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Biomedical subjects

P A Gurbel

Publications and source records attributed to P A Gurbel.

At least 19 recordsLinked to original sources
PubMed2001

Clinical utility of the platelet function analyzer (PFA-100) for the assessment of the platelet status in patients with congestive heart failure (EPCOT trial).

BACKGROUND: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of platelet function analyzer (PFA-100) in the CHF population. METHODS: Blood samples were obtained for measurement of adenosine diphosphate (ADP)/collagen and epinephrine/collagen shear-induced closure time (CT), whole blood aggregation, platelet contractile force, activity of glycoprotein (GP) IIb/IIIa, and P-selectin receptors in 100 consecutive outpatients with CHF. RESULTS: Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings as well. CT correlates well with whole blood aggregometry (r(2)=.587) and less with GP IIb/IIIa activity (r(2)=.326). No correlation has been observed for the CT with the platelet-bound P-selectin (r(2)=.041) and platelet contractile force measures (r(2)=.028). CONCLUSIONS: PFA-100 is indeed capable to serve as a platelet analyzer and may be successfully used as a screening device. However, patients with heart failure enrolled in the EPCOT trial exhibited a marginal, sometimes oppositely directed changes in the platelet function, challenging the diagnostic utility of PFA-100 to serve as a useful tool for the identification of platelet abnormalities, predicting clinical outcomes, or for the monitoring of antiplatelet strategies in this population.

Adenosine Diphosphate↗
PubMed2001

Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors.

Recently, clinical depression has been identified as an independent risk factor for increased mortality in patients following acute coronary events. Although the underlying mechanisms of this link remain uncertain, increased platelet activity has been suggested but never proven as the mechanism responsible for this association. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI), and is an effective antidepressant agent. Its major liver metabolite, N-desmethylsertraline (NDMS), is known to be neurologically inactive. We assessed the in vitro effects of escalating concentrations of sertraline and NDMS on human platelets by aggregometry in plasma and whole blood, by expression of major surface receptors with flow cytometry in washed cells and in the whole blood, and quantitatively by various platelet function analysers in healthy volunteers and patients with coronary artery disease. Pretreatment of blood samples with sertraline and NDMS resulted in a dose-dependent inhibition of platelet-rich plasma aggregation induced by 5 microM ADP (P =, 0.002), by 10 microM ADP (P = 0.0017), by collagen (P = 0.008), and by thrombin (P = 0.026). Whole blood platelet aggregability was also significantly reduced when induced by 20 microM ADP (P = 0.006), and by collagen (P = 0.01). Surface expression of CD9 (P = 0.004), GP Ib (P = 0.0001), GP IIb/IIIa (P = 0.007), VLA-2 (P = 0.01), P-selectin (P = 0.02), and PECAM-1 (P = 0.01), but not the vitronectin receptor, was also reduced in sertraline and NDMS pretreated washed platelets. Whole blood flow cytometry revealed significant inhibition of GP IIb/IIIa (P = 0.008), and P-selectin expression (P = 0.0001) in NDMS treated samples. Closure time was delayed for the collagen-ADP cartridge (P = 0.009), and for the collagen-epinephrin cartridge (P = 0.01), indicating platelet inhibition in whole blood under high shear conditions. Rapid platelet-function assay revealed a decreased (P = 0.002) ability of platelets to agglutinate fibrinogen-coated beads, suggesting GP IIb/IIIa inhibition. Both sertraline, and its neurologically inactive metabolite NDMS, exhibited significant dose-dependent inhibition of human platelets. The documented anti-platelet effects of sertraline and NDMS may be directly related to the mortality benefits of SSRIs after ischemic events including myocardial infarction and stroke.

Coronary Disease↗
PubMed2001

Usefulness of combining necrosis and platelet markers in triaging patients presenting with chest pain to the emergency department.

