","year":"2005","journal-title":"J Trauma-Injury Infect Crit Care"},{"issue":"5","key":"2025092002194250000_R10","first-page":"1271","article-title":"Coagulation changes to systemic acidosis and bicarbonate correction in swine","volume":"71","author":"Darlington","year":"2011","journal-title":"J Trauma"},{"issue":"13","key":"2025092002194250000_R11","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1002\/anie.201409639","article-title":"Clotting activity of polyphosphate-functionalized silica nanoparticles","volume":"54","author":"Kudela","year":"2015","journal-title":"Angew Chem Int Ed Engl"},{"issue":"20","key":"2025092002194250000_R12","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1182\/blood-2010-01-266791","article-title":"Polyphosphate exerts differential effects on blood clotting, depending on polymer size","volume":"116","author":"Smith","year":"2010","journal-title":"Blood"},{"issue":"10","key":"2025092002194250000_R13","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1111\/j.1538-7836.2008.03104.x","article-title":"Polyphosphate as a general procoagulant agent","volume":"6","author":"Smith","year":"2008","journal-title":"J Thromb Haemost"},{"issue":"S2","key":"2025092002194250000_R14","article-title":"A synthetic short-chain polyphosphate (polyP) complexed with silica nanoparticle (SNP), has pro-hemostatic activities as assessed by in vitro and ex vivo studies","volume":"8","author":"Kudela","year":"2024","journal-title":"Res Pract Thromb Haemostasis - Abstracts from the ISTH 2024 Congress"},{"key":"2025092002194250000_R15","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1172\/JCI105716","article-title":"The phospholipid requirement of tissue factor in blood coagulation","volume":"47","author":"Nemerson","year":"1968","journal-title":"J Clin Invest"},{"issue":"18","key":"2025092002194250000_R16","doi-asserted-by":"publisher","first-page":"4390","DOI":"10.1021\/cm071457b","article-title":"Controlling bioprocesses within organic surfaces: layered clay hemostatic agents","volume":"19","author":"Baker","year":"2007","journal-title":"Chem. 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