Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists

Alan D. Michelson, Mark I. Furman, Pascal Goldschmidt-Clermont, Mary Ann Mascelli, Craig Hendrix, Lindsay Coleman, Jeanette Hamlington, Marc R. Barnard, Thomas Kickler, Douglas J. Christie, Sourav Kundu, Paul F. Bray

Research output: Contribution to journalArticle

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Abstract

Background - 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. Methods and Results - 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 α(IIb)β33). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(At,A2), and 16 Pl(A2,A2)). Compared with Pl(At,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. Conclusions - 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.

Original languageEnglish
Pages (from-to)1013-1018
Number of pages6
JournalCirculation
Volume101
Issue number9
StatePublished - Mar 7 2000
Externally publishedYes

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varespladib methyl
Blood Platelets
Platelet Membrane Glycoprotein IIb
Adenosine Diphosphate
P-Selectin
Gene Dosage
Platelet Aggregation Inhibitors
Platelet Activation
Integrins
Fibrinogen
Aspirin
Alleles
Genotype

Keywords

  • Coronary disease
  • Inhibitors
  • Platelets
  • Polymorphisms

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Michelson, A. D., Furman, M. I., Goldschmidt-Clermont, P., Mascelli, M. A., Hendrix, C., Coleman, L., ... Bray, P. F. (2000). Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation, 101(9), 1013-1018.

Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. / Michelson, Alan D.; Furman, Mark I.; Goldschmidt-Clermont, Pascal; Mascelli, Mary Ann; Hendrix, Craig; Coleman, Lindsay; Hamlington, Jeanette; Barnard, Marc R.; Kickler, Thomas; Christie, Douglas J.; Kundu, Sourav; Bray, Paul F.

In: Circulation, Vol. 101, No. 9, 07.03.2000, p. 1013-1018.

Research output: Contribution to journalArticle

Michelson, AD, Furman, MI, Goldschmidt-Clermont, P, Mascelli, MA, Hendrix, C, Coleman, L, Hamlington, J, Barnard, MR, Kickler, T, Christie, DJ, Kundu, S & Bray, PF 2000, 'Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists', Circulation, vol. 101, no. 9, pp. 1013-1018.
Michelson AD, Furman MI, Goldschmidt-Clermont P, Mascelli MA, Hendrix C, Coleman L et al. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation. 2000 Mar 7;101(9):1013-1018.
Michelson, Alan D. ; Furman, Mark I. ; Goldschmidt-Clermont, Pascal ; Mascelli, Mary Ann ; Hendrix, Craig ; Coleman, Lindsay ; Hamlington, Jeanette ; Barnard, Marc R. ; Kickler, Thomas ; Christie, Douglas J. ; Kundu, Sourav ; Bray, Paul F. / Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. In: Circulation. 2000 ; Vol. 101, No. 9. pp. 1013-1018.
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abstract = "Background - 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. Methods and Results - 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 α(IIb)β33). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(At,A2), and 16 Pl(A2,A2)). Compared with Pl(At,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. Conclusions - 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.",
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T1 - Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists

AU - Michelson, Alan D.

AU - Furman, Mark I.

AU - Goldschmidt-Clermont, Pascal

AU - Mascelli, Mary Ann

AU - Hendrix, Craig

AU - Coleman, Lindsay

AU - Hamlington, Jeanette

AU - Barnard, Marc R.

AU - Kickler, Thomas

AU - Christie, Douglas J.

AU - Kundu, Sourav

AU - Bray, Paul F.

PY - 2000/3/7

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N2 - Background - 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. Methods and Results - 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 α(IIb)β33). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(At,A2), and 16 Pl(A2,A2)). Compared with Pl(At,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. Conclusions - 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.

AB - Background - 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. Methods and Results - 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 α(IIb)β33). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(At,A2), and 16 Pl(A2,A2)). Compared with Pl(At,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. Conclusions - 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.

KW - Coronary disease

KW - Inhibitors

KW - Platelets

KW - Polymorphisms

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