Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists
Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2000-03, Vol.101 (9), p.1013-1018 |
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| container_title | Circulation (New York, N.Y.) |
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| creator | Michelson, A D Furman, M I Goldschmidt-Clermont, P Mascelli, M A Hendrix, C Coleman, L Hamlington, J Barnard, M R Kickler, T Christie, D J Kundu, S Bray, P F |
| description | Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.
In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.
Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions. |
| doi_str_mv | 10.1161/01.CIR.101.9.1013 |
| format | Article |
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In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.
Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/01.CIR.101.9.1013</identifier><identifier>PMID: 10704169</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Abciximab ; Adenosine Diphosphate - pharmacology ; Adult ; Amino Acid Substitution - genetics ; Antibodies, Monoclonal - pharmacology ; Aspirin - pharmacology ; Blood Platelets - drug effects ; Blood Platelets - metabolism ; Cell Membrane - metabolism ; Dose-Response Relationship, Drug ; Female ; Fibrinogen - metabolism ; Gene Dosage ; Genotype ; Humans ; Immunoglobulin Fab Fragments - pharmacology ; Male ; P-Selectin - metabolism ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex - genetics ; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism ; Polymorphism, Genetic - genetics ; Polymorphism, Genetic - physiology ; Reference Values</subject><ispartof>Circulation (New York, N.Y.), 2000-03, Vol.101 (9), p.1013-1018</ispartof><rights>Copyright American Heart Association, Inc. Mar 7, 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-d6cccccb29211b97487d64fb2063f94f778b0b53cdcf585cf45d543bc2cdde1f3</citedby><cites>FETCH-LOGICAL-c369t-d6cccccb29211b97487d64fb2063f94f778b0b53cdcf585cf45d543bc2cdde1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10704169$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Michelson, A D</creatorcontrib><creatorcontrib>Furman, M I</creatorcontrib><creatorcontrib>Goldschmidt-Clermont, P</creatorcontrib><creatorcontrib>Mascelli, M A</creatorcontrib><creatorcontrib>Hendrix, C</creatorcontrib><creatorcontrib>Coleman, L</creatorcontrib><creatorcontrib>Hamlington, J</creatorcontrib><creatorcontrib>Barnard, M R</creatorcontrib><creatorcontrib>Kickler, T</creatorcontrib><creatorcontrib>Christie, D J</creatorcontrib><creatorcontrib>Kundu, S</creatorcontrib><creatorcontrib>Bray, P F</creatorcontrib><title>Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.
In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.
Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.</description><subject>Abciximab</subject><subject>Adenosine Diphosphate - pharmacology</subject><subject>Adult</subject><subject>Amino Acid Substitution - genetics</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Aspirin - pharmacology</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - metabolism</subject><subject>Cell Membrane - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Fibrinogen - metabolism</subject><subject>Gene Dosage</subject><subject>Genotype</subject><subject>Humans</subject><subject>Immunoglobulin Fab Fragments - pharmacology</subject><subject>Male</subject><subject>P-Selectin - metabolism</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - genetics</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</subject><subject>Polymorphism, Genetic - genetics</subject><subject>Polymorphism, Genetic - physiology</subject><subject>Reference Values</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUE1Lw0AQXUSxtfoDvEjwIHpI3dmPbPdYitZAwSB6XpLNrqYk2ZhNhP57t7QHcWDmMfDm8eYhdA14DpDAI4b5Kn2bQ0C5n_QETYETFjNO5SmaYoxlLCghE3Th_TasCRX8HE0AC8wgkVOUZXU-mNoM0TqL0jTNo6y-Xz5Enat3jeu7r8o3Pior39X5LqC1pjftEHnT-mqofkIbHw0uyj9dW_nBX6Izm9feXB1xhj6en95XL_HmdZ2ulptY00QOcZnofRVEEoBCCrYQZcJsQYJFK5kVYlHgglNdassXXFvGS85ooYkuSwOWztDdQbfr3fdo_KCaymtT13lr3OiVwJKFJ2Ug3v4jbt3Yt8GbIkAEByA4kOBA0r3zvjdWdX3V5P1OAVb7rBUGFbIOKyi5nzTc3ByFx6Ix5Z-LQ7j0F1bIees</recordid><startdate>20000307</startdate><enddate>20000307</enddate><creator>Michelson, A