Elevating local concentrations of GPIIb–IIIa antagonists counteracts platelet thrombus stability
Glycoprotein IIb–IIIa (GPIIb–IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus st...
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| Veröffentlicht in: | Journal of thrombosis and thrombolysis 2013-07, Vol.36 (1), p.31-41 |
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| creator | Speich, Henry E. Furman, Ronit R. Lands, Lindsey T. Moodie, Geoffrey D. Jennings, Lisa K. |
| description | Glycoprotein IIb–IIIa (GPIIb–IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus stability. Light transmission aggregometry was used to examine the effects of exposing human platelet aggregates to extremely high local levels of GPIIb–IIIa antagonists versus conventional therapeutic levels in vitro. Freshly-formed or aged platelet aggregates were subjected to GPIIb–IIIa antagonists (abciximab, eptifibatide) or direct thrombin inhibitor bivalirudin at concentrations simulating either conventional intravenous (IV) or LIC administration. The degree of antagonist-induced disaggregation was significantly higher using elevated (LIC) doses versus conventional (IV) doses (60.1 % vs. 7.4 % for abciximab, 41.6 % or 45.3 % vs. 17.6 % for eptifibatide,
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| doi_str_mv | 10.1007/s11239-012-0814-7 |
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p
< 0.01). Bivalirudin did not promote disaggregation. Microscopy confirmed noticeably smaller, more dispersed aggregates for antagonist LIC treatments. Dosing at LIC levels also induced more disaggregation than IV levels when aggregates were aged for 30 min prior to exposure. An in vitro perfusion model was used to simulate the fluid dynamics of IV or LIC administration of abciximab using a microporous local drug delivery balloon catheter such as the Atrium ClearWay™ RX. The perfusion model resulted in more rapid thrombus clearance with LIC dosing levels compared to IV. In summary, boosting the concentration of GPIIb–IIIa antagonists enhances dispersal of human platelet aggregates in vitro. These data provide a foundation for investigating increased local concentrations of GPIIb–IIIa antagonists in patients, as with LIC administration.</description><identifier>ISSN: 0929-5305</identifier><identifier>EISSN: 1573-742X</identifier><identifier>DOI: 10.1007/s11239-012-0814-7</identifier><identifier>PMID: 23073747</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Antibodies, Monoclonal - pharmacology ; Antithrombins - pharmacology ; Cardiology ; Coronary Vessels - metabolism ; Coronary Vessels - pathology ; Female ; Hematology ; Hirudins - pharmacology ; Humans ; Immunoglobulin Fab Fragments - pharmacology ; Male ; Medicine ; Medicine & Public Health ; Peptide Fragments - pharmacology ; Peptides - pharmacology ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors ; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism ; Recombinant Proteins - pharmacology ; Thrombosis - metabolism ; Thrombosis - pathology</subject><ispartof>Journal of thrombosis and thrombolysis, 2013-07, Vol.36 (1), p.31-41</ispartof><rights>The Author(s) 2012</rights><rights>Springer Science+Business Media New York 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-2e0fbdaa2dbda3221b0eb42103d394d748d0c2dc4b1b25e78eeacaafcbb0a5383</citedby><cites>FETCH-LOGICAL-c470t-2e0fbdaa2dbda3221b0eb42103d394d748d0c2dc4b1b25e78eeacaafcbb0a5383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11239-012-0814-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11239-012-0814-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23073747$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Speich, Henry E.</creatorcontrib><creatorcontrib>Furman, Ronit R.</creatorcontrib><creatorcontrib>Lands, Lindsey T.</creatorcontrib><creatorcontrib>Moodie, Geoffrey D.</creatorcontrib><creatorcontrib>Jennings, Lisa K.