Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment

Platelet multidrug resistance protein4 (MRP4)-overexpression has a role in reducing aspirin action. Aspirin in vivo treatment enhances platelet MRP4 expression and MRP4 mediated transport inhibition reduces platelet function and delays thrombus formation. The aim of our work was to verify whether MRP4 expression is enhanced in platelets obtained from patients under chronic aspirin treatment and whether it correlates with residual platelet reactivity. We evaluated changes on mRNA and protein-MRP4 expression and platelet aggregation in four populations: healthy volunteers (HV), aspirin-free control population (CTR), patients who started the treatment less than one month ago (ASA<1 month patients) and aspirinated patients who started the treatment more than two months ago (ASA>2 months patients). In platelets obtained from ASA>2 months patients, it was found a statistically significant MRP4 enhancement of both mRNA and protein expression compared to HV, CTR and ASA<1 month patients. Platelets obtained from ASA>2 months patients that present high levels of platelet MRP4, have higher serum TxB2 levels and collagen-induced platelet aggregation compared to patient with low levels of MRP4 in platelets. In addition collagen induced platelet aggregation is higher in in vitro aspirinated platelets obtained from patients with high levels of MRP4 patients compared to those obtained from patients with low MRP4 levels. We can assert that, in patients under chronic aspirin treatment, platelets that present high MRP4 levels have an increase of residual platelet reactivity, which is due in part to incomplete COX-1 inhibition, and in part to COX-1-independent mechanism.

[1]  B. Giusti,et al.  High on-aspirin platelet reactivity predicts cardiac death in acute coronary syndrome patients undergoing PCI. , 2016, European journal of internal medicine.

[2]  L. Frati,et al.  Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and Multidrug Resistance Protein 4 expression in human platelets. , 2016, Vascular pharmacology.

[3]  J. Schuetz,et al.  The ABCC4 membrane transporter modulates platelet aggregation. , 2015, Blood.

[4]  C. Denis,et al.  Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice. , 2015, Blood.

[5]  A. Montemari,et al.  Arachidonic acid-stimulated platelet tests: Identification of patients less sensitive to aspirin treatment , 2015, Platelets.

[6]  D. Voora,et al.  Personalized antiplatelet and anticoagulation therapy: applications and significance of pharmacogenomics , 2015, Pharmacogenomics and personalized medicine.

[7]  D. Angiolillo,et al.  Aspirin treatment and outcomes in patients undergoing percutaneous coronary intervention: is there a role for pharmacodynamic testing? , 2014, Journal of the American College of Cardiology.

[8]  H. Schunkert,et al.  Aspirin treatment and outcomes after percutaneous coronary intervention: results of the ISAR-ASPI registry. , 2014, Journal of the American College of Cardiology.

[9]  Shih-Yi Huang,et al.  Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo. , 2014, European journal of pharmacology.

[10]  Pankaj Sharma,et al.  Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects. , 2014, British journal of clinical pharmacology.

[11]  C. Gaudio,et al.  Aspirin influences megakaryocytic gene expression leading to up-regulation of multidrug resistance protein-4 in human platelets , 2014, British journal of clinical pharmacology.

[12]  A. Ferro,et al.  Mechanisms of aspirin resistance. , 2014, Pharmacology & therapeutics.

[13]  W. Kraus,et al.  Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events. , 2013, Journal of the American College of Cardiology.

[14]  A. Borgognone,et al.  Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport , 2012, Thrombosis and Haemostasis.

[15]  C. Gaudio,et al.  Aspirin extrusion from human platelets through multidrug resistance protein-4-mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. , 2011, Journal of the American College of Cardiology.

[16]  J. T. ten Berg,et al.  High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention , 2011, Heart.

[17]  A. Kaltoft,et al.  Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. , 2010, JACC. Cardiovascular interventions.

[18]  Andrew D. Johnson,et al.  Relation of Platelet and Leukocyte Inflammatory Transcripts to Body Mass Index in the Framingham Heart Study , 2010, Circulation.

[19]  M. Furman,et al.  Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization , 2009, Circulation.

[20]  F. Santilli,et al.  Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance". , 2009, Journal of the American College of Cardiology.

[21]  B. Giusti,et al.  Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function , 2008, Thrombosis and Haemostasis.

[22]  Deepak L. Bhatt,et al.  Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk , 2008, Circulation.

[23]  F. Sofi,et al.  Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events--a meta-analysis. , 2008, International journal of cardiology.

[24]  W. Gianni,et al.  Celecoxib upregulates multidrug resistance proteins in colon cancer: lack of synergy with standard chemotherapy. , 2008, Current cancer drug targets.

[25]  W Scott Beattie,et al.  Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis , 2008, BMJ : British Medical Journal.

[26]  New European guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction--what are the new and key messages. , 2007, Polskie Archiwum Medycyny Wewnetrznej.

[27]  J. Eikenboom,et al.  Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. , 2007, Archives of internal medicine.

[28]  Colin Baigent,et al.  Low-dose aspirin for the prevention of atherothrombosis. , 2005, The New England journal of medicine.

[29]  F. Violi,et al.  Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin , 2005, Journal of thrombosis and haemostasis : JTH.

[30]  A. Weyrich,et al.  Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Gazzaniga,et al.  Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. , 2004, Journal of the American College of Cardiology.

[32]  B. Goh,et al.  Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. , 2004, The international journal of biochemistry & cell biology.

[33]  E. Topol,et al.  A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. , 2003, Journal of the American College of Cardiology.

[34]  S. Yusuf,et al.  Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events , 2002, Circulation.

[35]  P. Gazzaniga,et al.  Evidence for separate effects of U73122 on phospholipase C and calcium channels in human platelets. , 1998, Biochemical pharmacology.

[36]  G. FitzGerald,et al.  Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. , 1983, The Journal of clinical investigation.

[37]  G. Born,et al.  Aggregation of Blood Platelets by Adenosine Diphosphate and its Reversal , 1962, Nature.