Cardiovascular disease continues to be the primary cause of morbidity and mortality in North America. The risk of premature atherosclerosis and platelet-dependent cardiovascular events rises with increasing obesity. Complicating this observation is that not all individuals with elevated BMI go on to develop athero-thrombotic disease. We measured expression of 48 genes by high-throughput quantitative reverse transcription PCR in over 2250 participants of the Framingham Offspring and Omni minority cohorts (FHS) using RNA from isolated platelets and found that specific mitochondrial transcripts were significantly and specifically associated with higher body mass index. To determine if there were associated changes in platelet function, we studied select platelet transcripts and function from individuals after short term triglyceride emulsion infusion (acute effect) and identified similar alterations in platelet transcripts that associated with changes in platelet activation. Thus, the central hypothesis of this project is: In the setting of obesity, the human platelet is reprogrammed as seen by altered platelet RNA, including mitochondrial transcripts, and these changes lead to a prothrombotic phenotype that influences the development of athero-thrombotic disease. The effect of obesity on the human platelet as seen in its transcript profile and platelet function will be studied as follows:
Aim 1. Characterize the molecular signature of platelets in the setting of increased BMI and determine if it is caused by short term fat intake or chronic obesity and if the changes are reversible with weight loss.
Aim 2. Determine the mechanism by which platelet reprogramming alters platelet function including the role of the mitochondria.
Aim 3. Determine if platelet reprogramming correlates with subclinical cardiovascular disease (CVD) and the development of clinical CVD. This information along with transcripts from Projects 1-3 and proteins screened in Aim 1 will establish a biomarker panel identifying individuals with elevated BMI at high risk for athero-thrombotic disease. This project seeks not only to define the mechanism by which platelet reprogramming alters function but will determine the human relevance and develop a transcript-based profile.

Public Health Relevance

Patients with type 2 diabetes, obesity, or the metabolic syndrome are at increased risk for blood clots (thrombosis) caused by cells called platelets. Our studies will determine how metabolic factors in the blood and tissues (the metabolic milieu), such as high glucose and lipids, make platelets more prone to induce thrombosis, providing new insights into the treatment and management of diabetes and obesity.

National Institute of Health (NIH)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Salt Lake City
United States
Zip Code
Koupenova, Milka; Vitseva, Olga; MacKay, Christopher R et al. (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124:791-802
Schubert, Sebastian; Weyrich, Andrew S; Rowley, Jesse W (2014) A tour through the transcriptional landscape of platelets. Blood 124:493-502
Clancy, Lauren; Freedman, Jane E (2014) New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis 37:12-6
Freedman, Jane E (2014) Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. Circ Res 114:1372-3
Major, Heather D; Campbell, Robert A; Silver, Robert M et al. (2014) Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia. Am J Obstet Gynecol 210:547.e1-7
Madden, Jesse L; Drakos, Stavros G; Stehlik, Josef et al. (2014) Baseline red blood cell osmotic fragility does not predict the degree of post-LVAD hemolysis. ASAIO J 60:524-8
Shi, Dallas S; Smith, Matthew C P; Campbell, Robert A et al. (2014) Proteasome function is required for platelet production. J Clin Invest 124:3757-66
Chen, Karin; Coonrod, Emily M; Kumanovics, Attila et al. (2013) Germline mutations in NFKB2 implicate the noncanonical NF-*B pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93:812-24
Franks, Zechariah; Campbell, Robert A; Vieira de Abreu, Adriana et al. (2013) Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration. Thromb Haemost 109:684-95
Freedman, Jane E; Tanriverdi, Kahraman (2013) Defining miRNA targets: balancing simplicity with complexity. Circulation 127:2075-7