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While platelets are central to thrombogenesis and inflammation, the molecular mechanisms of crosstalk between the 2 remain elusive. High-mobility group box 1 (HMGB1) regulates inflammation and stimulates platelet activation through Toll-like receptor 4. However, it remains unclear whether HMGB1 modulates other thrombotic agonists to regulate platelet activation. Herein, using human platelets, we demonstrate that HMGB1 significantly enhanced ADP-mediated platelet activation. Furthermore, inhibition of the purinergic receptor P2Y\n                    <jats:sub>12<\/jats:sub>\n                    attenuated HMGB1-dependent platelet activation. Mechanistically, we show that HMGB1 stimulated ADP secretion, while concomitantly increasing P2Y\n                    <jats:sub>12<\/jats:sub>\n                    levels at the platelet membrane. We show that in SCD patients, increased plasma HMGB1 levels were associated with heightened platelet activation and surface P2Y\n                    <jats:sub>12<\/jats:sub>\n                    expression. Treatment of healthy platelets with plasma from SCD patients enhanced platelet activation and surface P2Y\n                    <jats:sub>12<\/jats:sub>\n                    , and increased sensitivity to ADP-mediated activation, and these effects were linked to plasma HMGB1. We conclude that HMGB1-mediated platelet activation involves ADP-dependent P2Y\n                    <jats:sub>12<\/jats:sub>\n                    signaling, and HMGB1 primes platelets for ADP signaling. This complementary agonism between ADP and HMGB1 furthers the understanding of thromboinflammatory signaling in conditions such as SCD, and provides insight for therapeutic P2Y\n                    <jats:sub>12<\/jats:sub>\n                    inhibition.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.174575","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:40:43Z","timestamp":1779140443000},"source":"Crossref","is-referenced-by-count":5,"title":["High-mobility group box 1 increases platelet surface P2Y12 and platelet activation in sickle cell disease"],"prefix":"10.1172","volume":"9","author":[{"given":"Deirdre","family":"Nolfi-Donegan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Hematology\/Oncology, Children\u2019s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA."},{"name":"University of Pittsburgh School of Medicine,"},{"name":"Pittsburgh Heart, Lung, Blood Vascular Medicine 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