| The spatial dynamics of fibrin clot dissolution catalyzed by erythrocyte-bound vs. free fibrinolytics. | |
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MedLine Citation:
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PMID: 20149071 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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SUMMARY BACKGROUND: Coupling fibrinolytic plasminogen activators to red blood cells (RBCs) has been proposed as an effective, yet safe method of thromboprophylaxis, because of increased circulation lifetime and reduced propensity to induce hemorrhage by selectivity for nascent thrombi rather than pre-formed hemostatic clots. OBJECTIVES AND METHODS: We used confocal microscopy of fluorescently labeled fibrin and erythrocytes in plasma-derived clots to study the spatial dynamics of lysis catalyzed by RBC-coupled vs. free plasminogen activators (RBC-PA vs. PA). RESULTS: Clot lysis catalyzed by free PA progressed gradually and uniformly. In contrast, distinct holes formed surrounding RBC-PA while the rest of the clot remained intact until these holes enlarged sufficiently to merge, causing sudden clot dissolution. Compared with naïve RBCs within clots lysed by free PA, RBC-PA moved faster inside the fibrin network prior to clot dissolution, providing a potential mechanism for spatial propagation of RBC-PA induced lysis. We also showed the focal nature of fibrinolysis by RBC-PA as dense loading of PA onto RBCs initiates more efficient lysis than equal amounts of PA spread sparsely over more RBCs. In an in vitro model of clots exposed to buffer flow, incorporated RBC-PA increased permeability and formed channels eventually triggering clot dissolution, whereas clots containing free PA remained intact. CONCLUSIONS: Clot lysis by RBC-PA begins focally, has a longer lag phase when measured by residual mass than homogeneous lysis by PA, is propagated by RBC-PA motility and provides more effective clot reperfusion than free PA, making RBC-PA attractive for short-term thromboprophylaxis. |
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Authors:
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K C Gersh; S Zaitsev; V Muzykantov; D B Cines; J W Weisel |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-09 |
Journal Detail:
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Title: Journal of thrombosis and haemostasis : JTH Volume: 8 ISSN: 1538-7836 ISO Abbreviation: J. Thromb. Haemost. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-06-22 Completed Date: 2010-10-21 Revised Date: 2012-05-10 |
Medline Journal Info:
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Nlm Unique ID: 101170508 Medline TA: J Thromb Haemost Country: England |
Other Details:
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Languages: eng Pagination: 1066-74 Citation Subset: IM |
Affiliation:
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Department of Cell & Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6058, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biocatalysis Erythrocytes / drug effects* Fibrin* Fibrinolytic Agents / pharmacology* Humans Mice Microscopy, Confocal Solubility |
| Grant Support | |
ID/Acronym/Agency:
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5-T32-HL007971-06/HL/NHLBI NIH HHS; HD57355/HD/NICHD NIH HHS; HL030954/HL/NHLBI NIH HHS; HL076406/HL/NHLBI NIH HHS; HL82545/HL/NHLBI NIH HHS; R01 HL030954-24/HL/NHLBI NIH HHS; R01 HL090697/HL/NHLBI NIH HHS; R01 HL090697-04/HL/NHLBI NIH HHS; R01 HL090774-03/HL/NHLBI NIH HHS; R01-HL090697/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fibrinolytic Agents; 9001-31-4/Fibrin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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