Thrombin Regulated Platelet Activation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00855296
Recruitment Status : Completed
First Posted : March 4, 2009
Last Update Posted : April 11, 2017
Information provided by (Responsible Party):
Heidi Hamm, Vanderbilt University

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.

Condition or disease
Coronary Artery Disease Acute Coronary Syndrome

  Show Detailed Description

Study Type : Observational
Actual Enrollment : 69 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Thrombin Regulated Platelet Activation
Study Start Date : September 2006
Actual Primary Completion Date : June 2013
Actual Study Completion Date : June 2013

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Biospecimen Retention:   Samples With DNA
Whole blood

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Patients undergoing angioplasty

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00855296

United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Principal Investigator: Heidi E. Hamm, Ph.D. Vanderbilt Universtiy Medical Center, Pharmacology

Responsible Party: Heidi Hamm, Professor and Chair of Pharmacology, Vanderbilt University Identifier: NCT00855296     History of Changes
Other Study ID Numbers: 050182
First Posted: March 4, 2009    Key Record Dates
Last Update Posted: April 11, 2017
Last Verified: April 2017

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Acute Coronary Syndrome
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases