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Biomedical subjects

Jane E Freedman

Publications and source records attributed to Jane E Freedman.

At least 19 recordsLinked to original sources
PubMed2026

Plasma von Willebrand Factor and ADAMTS13 Interact With APOE-ε4 in Predicting Longitudinal Brain Atrophy and Cognitive Decline Over a 9-Year Follow-Up.

BACKGROUND: Von Willebrand factor (VWF) and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) are linked to dementia risk, and limited evidence suggests apolipoprotein E (APOE)-&#x3b5;4 alters VWF release. This study assessed whether baseline VWF and ADAMTS13 levels predict neurodegeneration and cognitive decline and evaluated effect modification by APOE-&#x3b5;4 carriership. METHODS: Vanderbilt Memory and Aging Project cohort participants (n=332, 73&#xb1;7&#x2009;years, 59% male) completed serial blood draw, neuropsychological assessment, and brain magnetic resonance imaging over 6.4&#x2009;years (range 1.4-9.7&#x2009;years). Baseline plasma VWF and ADAMTS13 levels were quantified using mass spectrometry and Olink. Fully adjusted linear mixed-effects models related protein&#xd7;time and protein&#xd7;APOE-&#x3b5;4&#xd7;time interaction terms to longitudinal brain magnetic resonance imaging and neuropsychological outcomes. RESULTS: Lower baseline ADAMTS13 predicted faster declines in language (&#x3b2;=0.11, P=0.01), information processing speed (&#x3b2;=0.27, P=0.001), executive function (&#x3b2;=0.01, P=0.03), episodic memory (&#x3b2;=0.01, P=0.03), and visuospatial ability (&#x3b2;=0.11, P=0.001) and faster increases in global (&#x3b2;=-0.29, P=0.01) and frontal (&#x3b2;=-0.17, P=0.01) white matter hyperintensity volumes. Associations between ADAMTS13 and faster rates of cognitive decline and white matter injury were driven by APOE-&#x3b5;4 carriers. Models relating VWF to longitudinal outcomes were null. APOE-&#x3b5;4 interacted with VWF on longitudinal gray matter volumetric outcomes, such that faster rates of global gray matter atrophy were observed with higher baseline VWF levels among APOE-&#x3b5;4 noncarriers only (&#x3b2;=-1530.5, P<0.001). CONCLUSIONS: ADAMTS13 shows promise as a potential plasma biomarker for brain aging outcomes, but additional research is warranted to understand the performance of VWF in the presence versus absence of an APOE-&#x3b5;4 allele.

Humans↗
PubMed2006

The many antithrombotic actions of nitric oxide.

Vessel occlusion within a coronary artery is the precipitating event in unstable coronary syndromes and is primarily due to rupture of atheromatous plaque and subsequent thrombus formation. In the nondiseased vessel, the intact endothelium releases the vasodilator and antithrombotic agent nitric oxide (NO) preventing platelet adherence and activation. In the diseased vessel and during unstable coronary syndromes, release of both endothelial and platelet NO is impaired contributing to thrombus formation. Nitric oxide availability in the vascular system has been associated with various disease states, genetic variants, and medication use. Recently, through the development of new NO donors and by targeting specific signaling pathways, there has been an attempt to enhance the antithrombotic actions of NO as a means to manipulate arterial thrombosis.

Animals↗
PubMed2005

Molecular regulation of platelet-dependent thrombosis.

Hemostasis is a normal process preventing the sequelae of uncontrolled hemorrhage. In certain settings, these same processes cause adverse clinical events due to thrombotic occlusion of a vessel. The majority of unstable coronary syndromes result from disruption of an atherosclerotic plaque, leading to the exposure of subintimal contents, which triggers coagulation and the formation of a platelet-rich thrombus. The central role of platelet activation in the events that lead to vessel occlusion is well known. However, this process is complex and influenced by a myriad of cellular and plasma-derived mediators that regulate the balance between occlusive and nonocclusive thrombosis.

