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A Uniform Shear Assay for Human Platelet and Cell Surface Receptors via Cone-plate Viscometry
Published on: June 5, 2019
Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists
A D Michelson1, M I Furman, P Goldschmidt-Clermont
1Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Circulation
|March 7, 2000
Summary
The Pl(A2) gene variant in platelets increases their reactivity and activation. This genetic difference in platelet function may explain inherited predisposition to coronary events.
Area of Science:
- Cardiovascular Genetics
- Hematology
- Molecular Biology
Background:
- Inherited predisposition and platelet hyperreactivity are linked to ischemic coronary events.
- Mechanisms underlying genetic differences in platelet function remain unclear.
- The Pl(A2) polymorphism of glycoprotein IIIa (GP IIIa) is associated with coronary syndromes, prompting investigation into its role in platelet hyperreactivity.
Purpose of the Study:
- To characterize functional parameters of platelets with the Pl(A) (HPA-1) polymorphism.
- To investigate the impact of the Leu (Pl(A1)) to Pro (Pl(A2)) substitution in GP IIIa on platelet activation and function.
- To determine if the Pl(A2) variant contributes to platelet hyperreactivity and influences response to antiplatelet agents.
Main Methods:
- Studied 56 healthy donors genotyped for the Pl(A) polymorphism (Pl(A1,A1), Pl(A1,A2), Pl(A2,A2)).
- Assessed surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to adenosine diphosphate (ADP).
- Evaluated platelet aggregation sensitivity to aspirin and abciximab.
Main Results:
- Pl(A2)-positive platelets exhibited a gene dosage effect with significantly greater P-selectin, fibrinogen binding, and GP IIb/IIIa activation upon low-dose ADP stimulation compared to Pl(A1,A1) platelets.
- ADP-stimulated GP IIb/IIIa expression was significantly higher in Pl(A2,A2) platelets.
- Platelets heterozygous for Pl(A) alleles (Pl(A1,A2)) showed increased sensitivity to aspirin and abciximab inhibition of aggregation.
Conclusions:
- Pl(A2)-positive platelets demonstrate a reduced threshold for activation.
- Heterozygous Pl(A) platelets exhibit heightened sensitivity to common antiplatelet drugs.
- These in vitro findings suggest potential relevance for understanding in vivo thrombotic conditions and personalized antiplatelet therapy.
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