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Aspirin insensitive thrombophilia: transcript profiling of blood identifies platelet abnormalities and HLA restriction.

Abstract
Aspirin is the most widely used antiplatelet agent because it is safe, efficient, and inexpensive. However, a significant subset of patients does not exhibit a full inhibition of platelet aggregation, termed 'aspirin resistance' (AR). Several major studies have observed that AR patients have a 4-fold increased risk of myocardial infarction (MI), stroke, and other thrombotic events. Arachidonic acid-stimulated whole blood aggregation was tested in 132 adults at risk for ischemic events, and identified an inadequate response to aspirin therapy in 9 patients (6.8%). Expression profiling of blood RNA by microarray was used to generate new hypotheses about the etiology of AR. Among the differentially expressed genes, there were decreases in several known platelet transcripts, including clusterin (CLU), glycoproteins IIb/IIIa (ITGA2B/3), lipocalin (LCN2), lactoferrin (LTF), and the thrombopoetin receptor (MPL), but with increased mRNA for the T-cell Th1 chemokine CXCL10. There was a strong association of AR with expression of HLA-DRB4 and HLA-DQA1. Similar HLA changes have been linked to autoimmune disorders, particularly antiphospholipid syndrome (APS), in which autoantibodies to phospholipid/protein complexes can trigger platelet activation. Consistent with APS, AR patients exhibited a 30% reduction in platelet counts. Follow-up testing for autoimmune antibodies observed only borderline titers in AR patients. Overall, these results suggest that AR may be related to changes in platelet gene expression creating a hyperreactive platelet, despite antiplatelet therapy. Future studies will focus on determining the protein levels of these differential transcripts in platelets, and the possible involvement of HLA restriction as a contributing factor.
AuthorsPayam Fallahi, Richard Katz, Ian Toma, Ranyang Li, Jonathan Reiner, Kiersten VanHouten, Larry Carpio, Lorraine Marshall, Yi Lian, Sujata Bupp, Sidney W Fu, Frederick Rickles, David Leitenberg, Yinglei Lai, Babette B Weksler, Frederik Rebling, Zhaoqing Yang, Timothy A McCaffrey
JournalGene (Gene) Vol. 520 Issue 2 Pg. 131-8 (May 15 2013) ISSN: 1879-0038 [Electronic] Netherlands
PMID23454623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier B.V. All rights reserved.
Chemical References
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • HLA-DRB4 Chains
  • Platelet Aggregation Inhibitors
  • RNA, Messenger
  • Aspirin
Topics
  • Aspirin (pharmacology, therapeutic use)
  • Blood (metabolism)
  • Blood Platelet Disorders (blood, diagnosis, genetics)
  • Blood Platelets (metabolism, pathology)
  • Drug Resistance (genetics)
  • Female
  • Gene Expression Profiling
  • HLA-DQ alpha-Chains (genetics, metabolism, physiology)
  • HLA-DRB4 Chains (genetics, metabolism, physiology)
  • Histocompatibility Testing
  • Humans
  • Male
  • Microarray Analysis
  • Middle Aged
  • Platelet Aggregation Inhibitors (pharmacology, therapeutic use)
  • RNA, Messenger (analysis, metabolism)
  • Thrombophilia (blood, drug therapy, genetics, pathology)

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