{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:49:16Z","timestamp":1792802956802,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Veterinary Academic Leadership Program from North Carolina State University","award":["254010-08502"],"award-info":[{"award-number":["254010-08502"]}],"id":[{"id":"https:\/\/ror.org\/04tj63d06","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Sepsis and systemic inflammatory response syndrome (SIRS) are major contributors to morbidity and mortality in dogs, with limited therapeutic advancements. A key factor in this disease progression is the excessive formation of neutrophil extracellular traps (NETs). This study aimed to evaluate the ability of non-anticoagulant heparin (NACH) and unfractionated heparin (UFH) to modulate NET formation and platelet\u2013leukocyte, platelet\u2013neutrophil interactions in an\n                      <jats:italic>in vitro<\/jats:italic>\n                      canine model of septic and aseptic inflammation. We hypothesized that NACH would be non-inferior to UFH in attenuating histone-mediated NET formation and platelet\u2013leukocyte, platelet\u2013neutrophil aggregate formations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Eleven healthy staff-owned dogs were enrolled after confirmation of normal physical examinations and complete blood counts. Whole blood was collected and incubated with either calf thymus histone (0.5\u202fmg\/mL) or heated-killed\n                      <jats:italic>E. coli<\/jats:italic>\n                      O111:B4 (1\u202f\u00d7\u202f10\n                      <jats:sup>6<\/jats:sup>\n                      ) to simulate SIRS and sepsis, respectively. Samples were then treated with increasing concentrations of UFH (0, 0.4, 4 and 40\u202fU\/mL) or NACH (0, 1, 5, 10\u202f\u03bcg\/mL). Platelet\u2013leukocyte and neutrophil\u2013platelet aggregates were identified via flow cytometry using fluorophore-conjugated antibodies against platelets (CD61), leukocytes (CD18), and canine neutrophils. NET formation was assessed by quantifying cell-free DNA and intracellular citrullinated histones H3 (citH3) by flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NACH at 10\u202f\u03bcg\/mL significantly reduced histone-induced platelet\u2013leukocyte (29.0%\u202f\u00b1\u202f22.5) and platelet\u2013neutrophil (22.7%\u202f\u00b1\u202f15.1) aggregates compared to vehicle controls (37.7%\u202f\u00b1\u202f23.7 and 31.8%\u202f\u00b1\u202f20.9;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.045). UFH did not significantly reduce histone-induced platelet\u2013leukocyte interactions but showed a dose-dependent reduction in\n                      <jats:italic>E. coli<\/jats:italic>\n                      -induced platelet\u2013leukocyte aggregates, with 40\u202fIU\/mL being the most effective (UFH 40\u202fU\/mL\u202f=\u202f13.65%, IQR: 9.0 to 24.05 vs. UFH 0\u202fU\/mL\u202f=\u202f18.10%, IQR: 12.68 to 36.18,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.047). Both NACH and UFH modulated neutrophil citH3 expression in\n                      <jats:italic>E. coli<\/jats:italic>\n                      model, but only high-dose NACH was able to module neutrophil extracellular trap formation in the histone mediated model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      NACH effectively reduces histone-induced leukocyte and neutrophil\u2013platelet aggregation, while UFH is more effective against\n                      <jats:italic>E. coli<\/jats:italic>\n                      -mediated responses. Both forms of heparin modulate NETs formation, highlighting their distinct stimulus-specific anti-inflammatory effects.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fvets.2026.1778453","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:39:46Z","timestamp":1776227986000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-anticoagulant heparin attenuates histone-mediated platelet\u2013leukocyte aggregation and neutrophil extracellular trap formation in a canine whole blood model"],"prefix":"10.3389","volume":"13","author":[{"given":"Maria A.","family":"Guzm\u00e1n","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University","place":["Raleigh, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lunden","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University","place":["Raleigh, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald H. L.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University","place":["Raleigh, NC, United States"]},{"name":"Feline Health Center, College of Veterinary Medicine, North Carolina State University","place":["Raleigh, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/vec.13359","article-title":"Defining sepsis in small animals","volume":"34","author":"Cortellini","year":"2024","journal-title":"J Vet Emerg Crit Care"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/vec.13293","article-title":"Evaluating the clinical utility of the systemic inflammatory response syndrome criteria in dogs and cats presenting to an emergency 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