PAR Regulation of Platelet Function in Diabetic Patients

NCT00855374 | Completed DMC

• 1 other identifier: 070474
• Study Type: observational
• Target: 195
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Coronary Artery Disease; Acute Coronary Syndrome; Diabetes; Metabolic Syndrome

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Diabetic patients in the Vanderbilt General Clinical Research Center

You may qualify if:

• Age: over 18, Sex: male and female.
• Patients who undergo clinically indicated coronary angiography and/or PCI. Patients in Group 1 (elective PCI) include those presented with stable angina (ACC definition for stable angina).
• Coronary angiography reveals severe stenosis (\>70%) that requires PCI.
• Patients in Group 2 (elective PCI in subjects with diabetes) include those who present with stable angina, or with findings on non-invasive testing (exercise or pharmacologic stimulation with imaging by nuclear perfusion imaging or stress echocardiography) in whom coronary angiography reveals severe stenosis (\>70%) that requires PCI.
• Patients in Group 2 (ACS) include those presented with unstable angina or non-ST elevation myocardial infarction (as defined by the ACC).
• Coronary angiography reveals severe stenosis (\>70%) that requires PCI.

You may not qualify if:

• Significant left main coronary artery disease.
• Severely impaired left ventricular systolic function (EF\<35%).
• Prior treatment with enoxaparin, Bivalirudin (or other thrombin inhibitors), Warfarin, or thrombolytic agents \<48 hours. Prior history of myocardial infarction (\<6 weeks).
• Prior history of stroke (\<6 weeks).
• Prior history of coronary intervention (\<6 weeks).
• History of HIV/AIDS.
• The patients will be identified in the following manner:
• All subjects will be picked from a pool of patients diagnosed with stable angina and diabetes from the Vanderbilt Page-Campbell Heart Institute at Vanderbilt University Medical Center and undergo a complete history and physical examination. Patients with acute coronary syndrome will be referred from the acute cardiology patient service at Vanderbilt University Medical Center.
• Subjects with hematologic, renal (creatinine \> 2.0 mg/dl), hepatic, inflammatory, and neoplastic disorders, and those who sustained a recent (\< 1 month) myocardial infarction, ACS, or stroke will be excluded.
• Patients who used nonsteroidal anti-inflammatory drugs, corticosteroids, or hormone replacement therapy will also be excluded.
• Pregnancy will be excluded in women of child bearing potential by measurement of urine ß-HCG (it is standard of care to determine if a woman is pregnant prior to elective PCI and will be screened as part of their PHI).
• For healthy volunteers, pregnancy will be excluded per verbal report.
• Data will be collected regarding patient demographics including height and weight, abdominal circumference, blood pressure, comorbid medical conditions, triglycerides, HDL, fasting glucose and medication use (including prescription of antithrombotic agents, ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel antagonists and HMG-CoA inhibitors).

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood

MeSH Terms

Conditions

Coronary Artery Disease; Acute Coronary Syndrome; Diabetes Mellitus; Metabolic Syndrome

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism

Study Officials

• Heidi E Hamm, Ph.D.

  Vanderbilt University Medical Center, Pharmacology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chair of Pharmacology

Study Record Dates

• First Submitted: March 2, 2009
• First Posted: March 4, 2009
• Study Start: June 1, 2008
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: April 11, 2017

Record last verified: 2017-04

Locations

US (1)