BACKGROUND: Myocardial injury and platelet activation play important roles in the pathogenesis of unstable coronary syndromes. We sought to determine whether the combined measurement of platelet and necrosis markers would improve risk stratification, and yield higher diagnostic utility in patients presenting to the emergency department with chest pain. METHODS AND RESULTS: Platelet and soluble P-selectin together with myoglobin, creatine kinase, CK-MB fraction, and troponin I were measured from the autologous samples in 122 consecutive patients. Statistical analysis revealed strong Spearman correlation coefficients (0.141--0.412; p<0.001) between platelet expression of P-selectin and plasma levels of necrosis markers. Platelet P-selectin and necrosis markers were independent predictors (c-index>0.7) for acute myocardial infarction, while plasma P-selectin exhibited random distribution. Elevated soluble P-selectin and myoglobin were the most valuable in identifying patients with congestive heart failure. None of the markers were useful for triaging chest pain patients with unstable angina. Analysis of incremental gains (Chi-squares) reveals that with respect to platelet P-selectin, myoglobin adds 50 % to AMI diagnostic value, and creatine kinase yields an additional 20 % in triaging these patients. The diagnostic value of soluble P-selectin is substantially (72 %) increased by myoglobin measurements, and enhanced even further (44 %) by adding cardiac troponin I for identifying heart failure patients among the chest pain population. CONCLUSION: Simultaneous determination of platelet and necrosis markers improve the early diagnosis of acute myocardial infarction and congestive heart failure among patients with chest pain presenting into the Emergency Department. Well controlled clinical trials are needed to prove the advantage of combining platelet and necrosis data over presently used techniques in emergency medicine.

Adult↗
PubMed2001

Uniform platelet activation exists before coronary stent implantation despite aspirin therapy.

BACKGROUND: Platelets play an important role in the natural history of coronary artery disease. Enhanced platelet aggregation and receptor expression unquestionably occur after coronary stent implantation; however, the functional characteristics of platelets before stenting have not been fully elucidated. METHODS: Platelets were assessed before intervention by platelet-rich plasma aggregation (PA) with 5 mmol adenosine diphosphate (ADP) and 1 mg/mL collagen; whole blood aggregation (WBA) by 1 mg/mL collagen; shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 126 patients undergoing elective coronary artery stent placement. All patients received aspirin for at least 7 days. The data were compared with those from 64 healthy volunteers. RESULTS: Each test revealed sustained platelet activation in patients undergoing coronary stenting compared with control values. These differences were significant for collagen-induced PA (P =.031); CF (P =.0001); expression of glycoprotein (GP) IIb/IIIa (P =.0001); P-selectin (P =.0008); platelet/endothelial cell adhesion molecule (PECAM)-1 (P =.0001); CD107a (P =.0001); CD107b (P =.0004); and CD63 (P =.009). CONCLUSION: Platelets are indeed activated before coronary stenting despite antecedent therapy with aspirin.

Adult↗
PubMed2001

Platelet function and fibrinolytic agents: two sides of a coin?

Fibrinolytic therapy is the established treatment for the management of patients with ST elevation acute myocardial infarction (AMI). Present fibrinolytic regimens have a number of shortcomings, including the failure to produce early and sustained reperfusion, as well as failure to prevent reocclusion in at least some patients. Platelets play an important role in coronary thrombosis responsible for AMI. The effect of coronary fibrinolysis on platelets has been extensively debated in the literature with evidence of both platelet activation and inhibition. Among fibrinolytic agents, tissue plasminogen activator (t-PA) is considered to be the mainstay in the treatment of coronary artery disease. The native t-PA molecule has been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. The result is a group of mutant t-PA variants considered third-generation plasminogen activators. TNK-t-PA is one bioengineered variant of t-PA. Another third-generation plasminogen activator is reteplase (r-PA). Like TNK-t-PA, it is a variant of t-PA that has been developed to establish a more rapid, complete, and stable coronary artery patency, thus promising reduced mortality. Both r-PA and TNK-t-PA are effective when given as bolus therapy. This feature may facilitate more rapid treatment as well as decrease overall costs of treatment. New fibrinolytic regimens include potent antiplatelet agents that may improve sustained reperfusion. This review summarizes the latest and often confusing data on the interaction between fibrinolytic therapy and platelets in certain in vitro, animal and clinical scenarios.

Animals↗
PubMed2001

The potential of monoclonal antibodies to reduce reperfusion injury in myocardial infarction.

