{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:17:38Z","timestamp":1788790658962,"version":"build-2803163510"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Heparin-induced thrombocytopenia (HIT) is now recognized as one subset of a broader group of disorders: anti-platelet factor 4 (anti-PF4) disorders. This review provides an updated framework for anti-PF4 immunothrombosis without proximate heparin exposure\u2014a clinical syndrome with phenotypic and laboratory features resembling classic HIT but with no recent heparin use (no heparin exposure within 14 days before onset). The core characteristics are a \u226550% platelet count decrease from baseline or an absolute platelet count &amp;lt;100\u00d710\n                    <jats:sup>9<\/jats:sup>\n                    \/L, often associated with elevated arterial or venous thrombosis risk. Historically, these heparin-independent syndromes encompass spontaneous HIT-like syndrome, vaccine-induced immune thrombotic thrombocytopenia (VITT\/TTS), and autoimmune HIT (aHIT)\u2014notably, nearly all aHIT cases are initiated by prior heparin exposure before progressing to sustained heparin-independent platelet-activating antibodies. This review exclusively focuses on patients with no heparin exposure within 14 days of symptom onset, including: (1) patients with prior heparin exposure &amp;gt;14 days ago whose antibodies have evolved heparin-independent pathogenicity (aHIT), (2) patients with truly spontaneous HIT-like syndrome without any prior heparin, and (3) VITT. For aHIT specifically, prior heparin exposure is the initiating event in &amp;gt;95% of cases, but the antibodies become heparin-independent over time; thus these patients fall within our 14-day window of interest when presenting with delayed-onset thrombocytopenia beyond the acute heparin exposure phase. Pathogenesis centers on PF4-driven abnormal immune responses: PF4 forms complexes with polyanions (von Willebrand factor [VWF], pathogen surface molecules, etc.), inducing pathogenic antibodies that activate platelets via Fc\u03b3RIIA, creating a self-amplifying \u201cimmune activation\u2013thrombosis\u201d cycle. Diagnosis requires combined clinical, laboratory, and imaging evaluation to distinguish from other thrombocytopenia-with-thrombosis disorders. Current treatment includes non-heparin anticoagulation plus high-dose IVIG for heparin-independent forms. Future research should validate diagnostic criteria, biomarkers, and targeted therapies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1828051","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:20:30Z","timestamp":1788787230000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The hidden threat: understanding anti-PF4 disorders without proximate heparin exposure"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhiyan","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Trial Research Center, Beijing Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Cui","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/17474086.2021.1905512","article-title":"Heparin-induced thrombocytopenia: pathophysiology, diagnosis and 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