Blood accessibility to fibrin in venous thrombosis is thrombus age-dependent and predicts fibrinolytic efficacy: An in vivo fibrin molecular imaging study

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dc.contributor.authorStein-Merlob, Ashley
dc.contributor.authorKessinger, Chase
dc.contributor.authorErdem, Sultan Sibel
dc.contributor.authorZelada, Henry
dc.contributor.authorHilderbrand, Scott
dc.contributor.authorLin, Charles
dc.contributor.authorJaff, Michael
dc.contributor.authorJaff, Michael
dc.contributor.authorReed, Guy
dc.contributor.authorHenke, Peter
dc.contributor.authorMcCarthy, Jason
dc.contributor.authorJaffer, Farouc Amin
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:36:43Z
dc.date.available10.07.201910:49:14
dc.date.available2019-07-10T19:36:43Z
dc.date.issued2015
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyokimya Ana Bilim Dalı
dc.description.abstractFibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.
dc.description.sponsorshipNational Institutes of Health: R01HL108229en_US
dc.description.sponsorshipNational Institutes of Health: R01HL122238en_US
dc.description.sponsorshipNational Institutes of Health: R42HL092750en_US
dc.description.sponsorshipNational Institutes of Health: R44HL092750en_US
dc.identifier.citationStein-Merlob, A., Kessinger, C., Erdem, S. S., Zelada, H., Hilderbrand, S., Lin, C. ... Jaffer, F. A. (2015). Blood accessibility to fibrin in venous thrombosis is thrombus age-dependent and predicts fibrinolytic efficacy: An in vivo fibrin molecular imaging study. Theranostics, 5(12), 1317-1327. https://dx.doi.org/10.7150/thno.12494
dc.identifier.doi10.7150/thno.12494
dc.identifier.endpage1327
dc.identifier.issn1838-7640
dc.identifier.issue12
dc.identifier.scopusqualityQ1
dc.identifier.startpage1317
dc.identifier.urihttps://hdl.handle.net/20.500.12511/1240
dc.identifier.urihttps://dx.doi.org/10.7150/thno.12494
dc.identifier.volume5
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherIvyspring International Publisher
dc.relation.ispartofTheranosticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectFibrin
dc.subjectFibrinolysis
dc.subjectMolecular Imaging
dc.subjectPulmonary Embolism
dc.subjectVenous Thrombosis
dc.titleBlood accessibility to fibrin in venous thrombosis is thrombus age-dependent and predicts fibrinolytic efficacy: An in vivo fibrin molecular imaging study
dc.typeArticle

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