PAR Regulation of Platelet Function in Diabetic Patients
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology, Endocrine, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/2/2016 |
| Start Date: | June 2008 |
| End Date: | June 2013 |
| Contact: | Nancy Colowick, M.Ed. |
| Email: | nancy.e.colowick@vanderbilt.edu |
| Phone: | 615-322-5268 |
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.
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.
Given the known roles of proteases and PARs in coagulation, inflammation, pain, healing and
protection, the need for development of a PAR antagonist as a therapeutic agent for
treatment of thrombosis, atherosclerosis and inflammation is well-recognized. Thus, blocking
PAR action by inhibiting the PAR-G protein interface is an alternative target for blocking
downstream consequences of thrombin-mediated cellular activation. Since there are two PARs
on human platelets, PAR1 and PAR4, it is critical to define the roles of both receptors in
several likely clinical settings where PAR antagonists would be used. In this proposal both
the G protein pathways underlying PAR signaling mechanisms as well as their roles in
pathologies characterized by activated platelets will be studied in detail. We propose in
our grant to investigate the specific roles of individual PARs in mediating the events
leading to the multi-stage process of platelet activation and clot formation. The long term
goals of these studies are to determine novel PAR-specific anti-platelet therapies. The 2002
estimates of the DHHS suggest that 6.3% of the population of the United States (18.2 Million
people) have diabetes, with estimated annual costs of $132 Billion (Centers for Disease
Control and Prevention). The complications of coronary artery and of cerebrovascular disease
account for up to 65% of deaths in patients with diabetes. The prevalence, complexity and
complications of cardiovascular disease are increased in patients with diabetes. This
appears related to the frequent association of diabetes and of insulin resistance with
traditional risk factors for atherosclerosis. Recent studies by Haffner and other
investigators have established the concept of diabetes as a coronary risk equivalent; this
is reflected in the guidelines for therapeutic targets set by the ADA, AHA and ACC.
The clinical importance of platelet activation is reflected by the benefits of aspirin and
clopidogrel and GPIIbIIIa inhibitors in diabetics. Epidemiologic data demonstrates that the
metabolic syndrome is associated with an increased incidence of atherosclerotic events. Type
2 diabetes shares many features in common with the metabolic syndrome, and may represent a
precursor condition, Stern described this in the "common soil hypothesis". Hsueh and Law
have more recently proposed that the progression of insulin resistance to type 2 diabetes
parallels the progression of endothelial dysfunction to atherosclerosis.
These studies were designed to study PAR signaling and G protein activation states in
patients with platelet activation in the setting of the continuum of the metabolic syndrome
and diabetes mellitus. The degree of platelet activation as determined by assays of platelet
reactivity and by the expression of markers of platelet activation will be correlated with
the changes in PAR signaling. These studies will provide a comprehensive assessment of
platelet activation in the setting of the metabolic syndrome, and will compare the extent of
activation in this setting with that in a group of contemporaneously studied patients with
diabetes mellitus. Finally, the influence of the direct thrombin inhibitor, bivalirudin on
platelet activation and signaling will be assessed.
protection, the need for development of a PAR antagonist as a therapeutic agent for
treatment of thrombosis, atherosclerosis and inflammation is well-recognized. Thus, blocking
PAR action by inhibiting the PAR-G protein interface is an alternative target for blocking
downstream consequences of thrombin-mediated cellular activation. Since there are two PARs
on human platelets, PAR1 and PAR4, it is critical to define the roles of both receptors in
several likely clinical settings where PAR antagonists would be used. In this proposal both
the G protein pathways underlying PAR signaling mechanisms as well as their roles in
pathologies characterized by activated platelets will be studied in detail. We propose in
our grant to investigate the specific roles of individual PARs in mediating the events
leading to the multi-stage process of platelet activation and clot formation. The long term
goals of these studies are to determine novel PAR-specific anti-platelet therapies. The 2002
estimates of the DHHS suggest that 6.3% of the population of the United States (18.2 Million
people) have diabetes, with estimated annual costs of $132 Billion (Centers for Disease
Control and Prevention). The complications of coronary artery and of cerebrovascular disease
account for up to 65% of deaths in patients with diabetes. The prevalence, complexity and
complications of cardiovascular disease are increased in patients with diabetes. This
appears related to the frequent association of diabetes and of insulin resistance with
traditional risk factors for atherosclerosis. Recent studies by Haffner and other
investigators have established the concept of diabetes as a coronary risk equivalent; this
is reflected in the guidelines for therapeutic targets set by the ADA, AHA and ACC.
The clinical importance of platelet activation is reflected by the benefits of aspirin and
clopidogrel and GPIIbIIIa inhibitors in diabetics. Epidemiologic data demonstrates that the
metabolic syndrome is associated with an increased incidence of atherosclerotic events. Type
2 diabetes shares many features in common with the metabolic syndrome, and may represent a
precursor condition, Stern described this in the "common soil hypothesis". Hsueh and Law
have more recently proposed that the progression of insulin resistance to type 2 diabetes
parallels the progression of endothelial dysfunction to atherosclerosis.
These studies were designed to study PAR signaling and G protein activation states in
patients with platelet activation in the setting of the continuum of the metabolic syndrome
and diabetes mellitus. The degree of platelet activation as determined by assays of platelet
reactivity and by the expression of markers of platelet activation will be correlated with
the changes in PAR signaling. These studies will provide a comprehensive assessment of
platelet activation in the setting of the metabolic syndrome, and will compare the extent of
activation in this setting with that in a group of contemporaneously studied patients with
diabetes mellitus. Finally, the influence of the direct thrombin inhibitor, bivalirudin on
platelet activation and signaling will be assessed.
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).
We found this trial at
1
site
1211 Medical Center Dr
Nashville, Tennessee 37232
Nashville, Tennessee 37232
(615) 322-5000
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