Blood Platelets↗
PubMed2005

Aspirin resistance and atherothrombotic disease.

Acute coronary syndromes and other manifestations of atherothrombotic disease are primarily caused by atherosclerotic plaque rupture or fissuring and subsequent occlusive or subocclusive thrombus formation. Platelets play a critical role in the pathophysiology of atherothrombotic disease, and aspirin is the most commonly used antiplatelet agent. Clinical trials have demonstrated the efficacy of aspirin in both primary and secondary prevention of myocardial infarction, stroke, and cardiovascular death. Despite its proven benefit, the absolute risk of recurrent vascular events among patients taking aspirin remains relatively high, an estimated 8% to 18% after two years. Therapeutic resistance to aspirin might explain a portion of this risk. Although formal diagnostic criteria and a validated method of measurement are lacking, aspirin resistance may affect between 5% and 45% of the population. Given the prevalence of cardiovascular disease, the potential impact of aspirin resistance is large. Currently, however, there are many unanswered questions regarding the biological mechanism, diagnosis, population prevalence, clinical relevance, and optimal therapeutic intervention for aspirin resistance.

Aspirin↗
PubMed2005

Plasma, serum, and platelet expression of CD40 ligand in adults with cardiovascular disease.

The application of soluble CD40 ligand (sCD40L) as a biomarker has garnered great scientific and clinical interest. However, there are many uncertainties with regard to the biology of sCD40L. Although presumed to be a marker of platelet activation, relative levels in plasma, serum, and platelet expression are unknown, as is the optimal method for its measurement. We measured CD40L from serum, platelet-poor plasma, and platelet surface in adults who had stable cardiovascular disease (CVD) and those who had unstable CVD (n = 40). Plasma sCD40L did not differ significantly between groups. Serum sCD40L was significantly lower (1.4 +/- 1.3 vs 5.2 +/- 3.7 ng/ml, p <0.001) and platelet membrane CD40L expression was higher (1.4 +/- 0.7% vs 0.9 +/- 0.6%, p = 0.03) in unstable compared with stable CVD. When the 2 groups were considered together, there was a significant correlation between plasma and serum sCD40L levels (rho = 0.4, p = 0.02) and negative correlations between plasma (rho = -0.3, p = 0.04) and serum (rho = -0.4, p = 0.01) sCD40L levels with platelet membrane CD40L expression. In unstable CVD, the correlation between sCD40L measurements was poor. Consistent with enhanced platelet activation, there was a positive correlation between platelet aggregation and surface CD40L expression (rho = 0.5, p = 0.02) and between platelet expression of CD40L and P-selectin (rho = 0.4, p = 0.05) in unstable CVD. There was no correlation between CD40L and platelet count or C-reactive protein. Only surface expression of CD40L compared with platelet-derived (plasma) or total (serum) CD40L level proved a reliable marker of platelet function in patients who had stable CVD and those who had unstable CVD. In conclusion, our data demonstrate the complex nature of CD40L and highlight the distinct processes of expression, shedding, and clearance of this ligand in patient populations.

Adult↗
PubMed2005

CD40 ligand influences platelet release of reactive oxygen intermediates.

OBJECTIVE: Soluble CD40 ligand (sCD40L) has been recently implicated in the pathogenesis of atherosclerosis. Elevated levels of sCD40L in acute coronary syndrome patients suggests enhanced platelet function; however, the exact mechanism by which this occurs is unknown. In this study, we examined the effect of sCD40L on platelet function and reactive oxygen and nitrogen species (RONS) generation. METHODS AND RESULTS: Platelet stimulation in the presence of recombinant sCD40L (rsCD40L) led to enhanced generation of RONS as measured by DCFHDA oxidation and confocal microscopy. Incubation with rsCD40L led to enhanced platelet P-selectin expression, aggregation, and platelet-leukocyte conjugation. Platelets isolated from CD40L-deficient mice had decreased agonist-induced NO release as compared with wild-type mice. Incubation of platelets with rsCD40L enhanced stimulation-induced p38 MAP kinase and Akt phosphorylation. CONCLUSIONS: Soluble CD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation, as well as increases stimulation-induced platelet release of RONS through activation of Akt and p38 MAP kinase signaling pathways. These data suggest that sCD40L regulates platelet-dependent inflammatory and thrombotic responses that contribute to the pathogenesis of atherothrombosis.

