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Vanderbilt University |
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Information provided by: | Vanderbilt University |
ClinicalTrials.gov Identifier: | NCT00855296 |
Thrombin is the most potent activator of platelets, and platelet activation is a hallmark of thrombosis. Coronary artery disease (CAD) is the major cause of mortality and morbidity in the United States and other industrialized countries, and thrombotic sequelae are the key cause of death in diabetes.
The accumulation of thrombin at sites of vascular injury provides one of the major mechanisms of recruiting platelets into a hemostatic plug. Thrombin works by activation of the G protein-coupled protease activated receptors PAR1 and PAR4 on human platelets to initiate signaling cascades leading to increases in [Ca]i, secretion of autocrine activators, trafficking of adhesion molecules to the plasma membrane, and shape change, which all promote platelet aggregation. The thrombin receptors work in a progressive manner, with PAR1 activated at low thrombin concentrations, and PAR4 recruited at higher thrombin concentrations. As direct thrombin inhibitors become widely used in clinical practice, it is important to assess their effects on vascular function. Our hypothesis is that PAR1 and PAR4 do not signal through the same G protein pathways, and that PAR4 is not a strong platelet agonist. To investigate this hypothesis, the investigators will study the G protein pathways downstream of PAR4, and assess ex-vivo platelet responsiveness to thrombin, PAR1, and PAR4 agonist peptides, both in normal human subjects, and along the stages of pathology, from patients with stable angina as well as unstable angina who are undergoing angioplasty. Similarly, the investigators will examine platelet function in patients with metabolic syndrome as well as diabetes, along the continuum from insulin resistance to full-blown disease. These studies will provide deeper insight into the G protein pathways used by PARs. They will elucidate the contribution of PAR receptors to normal platelet function as well as the abnormal platelet activation in thrombotic states. The long term goal is to understand the implications for PAR receptors as therapeutic targets for anti-platelet therapies that may carry less bleeding risk.
Condition |
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Coronary Artery Disease Acute Coronary Syndrome |
Study Type: | Observational |
Study Design: | Case Control, Prospective |
Official Title: | Thrombin Regulated Platelet Activation |
Whole blood
Estimated Enrollment: | 200 |
Study Start Date: | September 2006 |
Estimated Study Completion Date: | September 2011 |
Estimated Primary Completion Date: | June 2011 (Final data collection date for primary outcome measure) |
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
Sampling Method: | Probability Sample |
Patients undergoing angioplasty
Inclusion Criteria:
Exclusion Criteria:
Contact: Willie J Hudson, M.S. | 615-322-5268 | willie.j.hudson@vanderbilt.edu |
Contact: Matthew Duvernay, Ph.D. | 615-322-5268 | matthew.t.duvernay@Vanderbilt.Edu |
United States, Tennessee | |
Vanderbilt University Medical Center | Recruiting |
Nashville, Tennessee, United States, 37232 | |
Contact: Willie J Hudson, M.S. 615-322-5268 |
Principal Investigator: | Heidi E. Hamm, Ph.D. | Vanderbilt Universtiy Medical Center, Pharmacology |
Responsible Party: | Vanderbilt University ( Heidi E. Hamm ) |
Study ID Numbers: | 050182 |
Study First Received: | March 2, 2009 |
Last Updated: | March 31, 2009 |
ClinicalTrials.gov Identifier: | NCT00855296 History of Changes |
Health Authority: | United States: Institutional Review Board |
Thrombin Arterial Occlusive Diseases Coronary Disease Heart Diseases Myocardial Ischemia |
Acute Coronary Syndrome Vascular Diseases Arteriosclerosis Ischemia Coronary Artery Disease |
Arterial Occlusive Diseases Coronary Disease Pathologic Processes Disease Heart Diseases Myocardial Ischemia |
Syndrome Acute Coronary Syndrome Vascular Diseases Cardiovascular Diseases Arteriosclerosis Coronary Artery Disease |