D</creator><creator>Furman, M I</creator><creator>Goldschmidt-Clermont, P</creator><creator>Mascelli, M A</creator><creator>Hendrix, C</creator><creator>Coleman, L</creator><creator>Hamlington, J</creator><creator>Barnard, M R</creator><creator>Kickler, T</creator><creator>Christie, D J</creator><creator>Kundu, S</creator><creator>Bray, P F</creator><general>American Heart Association, Inc</general><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>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>20000307</creationdate><title>Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists</title><author>Michelson, A D ; Furman, M I ; Goldschmidt-Clermont, P ; Mascelli, M A ; Hendrix, C ; Coleman, L ; Hamlington, J ; Barnard, M R ; Kickler, T ; Christie, D J ; Kundu, S ; Bray, P F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-d6cccccb29211b97487d64fb2063f94f778b0b53cdcf585cf45d543bc2cdde1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Abciximab</topic><topic>Adenosine Diphosphate - pharmacology</topic><topic>Adult</topic><topic>Amino Acid Substitution - genetics</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Aspirin - pharmacology</topic><topic>Blood Platelets - drug effects</topic><topic>Blood Platelets - metabolism</topic><topic>Cell Membrane - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Fibrinogen - metabolism</topic><topic>Gene Dosage</topic><topic>Genotype</topic><topic>Humans</topic><topic>Immunoglobulin Fab Fragments - pharmacology</topic><topic>Male</topic><topic>P-Selectin - metabolism</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - genetics</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - metabolism</topic><topic>Polymorphism, Genetic - genetics</topic><topic>Polymorphism, Genetic - physiology</topic><topic>Reference Values</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Michelson, A D</creatorcontrib><creatorcontrib>Furman, M I</creatorcontrib><creatorcontrib>Goldschmidt-Clermont, P</creatorcontrib><creatorcontrib>Mascelli, M A</creatorcontrib><creatorcontrib>Hendrix, C</creatorcontrib><creatorcontrib>Coleman, L</creatorcontrib><creatorcontrib>Hamlington, J</creatorcontrib><creatorcontrib>Barnard, M R</creatorcontrib><creatorcontrib>Kickler, T</creatorcontrib><creatorcontrib>Christie, D J</creatorcontrib><creatorcontrib>Kundu, S</creatorcontrib><creatorcontrib>Bray, P F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Michelson, A D</au><au>Furman, M I</au><au>Goldschmidt-Clermont, P</au><au>Mascelli, M A</au><au>Hendrix, C</au><au>Coleman, L</au><au>Hamlington, J</au><au>Barnard, M R</au><au>Kickler, T</au><au>Christie, D J</au><au>Kundu, S</au><au>Bray, P F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2000-03-07</date><risdate>2000</risdate><volume>101</volume><issue>9</issue><spage>1013</spage><epage>1018</epage><pages>1013-1018</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.
In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.
Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>10704169</pmid><doi>10.1161/01.CIR.101.9.1013</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; American Heart Association Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | Abciximab Adenosine Diphosphate - pharmacology Adult Amino Acid Substitution - genetics Antibodies, Monoclonal - pharmacology Aspirin - pharmacology Blood Platelets - drug effects Blood Platelets - metabolism Cell Membrane - metabolism Dose-Response Relationship, Drug Female Fibrinogen - metabolism Gene Dosage Genotype Humans Immunoglobulin Fab Fragments - pharmacology Male P-Selectin - metabolism Platelet Aggregation - drug effects Platelet Aggregation Inhibitors - pharmacology Platelet Glycoprotein GPIIb-IIIa Complex - genetics Platelet Glycoprotein GPIIb-IIIa Complex - metabolism Polymorphism, Genetic - genetics Polymorphism, Genetic - physiology Reference Values |
| title | Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists |
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