Animals↗
PubMed2005

The effect of dipyridamole on vascular cell-derived reactive oxygen species.

Platelet and vascular stimulation leads to release of reactive oxygen species (ROS) that are known to influence vascular reactivity and thrombosis. Dipyridamole is a vasodilator and platelet inhibitor that has previously been shown to have direct antioxidant properties. The antioxidant effects of dipyridamole on vascular cell-derived ROS are not known; therefore, dipyridamole was incubated with endothelial cells and platelets and cellular redox status and release of endogenous ROS were assessed. Dipyridamole decreased intracellular basal ROS generation from endothelial cells as measured by DCFDA (2',7'-dichlorodihydrofluorescein diacetate) oxidation. Incubation of endothelial cells with dipyridamole also attenuated t-butylhydroperoxide-induced oxidative stress. Using a redox-sensitive fluorescent dye, dipyridamole improved cellular activity after treatment with t-butylhydroperoxide. Incubation with dipyridamole did not alter platelet release of nitric oxide or hydrogen peroxide but significantly attenuated superoxide release. Using flow cytometry and confocal microscopy, dipyridamole decreased platelet ROS generation. Dipyridamole also suppressed platelet-soluble CD40 ligand release. In summary, at therapeutically relevant concentrations, dipyridamole suppresses the formation of ROS in platelets and endothelial cells and improves cellular redox status. These data suggest that the redox-dependent properties of dipyridamole have a direct effect on vascular cells.

Antioxidants↗
PubMed2005

Grape seed and skin extracts inhibit platelet function and release of reactive oxygen intermediates.

Red wine and purple grape juice contain polymeric flavonoids with antioxidant properties believed to be protective against cardiovascular events but the alcohol and sugar content of these beverages has curtailed their medicinal use. Acute cardiac events are also associated with enhanced inflammation and thrombosis. In this study, the extracts from grape skins or seeds were examined for their anti-inflammatory properties and effect on platelet release of reactive oxygen intermediates. Incubation of platelets with seed or skin extract led to a decrease in platelet aggregation from 68.8+/-19.8% to 45+/-3.6% for seeds and to 27+/-7.2% for skin, respectively (P<0.05). Platelet incubation with grape skin or seed extracts led to a marked decrease in superoxide release from 73+/-6.2 to 2+/-3.4 for grape seeds and to 0.33+/-0.57 for grape skin (chemilum. units; P<0.05) as well as a significant increase in radical-scavenging activity, decrease in reactive oxygen species release by confocal microscopy, and enhanced platelet NO was measured using an NO-sensitive microelectrode. These effects were dose dependent for both grape extracts. Coincubation with seeds and skins led to additive inhibition of platelet aggregation, enhanced NO release, and prevented superoxide production. Incubation with seed or skin extracts led to an immediate attenuation of release of the inflammatory mediator, soluble CD40 ligand. Thus, the extracts from purple grape skins and seeds inhibit platelet function and platelet-dependent inflammatory responses at pharmacologically relevant concentrations. These findings suggest potentially beneficial platelet-dependent antithrombotic and anti-inflammatory properties of purple grape-derived flavonoids.

Blood Platelets↗
PubMed2004

Compensatory mechanisms influence hemostasis in setting of eNOS deficiency.

