{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:13Z","timestamp":1790189953931,"version":"4.1.0"},"reference-count":58,"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":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder caused by antibodies to PF4 (platelet factor 4)-heparin complexes that activate Fc\u03b3RIIA (Fc gamma receptor IIA). Existing HIT treatments inadequately suppress antibody-mediated cellular activation, leading to suboptimal thrombosis protection. Fc\u03b3RIIA antibodies prevent HIT IgG (immunoglobulin G)\u2013mediated cellular activation in vitro and thrombus formation in murine models, making them a potential therapeutic strategy for HIT. However, a clinical trial of an Fc\u03b3RIIA antibody was terminated due to tolerability issues, emphasizing the need for safer alternatives. We hypothesized that a monovalent anti-Fc\u03b3RIIA antibody could prevent HIT-associated thrombosis without eliciting adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We engineered a monovalent, scFv (single-chain variable fragment; sc9600) targeting Fc\u03b3RIIA and evaluated its activity using complementary in vitro and in vivo approaches. In vitro, studies in human platelets and whole blood assessed receptor binding, selectivity, and inhibition of HIT immune complex\u2013mediated cellular activation. To extend these findings, in vivo efficacy and safety were evaluated in mice expressing human Fc receptors, including models of immune thrombocytopenia and thrombosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      sc9600 bound Fc\u03b3RIIA on human platelets with nanomolar affinity, rapidly achieved surface occupancy, and did not promote Fc\u03b3RIIA internalization. sc9600 potently inhibited IgG-dependent platelet activation, including patient with HIT plasma, while preserving platelet responses to collagen and thrombin. Compared with clinically available drugs (Bruton tyrosine kinase\/spleen tyrosine kinase inhibitors and P2Y\n                      <jats:sub>12<\/jats:sub>\n                      antagonists), sc9600 showed greater selectivity for IgG-driven platelet activation with no impact on in vitro thrombus formation. In whole blood, sc9600 reduced HIT-immune complex\u2013mediated leukocyte activation, including monocyte tissue factor expression and neutrophil extracellular trap formation, without impairing phagocytosis. In vivo, sc9600 conjugated to mouse serum albumin was well tolerated, did not prolong bleeding, and protected against Fc\u03b3RIIA-dependent immune thrombocytopenia and thrombosis, whereas full-length 9600 retained residual biologic activity associated with platelet clearance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings suggest that single-chain or effector-null anti-Fc\u03b3RIIA blocking antibodies are a promising therapeutic strategy to treat HIT while minimally affecting hemostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324890","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:00:17Z","timestamp":1787216417000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Monovalent Anti-Fc\u03b3RIIA Antibody Blocks Immune-Mediated Thrombocytopenia and Thrombosis With Minimal Adverse Side Effects in Mice"],"prefix":"10.1161","volume":"46","author":[{"given":"Hem K.","family":"Tamang","sequence":"first","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Hospital Medical Center, OH (H.K.T., J.Y., B.E.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Yueng","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Hospital Medical Center, OH (H.K.T., J.Y., B.E.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Chyou","sequence":"additional","affiliation":[{"name":"Department of Inflammation, Amgen Research, Amgen, Inc, Rockville, MD (S.C., T.I.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-9081","authenticated-orcid":true,"given":"Brian R.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Platelet &amp; Neutrophil Immunology Laboratory, Blood Research Institute, Versiti, Milwaukee, WI (B.R.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-389X","authenticated-orcid":true,"given":"Donald R.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (D.R.L.), University of Cincinnati College of Medicine, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7745-6178","authenticated-orcid":true,"given":"Tamer I.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Department of Inflammation, Amgen Research, Amgen, Inc, Rockville, MD (S.C., T.I.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1701-4041","authenticated-orcid":true,"given":"Benjamin E.","family":"Tourdot","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Hospital Medical Center, OH (H.K.T., J.Y., B.E.T.)."},{"name":"Department of Pediatrics (B.E.T.), University of Cincinnati College of Medicine, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/1358863X19898253"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.315445"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2020.04.014"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09160-7"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99445"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","unstructured":"Kelton JG Sheridan D Santos A Smith J Steeves K Smith C Brown C Murphy WG. 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