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.

Outcomes of Interferon/Ribavirin Therapy in Patients with HCV Defined by Expression of Plasma Soluble Human Leukocyte Antigen-G but Not IL-37

“…These data might support that HLA-G secretion in most hepatic diseases is correlated with the intensity of inflammation and immunity. Moreover, the HLA expression may be a contributing factor to aspirin resistance and platinum resistance [ 22 , 23 ]. This means that abnormal expression of HLA is a poor prognostic mechanism for drug response.…”

Aspirin Exposure Reveals Novel Genes Associated With Platelet Function and Cardiovascular Events

“…We previously described (9) an o ut p atient c ardiology cohort (OPC, Supplemental Methods, Figure 1) treated with 81mg/day aspirin assessed with the VerifyNow Aspirin device and whole blood RNA microarray analysis.…”

“…(9) Three categories of individuals were profiled by microarray based on their aspirin response units (ARU): Aspirin resistant (AR, ARU > 550); High normal (HN, 500 < ARU < 550); Aspirin sensitive (AS, ARU < 550). ARS values are for each group are plotted and compared using two-sample t-tests.…”

Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts

“…In the context of a hypothesis-generating, exploratory study such as this, the prior analysis using 9 DEG methods may risk missing biologically important pathways in favor of statistical rigor. The datasets were re-analyzed using an RPKM threshold of 0.01, and combined fold-change (> 1.5) and p value (< 0.01, uncorrected) filtering approach that has proven useful in prior biomarker studies [ 66 , 67 ]. This triple filter identified 524 transcripts in the case–control study (Additional file 6 : Table S3), and 505 transcripts in the twin cohort (Additional file 7 : Table S4).…”