The balance between thrombosis and hemorrhage is carefully regulated. Nitric oxide (NO) is an important mediator of these processes, as it prevents platelet adhesion to the endothelium and inhibits platelet recruitment. Although endothelial NO synthase (eNOS)-deficient mice have decreased vascular reactivity and mild hypertension, enhanced thrombosis in vivo has not been demonstrated. To determine the role of endogenous NO in hemostasis, a model of carotid arterial injury and thrombosis was performed using eNOS-deficient and wild-type mice. Paradoxically, the eNOS-deficient animals had a prolongation of time to occlusion compared with the wild-type mice (P < 0.001). Consistent with this finding, plasma markers suggesting enhanced fibrinolysis [tissue plasminogen activator (t-PA) activity and antigen and D-dimer levels] were significantly elevated in eNOS-deficient animals. Vascular tissue expression of t-PA and platelet activity levels were not altered. In endothelial cells, t-PA is stored in Weibel-Palade bodies, and exocytosis of these storage granules is inhibited by NO. Thus in the absence of NO, release of Weibel-Palade body contents (and t-PA) could be enhanced; this observation is also supported by increased von Willebrand factor levels observed in eNOS-deficient animals. In summary, although eNOS deficiency attenuates vascular reactivity and increases platelet recruitment, it is also associated with enhanced fibrinolysis due to lack of NO-dependent inhibition of Weibel-Palade body release. These processes highlight the complexity of NO-dependent regulation of vascular homeostasis. Such compensatory mechanisms may partially explain the lack of spontaneous thrombosis, minimally elevated baseline blood pressure, and normal life span that are seen in animals deficient in a pivotal regulator of vascular patency.

Animals↗
PubMed2004

The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates.

Tamoxifen is effective in the prevention and treatment of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism for this effect is unknown. Reactive oxygen intermediates enhance platelet-dependent thrombosis, and in oncological studies, tamoxifen has been shown to increase production of reactive oxygen species. Therefore, the effects of tamoxifen and its bioactive metabolites on platelet activity and platelet reactive oxygen species were determined. Platelets were incubated with tamoxifen or the metabolites 4-hydroxy-tamoxifen (4-OH), N-desmethyl tamoxifen, or 4-hydroxy-N-desmethyl tamoxifen (endoxifen). Tamoxifen metabolites have been previously shown to possess enhanced bioactivity, and consistent with this observation, tamoxifen metabolites but not tamoxifen modestly increased platelet aggregation. These effects were similar with platelets isolated from male or female subjects. Platelet nitric oxide release or cGMP levels were not altered by incubation with tamoxifen or any of its metabolites. Incubation with tamoxifen metabolites increased stimulation-dependent platelet superoxide release [8.1 +/- 1.6 arbitrary units (a.u.) for control versus 15.2 +/- 3.5 a.u. for 4-OH; P < 0.01]. Coincubation with a superoxide dismutase mimetic eliminated the tamoxifen metabolite-induced enhancement of platelet aggregation. Corresponding to increased superoxide release, incubation with tamoxifen metabolites enhanced the functional activation of NADPH oxidase as determined by phosphorylation of its subunits p47(phox) and p67(phox). In summary, incubation of platelets with the active metabolites of tamoxifen increases stimulation-dependent superoxide release through a NADPH oxidase-dependent mechanism. This results in modest changes in platelet function and seems to be consistent with previous oncological studies demonstrating tamoxifen-dependent increase in reactive oxygen species generation.

Blood Platelets↗
PubMed2004

The clinician as investigator: participating in clinical trials in the practice setting.

The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are not affiliated with an academic medical center. Thus, there is a demonstrable need for physicians in private practice to enlist as investigators in these trials. This article is intended to encourage those physicians by describing the need and providing the rationale for their participation. It covers basic requirements for participating in clinical trials and outlines ethical, regulatory, financial, and other logistical issues of importance for the potential investigator and provides an algorithm for selecting a study for participation. Finally, the appendices review basic elements of study design and statistical principles, which may be of interest to a potential investigator.

Choice Behavior↗
PubMed2004

Glycoprotein IIb/IIIa inhibition enhances platelet nitric oxide release.

