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FRA Cre., United Kingdom; email: simonwilson3@nhs.net \n Chemicals/CAS: bivalirudin, 128270-60-0, 1191386-50-1; fibrin, 9001-31-4; antithrombin, 9000-94-6; Antithrombins; Biomarkers; bivalirudin; Fibrin; Hirudins; P-Selectin; Peptide Fragments; Recombinant Proteins; SELP protein, human \n Tradenames: jnj 9375", "unhandledTickets" : 0, "deleted" : false, "lastRefresh" : "2022-05-11T06:42:54.188+0000", "lastModified" : "2019-09-06T16:06:40.857+0000", "created" : "2019-09-06T16:06:22.333+0000", "creator" : { "otype" : "Admin", "mtid" : 10067746, "link" : "/api/admin/10067746", "label" : "Király Magdolna (DE admin 4)", "familyName" : "Király", "givenName" : "Magdolna", "published" : false, "snippet" : true }, "adminApproved" : "2019-09-06T16:06:40.877+0000", "adminApprover" : { "otype" : "Admin", "mtid" : 10067746, "link" : "/api/admin/10067746", "label" : "Király Magdolna (DE admin 4)", "familyName" : "Király", "givenName" : "Magdolna", "published" : false, "snippet" : true }, "core" : 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"idValue" : "85061962279", "realUrl" : "http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85061962279", "published" : false, "snippet" : true } ], "journal" : { "otype" : "Journal", "mtid" : 926, "link" : "/api/journal/926", "label" : "CARDIOVASCULAR RESEARCH 0008-6363 1755-3245", "pIssn" : "0008-6363", "eIssn" : "1755-3245", "reviewType" : "REVIEWED", "noIF" : false, "sciIndexed" : true, "scopusIndexed" : true, "lang" : "FOREIGN", "hungarian" : false, "published" : true, "oldId" : 926, "snippet" : true }, "volume" : "115", "issue" : "3", "firstPage" : "669", "lastPage" : "677", "firstPageOrInternalIdForSort" : "669", "pageLength" : 9, "publishedYear" : 2019, "abstractText" : "Aims JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis.Methods and results Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 mu g/mL), bivalirudin (6 mu g/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively. JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P <0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 mu g/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P= 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both).Conclusion Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. 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