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Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor
Background Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion. Methods GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb F...
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| Published in: | Xenotransplantation (Københaven) 2016-05, Vol.23 (3), p.222-236 |
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| creator | Burdorf, Lars Riner, Andrea Rybak, Elana Salles, Isabelle I. De Meyer, Simon F. Shah, Aakash Quinn, Kevin J. Harris, Donald Zhang, Tianshu Parsell, Dawn Ali, Franchesca Schwartz, Evan Kang, Elizabeth Cheng, Xiangfei Sievert, Evelyn Zhao, Yuming Braileanu, Gheorghe Phelps, Carol J. Ayares, David L. Deckmyn, Hans Pierson III, Richard N. Azimzadeh, Agnes M. |
| description | Background
Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion.
Methods
GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1‐desamino‐8‐d‐arginine vasopressin (DDAVP), 3 μg/kg (to pre‐deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each).
Results
Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre‐treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration.
Conclusions
The GPIb‐VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung. |
| doi_str_mv | 10.1111/xen.12236 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1795874697</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1795874697</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4686-22fd44c3264516a4ccca59ceb3ce72250b89f047b8186f1eb6e5e6eda524ecbd3</originalsourceid><addsrcrecordid>eNp1kc1u1DAUhSMEokNhwQsgL0FqZvwTO86STtsQUU2LKGp3luPctAbPZLCT0nkbHhVn0naHF7av9d1z5HuS5D3BcxLX4gE2c0IpEy-SGWFFkTIsi5fJDBdYpkLwm4PkTQg_McaMS_46OaA5kZIzOkv-Xjrdg4MeBfg9QOi97m23QXrTIG16ez-VzeDt5haV2l19vZjfLU8ygbb2Frkhvm7Bt0MYsXqH7oa1jhfXdQ2yAW29XWtv3Q6tobHRqhmh8rKqj8a9qhdVVemjvd99VLi2zkHtx_Is-nf-bfKq1S7Au8fzMPlxdnq1_JKeX5TV8vN5ajIhRUpp22SZYVRknAidGWM0LwzUzEBOKce1LFqc5bUkUrQEagEcBDSa0wxM3bDD5OOku_XdfhBqbYMB5_QGuiEokhdc5pko8oh-mlDjuxA8tGr65U4RrMZAVAxE7QOJ7IdH2aGOE3gmnxKIwGIC_lgHu_8rqZvT1ZNkOnXY0MPDc4f2v5TIWc7V9apUJ6vvxTe2OlYl-wcQzqWC</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1795874697</pqid></control><display><type>article</type><title>Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor</title><source>Wiley Online Library</source><creator>Burdorf, Lars ; Riner, Andrea ; Rybak, Elana ; Salles, Isabelle I. ; De Meyer, Simon F. ; Shah, Aakash ; Quinn, Kevin J. ; Harris, Donald ; Zhang, Tianshu ; Parsell, Dawn ; Ali, Franchesca ; Schwartz, Evan ; Kang, Elizabeth ; Cheng, Xiangfei ; Sievert, Evelyn ; Zhao, Yuming ; Braileanu, Gheorghe ; Phelps, Carol J. ; Ayares, David L. ; Deckmyn, Hans ; Pierson III, Richard N. ; Azimzadeh, Agnes M.</creator><creatorcontrib>Burdorf, Lars ; Riner, Andrea ; Rybak, Elana ; Salles, Isabelle I. ; De Meyer, Simon F. ; Shah, Aakash ; Quinn, Kevin J. ; Harris, Donald ; Zhang, Tianshu ; Parsell, Dawn ; Ali, Franchesca ; Schwartz, Evan ; Kang, Elizabeth ; Cheng, Xiangfei ; Sievert, Evelyn ; Zhao, Yuming ; Braileanu, Gheorghe ; Phelps, Carol J. ; Ayares, David L. ; Deckmyn, Hans ; Pierson III, Richard N. ; Azimzadeh, Agnes M.</creatorcontrib><description>Background
Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion.
Methods
GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1‐desamino‐8‐d‐arginine vasopressin (DDAVP), 3 μg/kg (to pre‐deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each).
Results
Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre‐treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration.