INTRODUCTION: Platelet aggregates form by fibrinogen binding to the membrane receptor glycoprotein IIb/IIIa (GPIIb/IIIa). While GPIIb/IIIa inhibitors block fibrinogen-platelet binding, stimulation of other functionally important platelet receptors may still occur. Blocking the GPIIb/IIIa receptor prevents platelet aggregation but not activation and the subsequent effect on other platelet pathways is largely unknown. MATERIALS AND METHODS: As activated platelets release reactive oxygen species that may influence thrombosis or vascular function, the effect of GPIIb/IIIa inhibitors on the platelet release of nitric oxide (NO) and superoxide was determined using an electrochemical detector and luminescence, respectively. Location of relevant platelet proteins and the interaction between platelets and leukocytes in the presence or absence of GPIIb/IIIa inhibition was determined. RESULTS: Although incubation with GPIIb/IIIa inhibitors completely abolished platelet aggregation, stimulation dependent NO release was significantly enhanced. Superoxide is known to alter the bioavailability of NO, and its contribution to the GPIIb/IIIa dependent increase in NO release was determined. In the presence of GPIIb/IIIa inhibitors, platelet superoxide release was significantly decreased. Preincubation with GPIIb/IIIa inhibitors also modified aggregation induced membrane translocation of the platelet proteins, endothelial NO synthase (eNOS) and NADPH oxidase (p67phox and p47phox), known to contribute to the generation of NO and superoxide, respectively. In the presence of leukocytes, abciximab incubation led to enhanced NO release and attenuated superoxide generation. CONCLUSION: These observations suggest that the pharmacological effects of GPIIb/IIIa antagonists on platelet function, apart from inhibition of aggregation, may contribute to their efficacy.

Abciximab↗
PubMed2004

Aspirin resistance: current concepts.

Aspirin is an effective antiplatelet agent with proven benefit in the prevention of atherothrombotic complications of cardiovascular disease. The antithrombotic effects of aspirin, however, are variable among individuals and this might explain, in part, why the absolute risk of recurrent vascular events in patients receiving aspirin therapy remains relatively high (8% - 18% after 2 years). Although formal diagnostic criteria are lacking, aspirin resistance generally describes the failure of aspirin to produce an expected biological response or the failure of aspirin to prevent atherothrombotic events. Aspirin resistance has been reported to occur in 5% to 45% of the general population; therefore, its detection is potentially of clinical importance. The biological mechanisms, population prevalence, laboratory methods for detection, and clinical relevance of aspirin resistance are discussed in this review.

Aspirin↗
PubMed2003

Regulation of endogenous reactive oxygen species in platelets can reverse aggregation.

OBJECTIVE: While much is known about the normal activation of platelets, there have been few observations demonstrating reversibility of the aggregation process. Inhibition of phosphoinositide 3-kinase (PI3-kinase) has been shown to cause platelet disaggregation. In addition, NO is a known potent inhibitor of platelet function. In this study, the role of PI3-kinase in the regulation of endogenous platelet NO and the relevance to platelet function was determined. METHODS AND RESULTS: Incubation of platelets with PI3-kinase inhibitors led to a dose-dependent increase in platelet NO and cGMP levels that were temporally related to the period of platelet disaggregation. Addition of ferroheme myoglobin eliminated both the augmented NO release and disaggregation. PI3-kinase inhibition decreased the functional activation of NADPH oxidase and this corresponded to decreased superoxide release. To confirm these findings, platelets from NOS III-deficient mice were studied. These platelets did not release NO, and PI3-kinase inhibition led to decreased superoxide but not platelet disaggregation. CONCLUSIONS: Overall, these results indicate that platelet-derived NO contributes to the process of platelet disaggregation. PI3-kinase plays a role in regulating NADPH oxidase-generated superoxide in platelets and, by altering the bioactivity of platelet NO, may be a potential method for reversing platelet aggregation and thrombus formation.

Animals↗