| 5th Annual Platelet Colloquium (2010) |
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Highlights of the 5th Annual Platelet Colloquium (2010) Primary Themes The overarching theme for the Colloquium’s 5-year anniversary program was the translation of fundamental scientific constructs in platelet biology to safe and effective patient care on a global scale. To this end, platelet genetics, genomics, proteomics, and pharmacogenetics served as the underpinnings for scholarly discussions around inherited and acquired variations in function and their collective impact on response to pharmacologic treatments. A bench-to-bedside forum featured basic science on platelet receptors and platforms for successful drug development. Objectives
Chairs
Richard C. Becker, MD of Duke University Medical Center
Susan S. Smyth, MD, PhD of the University of Kentucky
Harold L. Dauerman, MD of the University of Vermont Grants Educational grants were provided by the following companies:
Session I: Genetic Regulation of Hemostasis and Thrombosis History of Aspirin and Atherothrombosis
Valentin Fuster, MD Summary:“Man lives with atherosclerosis but dies from thrombosis.” Although aspirin remains a mainstay of antithrombotic treatment for numerous indications, 4 main issues regarding its use persist: 1) the problem of aspirin resistance, 2) how to reduce the risk of bleeding when aspirin is used with other antithrombotic agents, 3) how best to combine aspirin into a “polypill” with other medications, and 4) continuing unanswered questions about aspirin’s use in primary prevention. Mechanisms Regulating Platelet Hyperresponsiveness
Paul F. Bray, MD Summary:RNA expression differs significantly in hyperreactive versus hyporeactive platelet phenotypes. Differences in platelet expression of micro-RNA (miRNA) expression might predict reactivity in vitro and perhaps, ultimately, be linked with clinical outcomes. Genetic Regulation of Blood Clotting
Ethan J. Weiss, MD Summary:Recent research has shown that the middle-distal region on chromosome 11 contains a locus for reduced Factor XI activity—up to 50% reduction in some cases. The mechanism for this phenomenon continues to be elucidated. Integrated molecular profiling of the platelet thrombohemorrhagic phenotype
Wadie F. Bahou, MD Summary: Proteomic/transcriptomic technologies are feasible for use in platelet profiling. In the future, it may be possible to extrapolate findings to the more common platelet disorders and to different patient populations. Before this can happen, however, consortia must be developed for creation of standardized data definitions and processing procedures for ease in analysis. Session II: Genetic Identification of Novel Antithrombotic Targets Platelet Expression Profiling
Daniel I. Simon, MD Summary: Levels of the proteins CD69 and MRP-8 or -14 have been shown to be strong predictors of the risk of myocardial infarction, independent of standard clinical risk factors and levels of the inflammatory marker C-reactive protein. Further characterization of the platelet transcriptome and proteome should produce other targets for antithrombotic therapies. Platelet Polymorphisms and Platelet Function
Marlene S. Williams, MD Summary: Various polymorphisms of genes encoding platelet glycoproteins (Ia, Iba, VI, and IIb/IIIa receptors, for example) have been shown to be associated with increased cardiovascular risk. This appears to be especially relevant for certain patient subgroups, such as women. Identification of New Antiplatelet Targets Via Chemical Proteomics
Leslie V. Parise, PhD Summary: Competitive, activity-based profiling of proteins has aided in discovery of new aspects of platelet biology. This includes identification of a human platelet serine hydrolase that is required for aIIbb3and Rap1 activation, platelet aggregation, and secretion. Redefining Risk in Acute Coronary Syndromes: the Clinical Application of Genetic and Molecular Medicine
Lewis C. Becker, MD Summary: Risk in patients with acute coronary syndromes is currently defined by clinical presentation, and refined by biomarker levels, platelet function assays, and genetic profiles. Emerging genetic and molecular methods should optimize risk assessment and facilitate identification of new therapeutic targets to yield strong platelet inhibition without increased bleeding. Session III: Women, Minorities, and Risk/Benefit with Antiplatelet Therapies Gender Differences in Inflammation in Relation to Cardiovascular Disease
Mary Cushman, MD High levels of C-reactive protein are known to be associated with increased risk for cardiovascular disease, and this marker is increasingly used in clinical practice for risk assessment. Although more detailed information is needed about the link between CRP levels and risk in nonwhite and female patients, but interruption of inflammation pathways is attractive target for prevention of cardiovascular disease. Race and Gender Differences in Thrombogenicity: Influence on Stenting and Antiplatelet Therapy
Dominick J. Angiolillo, MD, PhD Summary: Sex- and race-specific disparities in the presentation, management, and outcomes of coronary disease might reflect differences in platelet function and response to antithrombotic therapies. Understanding these differences could lead to development of sex- and race-optimized therapy to prevent and treat ischemic coronary events. Women and Antiplatelet Therapy: Insights into Bleeding, Dosing, and Efficacy
Tracy Y. Wang, MD Summary: Women are less likely than men to receive evidence-based antiplatelet treatments; the excess bleeding risk noted among women might contribute to their undertreatment. We need 1) a better understanding of the mechanisms behind sex differences in platelet biology, and 2) robust clinical studies to examine these differences in response to various antiplatelet therapies. Early Investigator Award: Molecular Signatures of the Response to Aspirin
Deepak Voora, MD Summary: The newly developed platelet function score (PFS) has been shown to accurately predict cyclooxygenase (COX)-1-independent platelet function before and during aspirin treatment, and its findings correlate highly with those from other platelet-function tests. Refined versions of this and other tests are now in development. Session IV: A Bench-to bedside forum Genetic Polymorphisms and the Response to Antiplatelet Therapies
Marc S. Sabatine, MD, MPH Summary: The gene that codes for the CYP2C19 protein comes in at least 2 forms. Carriers of the CYP2C19 allele associated with reduced platelet function can represent about 30% of the population. During clopidogrel treatment, such individuals show reduced levels of the drug’s active metabolite, reduced platelet inhibition, and increased ischemic events and stent thrombosis. Carriers of the increased-function CYP2C19 allele make up about 40% of the population and show the opposite phenotype. Higher doses of clopidogrel might increase platelet inhibition in carriers of the reduced-functionCYP2C19 allele. Of note, the metabolism and pharmacodynamics of prasugrel and ticagrelor are not affected by these polymorphisms. The Platelet P2Y12 Receptor
Pamela B. Conley, PhD Summary: The novel platelet P2Y12 receptor blocker, elinogrel, preferentially inhibits thrombosis compared with the thienopyridines. This finding could relate to the increased levels of ADP noted in hemostasis versus thrombosis, the off-target effects of thienopyridines, or involvement of inducible P2Y12 receptors (poorly blocked by clopidogrel) in thrombosis. The Science and Translation of Glycoprotein IIb/IIIa, P2Y12, and PAR-1 Antagonists to Patient Care: Bench-to-Bedside Platforms for Success
Susan S. Smyth, MD, PhD Summary: Much progress has been made in the development of targeted antiplatelet agents. Remaining avenues of investigation include plaque-specific prophylaxis; treatment that is personalized for age, sex, platelet reactivity, genotype, and clinical risk factors (such as diabetes mellitus or renal disease); minimization of bleeding risk; and possible expansion of indications for antiplatelet therapies to systemic (inflammatory) diseases.
Click here for the PDF of the summaries from the meeting. |
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