Conclusions
The GPIb‐VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung.</description><identifier>ISSN: 0908-665X</identifier><identifier>EISSN: 1399-3089</identifier><identifier>DOI: 10.1111/xen.12236</identifier><identifier>PMID: 27188532</identifier><language>eng</language><publisher>Denmark: Blackwell Publishing Ltd</publisher><subject>Animals ; Animals, Genetically Modified ; Blood Platelets - cytology ; coagulation ; ex-vivo perfusion ; Fab ; GalTKO.hCD46 ; Glycoprotein ; GPIb ; GPIIb/IIIa ; Graft Survival - immunology ; Heterografts - immunology ; Humans ; lung ; Lung - immunology ; Lung - metabolism ; Lung Transplantation - methods ; platelet activation ; Platelet Activation - physiology ; Platelet Aggregation - genetics ; Platelet Aggregation - immunology ; Platelet Glycoprotein GPIb-IX Complex - genetics ; Platelet Glycoprotein GPIb-IX Complex - metabolism ; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism ; Swine ; Thrombocytopenia - etiology ; Transplantation, Heterologous - methods ; von Willebrand Factor - genetics ; von Willebrand Factor - metabolism ; Xenotransplantation</subject><ispartof>Xenotransplantation (Københaven), 2016-05, Vol.23 (3), p.222-236</ispartof><rights>2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4686-22fd44c3264516a4ccca59ceb3ce72250b89f047b8186f1eb6e5e6eda524ecbd3</citedby><cites>FETCH-LOGICAL-c4686-22fd44c3264516a4ccca59ceb3ce72250b89f047b8186f1eb6e5e6eda524ecbd3</cites><orcidid>0000-0002-5059-5597</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fxen.12236$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fxen.12236$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27188532$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Burdorf, Lars</creatorcontrib><creatorcontrib>Riner, Andrea</creatorcontrib><creatorcontrib>Rybak, Elana</creatorcontrib><creatorcontrib>Salles, Isabelle I.</creatorcontrib><creatorcontrib>De Meyer, Simon F.</creatorcontrib><creatorcontrib>Shah, Aakash</creatorcontrib><creatorcontrib>Quinn, Kevin J.</creatorcontrib><creatorcontrib>Harris, Donald</creatorcontrib><creatorcontrib>Zhang, Tianshu</creatorcontrib><creatorcontrib>Parsell, Dawn</creatorcontrib><creatorcontrib>Ali, Franchesca</creatorcontrib><creatorcontrib>Schwartz, Evan</creatorcontrib><creatorcontrib>Kang, Elizabeth</creatorcontrib><creatorcontrib>Cheng, Xiangfei</creatorcontrib><creatorcontrib>Sievert, Evelyn</creatorcontrib><creatorcontrib>Zhao, Yuming</creatorcontrib><creatorcontrib>Braileanu, Gheorghe</creatorcontrib><creatorcontrib>Phelps, Carol J.</creatorcontrib><creatorcontrib>Ayares, David L.</creatorcontrib><creatorcontrib>Deckmyn, Hans</creatorcontrib><creatorcontrib>Pierson III, Richard N.</creatorcontrib><creatorcontrib>Azimzadeh, Agnes M.</creatorcontrib><title>Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor</title><title>Xenotransplantation (Københaven)</title><addtitle>Xenotransplantation</addtitle><description>Background
Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion.
Methods
GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1‐desamino‐8‐d‐arginine vasopressin (DDAVP), 3 μg/kg (to pre‐deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each).
Results
Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre‐treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration.
Conclusions
The GPIb‐VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung.</description><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Blood Platelets - cytology</subject><subject>coagulation</subject><subject>ex-vivo perfusion</subject><subject>Fab</subject><subject>GalTKO.hCD46</subject><subject>Glycoprotein</subject><subject>GPIb</subject><subject>GPIIb/IIIa</subject><subject>Graft Survival - immunology</subject><subject>Heterografts - immunology</subject><subject>Humans</subject><subject>lung</subject><subject>Lung - immunology</subject><subject>Lung - metabolism</subject><subject>Lung Transplantation - methods</subject><subject>platelet activation</subject><subject>Platelet Activation - physiology</subject><subject>Platelet Aggregation - genetics</subject><subject>Platelet Aggregation - immunology</subject><subject>Platelet Glycoprotein GPIb-IX Complex - genetics</subject><subject>Platelet Glycoprotein GPIb-IX Complex - metabolism</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</subject><subject>Swine</subject><subject>Thrombocytopenia - etiology</subject><subject>Transplantation, Heterologous - methods</subject><subject>von Willebrand Factor - genetics</subject><subject>von Willebrand Factor - metabolism</subject><subject>Xenotransplantation</subject><issn>0908-665X</issn><issn>1399-3089</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp1kc1u1DAUhSMEokNhwQsgL0FqZvwTO86STtsQUU2LKGp3luPctAbPZLCT0nkbHhVn0naHF7av9d1z5HuS5D3BcxLX4gE2c0IpEy-SGWFFkTIsi5fJDBdYpkLwm4PkTQg_McaMS_46OaA5kZIzOkv-Xjrdg4MeBfg9QOi97m23QXrTIG16ez-VzeDt5haV2l19vZjfLU8ygbb2Frkhvm7Bt0MYsXqH7oa1jhfXdQ2yAW29XWtv3Q6tobHRqhmh8rKqj8a9qhdVVemjvd99VLi2zkHtx_Is-nf-bfKq1S7Au8fzMPlxdnq1_JKeX5TV8vN5ajIhRUpp22SZYVRknAidGWM0LwzUzEBOKce1LFqc5bUkUrQEagEcBDSa0wxM3bDD5OOku_XdfhBqbYMB5_QGuiEokhdc5pko8oh-mlDjuxA8tGr65U4RrMZAVAxE7QOJ7IdH2aGOE3gmnxKIwGIC_lgHu_8rqZvT1ZNkOnXY0MPDc4f2v5TIWc7V9apUJ6vvxTe2OlYl-wcQzqWC</recordid><startdate>201605</startdate><enddate>201605</enddate><creator>Burdorf, Lars</creator><creator>Riner, Andrea</creator><creator>Rybak, Elana</creator><creator>Salles, Isabelle I.</creator><creator>De Meyer, Simon F.</creator><creator>Shah, Aakash</creator><creator>Quinn, Kevin J.</creator><creator>Harris, Donald</creator><creator>Zhang, Tianshu</creator><creator>Parsell, Dawn</creator><creator>Ali, Franchesca</creator><creator>Schwartz, Evan</creator><creator>Kang, Elizabeth</creator><creator>Cheng, Xiangfei</creator><creator>Sievert, Evelyn</creator><creator>Zhao, Yuming</creator><creator>Braileanu, Gheorghe</creator><creator>Phelps, Carol J.</creator><creator>Ayares, David L.</creator><creator>Deckmyn, Hans</creator><creator>Pierson III, Richard N.</creator><creator>Azimzadeh, Agnes M.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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>7X8</scope><orcidid>https://orcid.org/0000-0002-5059-5597</orcidid></search><sort><creationdate>201605</creationdate><title>Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor</title><author>Burdorf, Lars ; Riner, Andrea ; Rybak, Elana ; Salles, Isabelle I. ; De Meyer, Simon F. ; Shah, Aakash ; Quinn, Kevin J. ; Harris, Donald ; Zhang, Tianshu ; Parsell, Dawn ; Ali, Franchesca ; Schwartz, Evan ; Kang, Elizabeth ; Cheng, Xiangfei ; Sievert, Evelyn ; Zhao, Yuming ; Braileanu, Gheorghe ; Phelps, Carol J. ; Ayares, David L. ; Deckmyn, Hans ; Pierson III, Richard N. ; Azimzadeh, Agnes M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4686-22fd44c3264516a4ccca59ceb3ce72250b89f047b8186f1eb6e5e6eda524ecbd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Blood Platelets - cytology</topic><topic>coagulation</topic><topic>ex-vivo perfusion</topic><topic>Fab</topic><topic>GalTKO.hCD46</topic><topic>Glycoprotein</topic><topic>GPIb</topic><topic>GPIIb/IIIa</topic><topic>Graft Survival - immunology</topic><topic>Heterografts - immunology</topic><topic>Humans</topic><topic>lung</topic><topic>Lung - immunology</topic><topic>Lung - metabolism</topic><topic>Lung Transplantation - methods</topic><topic>platelet activation</topic><topic>Platelet Activation - physiology</topic><topic>Platelet Aggregation - genetics</topic><topic>Platelet Aggregation - immunology</topic><topic>Platelet Glycoprotein GPIb-IX Complex - genetics</topic><topic>Platelet Glycoprotein GPIb-IX Complex - metabolism</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</topic><topic>Swine</topic><topic>Thrombocytopenia - etiology</topic><topic>Transplantation, Heterologous - methods</topic><topic>von Willebrand Factor - genetics</topic><topic>von Willebrand Factor - metabolism</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burdorf, Lars</creatorcontrib><creatorcontrib>Riner, Andrea</creatorcontrib><creatorcontrib>Rybak, Elana</creatorcontrib><creatorcontrib>Salles, Isabelle I.</creatorcontrib><creatorcontrib>De Meyer, Simon F.</creatorcontrib><creatorcontrib>Shah, Aakash</creatorcontrib><creatorcontrib>Quinn, Kevin J.</creatorcontrib><creatorcontrib>Harris, Donald</creatorcontrib><creatorcontrib>Zhang, Tianshu</creatorcontrib><creatorcontrib>Parsell, Dawn</creatorcontrib><creatorcontrib>Ali, Franchesca</creatorcontrib><creatorcontrib>Schwartz, Evan</creatorcontrib><creatorcontrib>Kang, Elizabeth</creatorcontrib><creatorcontrib>Cheng, Xiangfei</creatorcontrib><creatorcontrib>Sievert, Evelyn</creatorcontrib><creatorcontrib>Zhao, Yuming</creatorcontrib><creatorcontrib>Braileanu, Gheorghe</creatorcontrib><creatorcontrib>Phelps, Carol J.