{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T20:46:10Z","timestamp":1788468370449,"version":"build-2803163510"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Heparin-induced thrombocytopenia (HIT) is a major concern for all individuals that undergo cardiac bypass surgeries or require prolonged heparin exposure. HIT is a life- and limb-threatening adverse drug reaction with an immune response following the formation of ultra-large immune complexes that drive platelet activation through the receptor Fc\u03b3RIIA. Thrombotic events remain high following the standard of care treatment with anticoagulants, while increasing risk of bleeding complications. This study sought to investigate a novel approach to treatment of HIT. Recent reports demonstrate increased procoagulant activity in HIT; however, these reports required analysis ex vivo, and relevance in vivo remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Using human and mouse model systems, we investigated the cooperativity of PARs (protease-activated receptors) and Fc\u03b3RIIA in HIT. We challenged humanized Fc\u03b3RIIA transgenic mice with or without endogenous mouse Par4 (denoted as IIA-Par4\n              <jats:sup>+\/+<\/jats:sup>\n              or IIA-Par4\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>\/\u2212<\/jats:sup>\n              , respectively) with a well-established model IgG immune complex (anti [\u03b1]-CD9). Furthermore, we assessed the procoagulant phenotype and efficacy to treat HIT utilizing inhibitor of 12-LOX (12[S]-lipoxygenase), VLX-1005, previously reported to decrease platelet activation downstream of Fc\u03b3RIIA and PAR4, using the triple allele HIT mouse model.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              IIA-Par4\n              <jats:sup>+\/+<\/jats:sup>\n              mice given \u03b1CD9 were severely thrombocytopenic, with extensive platelet-fibrin deposition in the lung. In contrast, IIA-Par4\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice had negligible thrombocytopenia or pulmonary platelet-fibrin thrombi. We observed that pharmacological inhibition of 12-LOX resulted in a significant reduction in both platelet procoagulant phenotype ex vivo, and thrombocytopenia and thrombosis in our humanized mouse model of HIT in vivo.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These data demonstrate for the first time the need for dual platelet receptor (PAR and Fc\u03b3RIIA) stimulation for fibrin formation in HIT in vivo. These results extend our understanding of HIT pathophysiology and provide a scientific rationale for targeting the procoagulant phenotype as a possible therapeutic strategy in HIT.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.123.319434","type":"journal-article","created":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T10:50:00Z","timestamp":1687431000000},"page":"1808-1817","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition"],"prefix":"10.1161","volume":"43","author":[{"given":"Stephanie A.","family":"Renna","sequence":"first","affiliation":[{"name":"The Cardeza Foundation for Hematologic Research, Center for Hemostasis, Thrombosis and Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.A.R., X.Z., P.M., J.V.M., S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-6248","authenticated-orcid":true,"given":"Xuefei","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Cardeza Foundation for Hematologic Research, Center for Hemostasis, Thrombosis and Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.A.R., X.Z., P.M., J.V.M., S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya P.","family":"Kunapuli","sequence":"additional","affiliation":[{"name":"Sol Sherry Thrombosis Center and the Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5486-8695","authenticated-orcid":true,"given":"Peisong","family":"Ma","sequence":"additional","affiliation":[{"name":"The Cardeza Foundation for Hematologic Research, Center for Hemostasis, Thrombosis and Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.A.R., X.Z., P.M., J.V.M., S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5100-1933","authenticated-orcid":true,"given":"Michael","family":"Holinstat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor (M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"Boxer","sequence":"additional","affiliation":[{"name":"Veralox Therapeutics, Frederick, MD (M.B.B., D.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Maloney","sequence":"additional","affiliation":[{"name":"Veralox Therapeutics, Frederick, MD (M.B.B., D.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-5259","authenticated-orcid":true,"given":"James V.","family":"Michael","sequence":"additional","affiliation":[{"name":"The Cardeza Foundation for Hematologic Research, Center for Hemostasis, Thrombosis and Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.A.R., X.Z., P.M., J.V.M., S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-8560","authenticated-orcid":true,"given":"Steven E.","family":"McKenzie","sequence":"additional","affiliation":[{"name":"The Cardeza Foundation for Hematologic Research, Center for Hemostasis, Thrombosis and Vascular Biology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.A.R., X.Z., P.M., J.V.M., S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.1.182"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.01753.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.11059"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022007336"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012938"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10123386"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24759"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2021.3444"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215213"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.11.3691.bloodjournal84113691"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198703053161004"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15650"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7933.2003.00617.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-575878"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309868"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000132281.78948.65"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.5.1533.005k01_1533_1540"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09160-7"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.162.7.4311"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/35092573"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02201.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v98.8.2442"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15669"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-03-274969"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.13.4254"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-342352"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1990.tb02568.x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-02-631135"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1067\/mlc.2001.120049"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15049"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022007007"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021005453"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720553115"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.033527"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15510"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-539262"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017015552"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.b.10062"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-05-2010"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.282275"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2004.00783.x"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.078428"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aan2787"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.315154"},{"key":"e_1_3_3_46_2","unstructured":"Phase I Study of VLX-1005 in Healthy Subjects. ClinicalTrials.gov identifier: NCT04783545. Updated April 28 2022. Accessed March 20 2023. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT04783545"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99445"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009487"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615969"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003093"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1592\/phco.26.4.461"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e3181926928"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40256-021-00519-0"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medcli.2021.05.020"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2017.03.050"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012479"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mbc.0000172694.85233.a8"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.123.319434","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T18:01:27Z","timestamp":1747850487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.123.319434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10]]},"references-count":56,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1161\/ATVBAHA.123.319434"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.123.319434","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10]]},"assertion":[{"value":"2023-04-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}