</creatorcontrib><title>Elevating local concentrations of GPIIb–IIIa antagonists counteracts platelet thrombus stability</title><title>Journal of thrombosis and thrombolysis</title><addtitle>J Thromb Thrombolysis</addtitle><addtitle>J Thromb Thrombolysis</addtitle><description>Glycoprotein IIb–IIIa (GPIIb–IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus stability. Light transmission aggregometry was used to examine the effects of exposing human platelet aggregates to extremely high local levels of GPIIb–IIIa antagonists versus conventional therapeutic levels in vitro. Freshly-formed or aged platelet aggregates were subjected to GPIIb–IIIa antagonists (abciximab, eptifibatide) or direct thrombin inhibitor bivalirudin at concentrations simulating either conventional intravenous (IV) or LIC administration. The degree of antagonist-induced disaggregation was significantly higher using elevated (LIC) doses versus conventional (IV) doses (60.1 % vs. 7.4 % for abciximab, 41.6 % or 45.3 % vs. 17.6 % for eptifibatide,
p
< 0.01). Bivalirudin did not promote disaggregation. Microscopy confirmed noticeably smaller, more dispersed aggregates for antagonist LIC treatments. Dosing at LIC levels also induced more disaggregation than IV levels when aggregates were aged for 30 min prior to exposure. An in vitro perfusion model was used to simulate the fluid dynamics of IV or LIC administration of abciximab using a microporous local drug delivery balloon catheter such as the Atrium ClearWay™ RX. The perfusion model resulted in more rapid thrombus clearance with LIC dosing levels compared to IV. In summary, boosting the concentration of GPIIb–IIIa antagonists enhances dispersal of human platelet aggregates in vitro. These data provide a foundation for investigating increased local concentrations of GPIIb–IIIa antagonists in patients, as with LIC administration.</description><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antithrombins - pharmacology</subject><subject>Cardiology</subject><subject>Coronary Vessels - metabolism</subject><subject>Coronary Vessels - pathology</subject><subject>Female</subject><subject>Hematology</subject><subject>Hirudins - pharmacology</subject><subject>Humans</subject><subject>Immunoglobulin Fab Fragments - pharmacology</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides - pharmacology</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Thrombosis - metabolism</subject><subject>Thrombosis - pathology</subject><issn>0929-5305</issn><issn>1573-742X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kc9qFTEUxoMo9lp9ADcy4MbN1JM_M5nZCFJqHSjoQsFdOMlkbqfkJtckU-jOd_ANfRJznbZUwU1OyPmdL-fjI-QlhRMKIN8mShnva6Csho6KWj4iG9pIXkvBvj0mG-hZXzccmiPyLKUrAOh7YE_JEeMguRRyQ_SZs9eYZ7-tXDDoKhO8sT7H8hZ8qsJUnX8eBv3rx89hGLBCn3Eb_JxyKujis41oyn3vMFtnc5UvY9jpJVUpo57dnG-ekycTumRf3NZj8vXD2ZfTj_XFp_Ph9P1FbYSEXDMLkx4R2VhOzhjVYLVgFPjIezFK0Y1g2GiEppo1VnbWokGcjNaADe_4MXm36u4XvbPj6sKpfZx3GG9UwFn93fHzpdqGa8XbjkEvisCbW4EYvi82ZbWbk7HOobdhSYryVnYdl7It6Ot_0KuwRF_s_aFEy0V7EKQrZWJIKdrpfhkK6pCgWhNUJUF1SFDJMvPqoYv7ibvICsBWIJWW39r44Ov_qv4G89uq1g</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Speich, Henry E.</creator><creator>Furman, Ronit R.</creator><creator>Lands, Lindsey T.</creator><creator>Moodie, Geoffrey D.</creator><creator>Jennings, Lisa K.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130701</creationdate><title>Elevating local concentrations of GPIIb–IIIa antagonists counteracts platelet thrombus stability</title><author>Speich, Henry E. ; Furman, Ronit R. ; Lands, Lindsey T. ; Moodie, Geoffrey D. ; Jennings, Lisa K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-2e0fbdaa2dbda3221b0eb42103d394d748d0c2dc4b1b25e78eeacaafcbb0a5383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antithrombins - pharmacology</topic><topic>Cardiology</topic><topic>Coronary Vessels - metabolism</topic><topic>Coronary Vessels - pathology</topic><topic>Female</topic><topic>Hematology</topic><topic>Hirudins - pharmacology</topic><topic>Humans</topic><topic>Immunoglobulin Fab Fragments - pharmacology</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides - pharmacology</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Thrombosis - metabolism</topic><topic>Thrombosis - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Speich, Henry E.