</creatorcontrib><creatorcontrib>Ayares, David L.</creatorcontrib><creatorcontrib>Deckmyn, Hans</creatorcontrib><creatorcontrib>Pierson III, Richard N.</creatorcontrib><creatorcontrib>Azimzadeh, Agnes M.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Xenotransplantation (Københaven)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Burdorf, Lars</au><au>Riner, Andrea</au><au>Rybak, Elana</au><au>Salles, Isabelle I.</au><au>De Meyer, Simon F.</au><au>Shah, Aakash</au><au>Quinn, Kevin J.</au><au>Harris, Donald</au><au>Zhang, Tianshu</au><au>Parsell, Dawn</au><au>Ali, Franchesca</au><au>Schwartz, Evan</au><au>Kang, Elizabeth</au><au>Cheng, Xiangfei</au><au>Sievert, Evelyn</au><au>Zhao, Yuming</au><au>Braileanu, Gheorghe</au><au>Phelps, Carol J.</au><au>Ayares, David L.</au><au>Deckmyn, Hans</au><au>Pierson III, Richard N.</au><au>Azimzadeh, Agnes M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor</atitle><jtitle>Xenotransplantation (Københaven)</jtitle><addtitle>Xenotransplantation</addtitle><date>2016-05</date><risdate>2016</risdate><volume>23</volume><issue>3</issue><spage>222</spage><epage>236</epage><pages>222-236</pages><issn>0908-665X</issn><eissn>1399-3089</eissn><notes>University of Maryland Clinical Translational Science Institute</notes><notes>University of Maryland General Clinical Research Center</notes><notes>United Therapeutics, Inc</notes><notes>NIAID - No. U19 AI 090959</notes><notes>ArticleID:XEN12236</notes><notes>University of Maryland, Baltimore Foundation</notes><notes>ark:/67375/WNG-DNS9Q3NB-G</notes><notes>istex:3E93DFEFEC9BC1D413F5F9B86F34E5A7F0BB5D72</notes><notes>NIH</notes><notes>Revivicor, Inc</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Background
Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion.
Methods
GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1‐desamino‐8‐d‐arginine vasopressin (DDAVP), 3 μg/kg (to pre‐deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each).
Results
Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre‐treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration.
Conclusions
The GPIb‐VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung.</abstract><cop>Denmark</cop><pub>Blackwell Publishing Ltd</pub><pmid>27188532</pmid><doi>10.1111/xen.12236</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-5059-5597</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0908-665X |
| ispartof | Xenotransplantation (Københaven), 2016-05, Vol.23 (3), p.222-236 |
| issn | 0908-665X 1399-3089 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1795874697 |
| source | Wiley Online Library |
| subjects | Animals Animals, Genetically Modified Blood Platelets - cytology coagulation ex-vivo perfusion Fab GalTKO.hCD46 Glycoprotein GPIb GPIIb/IIIa Graft Survival - immunology Heterografts - immunology Humans lung Lung - immunology Lung - metabolism Lung Transplantation - methods platelet activation Platelet Activation - physiology Platelet Aggregation - genetics Platelet Aggregation - immunology Platelet Glycoprotein GPIb-IX Complex - genetics Platelet Glycoprotein GPIb-IX Complex - metabolism Platelet Glycoprotein GPIIb-IIIa Complex - metabolism Swine Thrombocytopenia - etiology Transplantation, Heterologous - methods von Willebrand Factor - genetics von Willebrand Factor - metabolism Xenotransplantation |
| title | Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T17%3A17%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Platelet%20sequestration%20and%20activation%20during%20GalTKO.hCD46%20pig%20lung%20perfusion%20by%20human%20blood%20is%20primarily%20mediated%20by%20GPIb,%20GPIIb/IIIa,%20and%20von%20Willebrand%20Factor&rft.jtitle=Xenotransplantation%20(K%C3%B8benhaven)&rft.au=Burdorf,%20Lars&rft.date=2016-05&rft.volume=23&rft.issue=3&rft.spage=222&rft.epage=236&rft.pages=222-236&rft.issn=0908-665X&rft.eissn=1399-3089&rft_id=info:doi/10.1111/xen.12236&rft_dat=%3Cproquest_cross%3E1795874697%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c4686-22fd44c3264516a4ccca59ceb3ce72250b89f047b8186f1eb6e5e6eda524ecbd3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1795874697&rft_id=info:pmid/27188532&rfr_iscdi=true |