Sepsis is a pro-coagulant illness characterized by injurious and widespread inflammation. Although the role of leukocytes and monocytes is well studied, there is a paucity of data on platelet biology in sepsis. Changes in platelet function may contribute directly to inflammation and thrombosis in sepsis. My preliminary data demonstrate that platelets isolated from sepsis patients produce new tissue factor (TF) mRNA and accelerate clot times. My data also shows that TF mRNA production correlates with illness severity and mortality. Thus, platelets appear to have biological functions important in sepsis. In the proposed application, I will study platelet activites in sepsis patients and healthy controls. My proposed studies will prospectively charaterize (1) novel synthesis of TF mRNA, (2) platelet activation measured with P-selectin flow cytometry, and (3) platelet turnover measured with thiazole orange flow cytometry. I will determine if these platelet activities and functions predict 28-day mortality, overt DIG, and venous thromboembolism (VTE) in sepsis patients. I will also compare these platelet activities in sepsis patients to health controls. These investigations may provide additional understanding of platelet functions and activities in human diseases. These novel observations will allow us to further characterize molecular pathways and to develop new therapies in the treatment of sepsis and VTE. These studies build on our robust preliminary data and will be accomplished in an extremely supportive environment. I have two mentors with strong research and mentoring experience, an advisory panel with national recognition for their expertise in inflammation and thrombosis, an personal track record of productive research, and a fully committed department. I also have constructed a career-development-plan that incorporates structured, didactic training in research methods, participation in ongoing research conferences, and training in the responsible conduct of research. These investigations will not only provide significant contributions to our understanding of platelet functions in sepsis and VTE, but will also lay the foundation for me to advance from junior investigator to an independently-funded clinician-scientist.

Public Health Relevance

The research proposed in this application will expand our understanding of how platelets influence morbidity and mortality in sepsis. These studies may ultimately provide new therapeutic targets to improve our care of patients with sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL092161-04
Application #
8269837
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Sarkar, Rita
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$155,025
Indirect Cost
$10,550
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A et al. (2016) Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection. Crit Care Med 44:e574-8
Brown, Samuel M; Sorensen, Jeffrey; Lanspa, Michael J et al. (2016) Multi-complexity measures of heart rate variability and the effect of vasopressor titration: a prospective cohort study of patients with septic shock. BMC Infect Dis 16:551
Vazquez, Sara; Rondina, Matthew T (2015) Direct oral anticoagulants (DOACs). Vasc Med 20:575-7
Franks, Zechariah; Carlisle, McKenzie; Rondina, Matthew T (2015) Current challenges in understanding immune cell functions during septic syndromes. BMC Immunol 16:11
Rondina, Matthew T; Carlisle, McKenzie; Fraughton, Tamra et al. (2015) Platelet-monocyte aggregate formation and mortality risk in older patients with severe sepsis and septic shock. J Gerontol A Biol Sci Med Sci 70:225-31
Kaplan, David; Casper, T Charles; Elliott, C Gregory et al. (2015) VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Chest 148:1224-30
Edholm, Karli; Ragle, Nathan; Rondina, Matthew T (2015) Antithrombotic management of atrial fibrillation in the elderly. Med Clin North Am 99:417-30
Stewart, Lauren K; Peitz, Geoffrey W; Nordenholz, Kristen E et al. (2015) Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism. J Thromb Thrombolysis 40:161-6
Brown, Samuel M; Grissom, Colin K; Rondina, Matthew T et al. (2015) Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome. Exp Lung Res 41:155-62
Brown, Samuel M; Tate, M Quinn; Jones, Jason P et al. (2015) Coefficient of Variation of Coarsely Sampled Heart Rate is Associated With Early Vasopressor Independence in Severe Sepsis and Septic Shock. J Intensive Care Med 30:420-5

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