</creatorcontrib><creatorcontrib>Furman, Ronit R.</creatorcontrib><creatorcontrib>Lands, Lindsey T.</creatorcontrib><creatorcontrib>Moodie, Geoffrey D.</creatorcontrib><creatorcontrib>Jennings, Lisa K.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of thrombosis and thrombolysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Speich, Henry E.</au><au>Furman, Ronit R.</au><au>Lands, Lindsey T.</au><au>Moodie, Geoffrey D.</au><au>Jennings, Lisa K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elevating local concentrations of GPIIb–IIIa antagonists counteracts platelet thrombus stability</atitle><jtitle>Journal of thrombosis and thrombolysis</jtitle><stitle>J Thromb Thrombolysis</stitle><addtitle>J Thromb Thrombolysis</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>36</volume><issue>1</issue><spage>31</spage><epage>41</epage><pages>31-41</pages><issn>0929-5305</issn><eissn>1573-742X</eissn><abstract>Glycoprotein IIb–IIIa (GPIIb–IIIa) antagonists have the capacity to destabilize coronary thrombi and restore vessel patency. Antagonist concentration and residence time, which can be increased by local intracoronary (LIC) administration, and thrombus age may be key factors that influence thrombus stability. Light transmission aggregometry was used to examine the effects of exposing human platelet aggregates to extremely high local levels of GPIIb–IIIa antagonists versus conventional therapeutic levels in vitro. Freshly-formed or aged platelet aggregates were subjected to GPIIb–IIIa antagonists (abciximab, eptifibatide) or direct thrombin inhibitor bivalirudin at concentrations simulating either conventional intravenous (IV) or LIC administration. The degree of antagonist-induced disaggregation was significantly higher using elevated (LIC) doses versus conventional (IV) doses (60.1 % vs. 7.4 % for abciximab, 41.6 % or 45.3 % vs. 17.6 % for eptifibatide,
p
< 0.01). Bivalirudin did not promote disaggregation. Microscopy confirmed noticeably smaller, more dispersed aggregates for antagonist LIC treatments. Dosing at LIC levels also induced more disaggregation than IV levels when aggregates were aged for 30 min prior to exposure. An in vitro perfusion model was used to simulate the fluid dynamics of IV or LIC administration of abciximab using a microporous local drug delivery balloon catheter such as the Atrium ClearWay™ RX. The perfusion model resulted in more rapid thrombus clearance with LIC dosing levels compared to IV. In summary, boosting the concentration of GPIIb–IIIa antagonists enhances dispersal of human platelet aggregates in vitro. These data provide a foundation for investigating increased local concentrations of GPIIb–IIIa antagonists in patients, as with LIC administration.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>23073747</pmid><doi>10.1007/s11239-012-0814-7</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies, Monoclonal - pharmacology Antithrombins - pharmacology Cardiology Coronary Vessels - metabolism Coronary Vessels - pathology Female Hematology Hirudins - pharmacology Humans Immunoglobulin Fab Fragments - pharmacology Male Medicine Medicine & Public Health Peptide Fragments - pharmacology Peptides - pharmacology Platelet Aggregation - drug effects Platelet Aggregation Inhibitors - pharmacology Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors Platelet Glycoprotein GPIIb-IIIa Complex - metabolism Recombinant Proteins - pharmacology Thrombosis - metabolism Thrombosis - pathology |
| title | Elevating local concentrations of GPIIb–IIIa antagonists counteracts platelet thrombus stability |
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