Genetic Dissection of Platelet Function in Health and Disease Using Systems Biology

Relevance of Platelet Functional Disorders in Health and Disease Molecular platelet disorders cause bleeding syndromes of varying severity, best characterized for cell-surface receptor defects involving αIIbβ3 and the GPIb-IX-V complex, and less frequently known to involve distinct signaling pathways or defects of granule formation.1 By contrast, there is a paucity of information on the molecular etiology of the “prothrombotic” platelet, despite long-standing evidence for the role of activated platelets in the development of focal ischemia.2,3 The latter observation is clearly supported by clinical studies of platelet activation markers during transitory and thrombotic vascular events.4–10 Causal evidence for the critical influence of platelets in human vascular events is highlighted by the efficacy of antiplatelet agents as therapeutic and prophylactic modalities in the setting of cerebrovascular ischemia,11–13 as established by observations of fewer nonfatal strokes in patients with prior stroke or transient ischemic attack, and fewer nonfatal strokes among patients treated for completed stroke.14,15 Comparable cardiovascular data exist demonstrating that interventions with antiplatelet agents offer therapeutic efficacy as interventional strategies for coronary artery disease (CAD), acute coronary syndromes, and percutaneous transluminal coronary angioplasty, either in acute settings or as prophylactic modalities.4–7,11,16,17 Antiplatelet agents, however, are not without toxicity, and “breakthrough” thromboembolic episodes remain prevalent.18 Thus the development of risk stratification strategies and/or platelet phenotypic/genotypic assays (“biomarkers”) able to predict responsiveness or adverse events have emerged as a research direction of the biopharmaceutical industry, and have the potential for widespread clinical application.