Author ORCID Identifier
Date Available
12-12-2025
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
Advisor
Dr. Sidney W. Whiteheart
Abstract
Obesity is a multifactorial disease with many comorbidities leading to multiorgan dysfunction. Current studies point towards dysregulation of platelet signaling as a driver for increased risk of cardiovascular disease and stroke. The exact mechanisms remain elusive due to the complex interplay of factors involved, warranting the need to further understand how platelets are affected. Our preliminary data evaluating changes in platelet and coagulation parameters from bariatric patients showed that obesity did not affect platelet count or clotting time as demonstrated in INR values. However, female patients had increased bleeding events before surgery that were decreased after surgery. Due to limitations in patient number, we were unable to conclude the same findings in male patients. Thus, we used a newly developed obese mouse model, MS-NASH, which mimics the multifaceted aspects of the human metabolic syndrome without the use of high-fat diets. MS-NASH males exhibited profound metabolic disruptions, including increased fat, lean, and water mass, along with dyslipidemia and hyperglycemia.
Notably, despite no change in plasma thrombin generation, MS-NASH mice demonstrated heightened bleeding tendencies, with a 45% rebleed rate in the tail transection injury model, pointing to a potential platelet defect. Progenitor megakaryocytes (MK) were increased in the marrow as were their ploidy; however, there was no change in platelet counts. Hematological analysis did show increased RBC count, mean platelet volume (MVP), platelet-large cell ratio (P-LCR), and platelet distribution width (PDW). Interestingly, there were decreases in platelet activation markers and surface receptors. Functionally, platelets from MS-NASH males showed a marked inability to form a stable thrombus under flow over immobilized collagen. Seahorse energy flux analysis revealed an inherent defect in MS-NASH platelet mitochondria function and glycolysis. Collectively, these findings show a profound impact on platelet function and thrombosis in this new obesity model and suggest its value in understanding the effects of obesity on hemostasis and thrombosis.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.521
Funding Information
This study was supported by the National Institutes of Health Grant (TL1TR001997) from 2021 to 2024 and grants from the National Heart Lung and Blood Institute and the National Institutes of Health ( HL56652, HL138179, and HL150818) from 2021 to 2024.
Recommended Citation
peng, chi, "THE DELINEATION OF PLATELET PATHOLOGY IN CARDIOMETABOLIC DISEASE" (2024). Theses and Dissertations--Pharmacology and Nutritional Sciences. 62.
https://uknowledge.uky.edu/pharmacol_etds/62
Included in
Animal Experimentation and Research Commons, Biochemistry Commons, Cardiovascular System Commons, Cells Commons, Cellular and Molecular Physiology Commons, Laboratory and Basic Science Research Commons