Reperfusion injury is mediated, in part, by the accumulation of platelets and leucocytes in the microvasculature after reflow. These components of the blood pool form aggregates that can obstruct flow in small vessels. In addition, mediators released from leucocytes and platelets further damage the reperfused myocardium. A strategy to limit reperfusion injury exploits the important role of membrane-bound adhesion molecules that attach platelets and leucocytes to themselves and to the vascular endothelium. Monoclonal antibodies against specific adhesion receptors effectively eliminate the function of the receptor. The most widely investigated receptors are P-selectin, present on platelets and the endothelium, CD11/CD18, present on leucocytes, and the fibrinogen receptor on platelets. Numerous animal studies have strongly supported the use of these monoclonal antibodies to block adhesion receptors as adjunctive reperfusion therapy. However, recent human trials have yielded disappointing results.

Abciximab↗
PubMed2000

Pathophysiology and therapeutic modification of thrombin generation in patients with coronary artery disease.

Thrombin plays a central role in thrombogenesis: it activates platelets, converts fibrinogen to fibrin, and activates factor XIII, which then crosslinks and stabilizes the fibrin clot. In addition, thrombin amplifies coagulation by activating factors VIII and V, key cofactors in the generation of activated factor X and thrombin, respectively. Even platelet function is influenced by thrombin. Hence, thrombin generation is most important both in the chronic progression of coronary atherosclerotic disease and in its conversion to acute events. To date, various therapeutic approaches capitalize on this knowledge by targeting specific thrombin-related pathways. Among the successful and carefully documented pharmacologic strategies in acute or chronic coronary heart disease are the use of unfractioned heparin, low-molecular-weight heparin, thrombolysis, hirudin, and/or inhibition of thrombin generation by glycoprotein IIb/IIIa antagonists, most often utilized on top of antiplatelet therapy (e.g., with acetylsalicylic acid) and/or vitamin K antagonism. The present review provides insights into the pathophysiology of thrombin generation in coronary atherosclerosis and gives an overview over the above mentioned therapeutic thrombin modifications.

Coronary Disease↗
PubMed2000

Hemostatic abnormalities in patients with congestive heart failure: diagnostic significance and clinical challenge.

Knowledge of the pathogenesis of congestive heart failure (CHF) has improved greatly in recent years. However, this disease continues to cause one of the highest morbidities and mortalities in the Western world. The pathophysiology of heart failure is complex and much of our understanding revolves strictly around the neurohormonal mechanisms involved. Various pharmacologic interventions have significantly improved morbidity and include ACE inhibitors, beta-blockers, diuretics, and inotropic agents. Yet, no consensus has been reached regarding the use of anticoagulants or antiplatelet agents. It has been suggested that CHF is associated with altered hemostasis, but whether this prothrombotic state contributes to the pathogenesis and progression of the disease is unknown. The purpose of this review article is to discuss our current knowledge of platelet activation, thrombin generation, fibrinolysis, and endothelial dysfunction in CHF patients, and the potential role of anticoagulants and/or antiplatelet agents in preventing these hemostatic abnormalities.

Anticoagulants↗
PubMed2000

Soluble P-selectin is not a surrogate marker for platelet P-selectin: evidence from a multicenter chest pain study group.

It has been reported that platelet expression and plasma levels of soluble P-selectin are increased in patients with unstable coronary artery syndromes. However, the origin of soluble P-selectin remains unknown. We sought to determine whether platelet expression of P-selectin correlates with plasma levels in the population of patients presenting to the emergency department with chest pain. In 338 patients presenting with chest pain to the emergency departments of three different hospitals, simultaneous soluble and platelet P-selection levels were determined using enzyme-linked immunosorbent assay (ELISA) and whole blood flow cytometry, respectively. Using regression analysis no correlation (R(2)=0.055) was found between soluble and platelet-bound P-selectin for the study population, including those patients with noncardiac chest pain (R(2)=0.019), unstable angina (R(2)=0.007), acute myocardial infraction (R(2)=0.033), congestive heart failure (R(2)=0.231), and gastrointestinal illness (R(2)=0.020). The platelet expression of P-selectin is unrelated to the level found in plasma in patients with acute chest pain, irrespective of the etiology of chest pain. Dissociation between platelet and soluble P-selectin suggests that the soluble form cannot serve as a surrogate marker to indicate platelet activation in the chest pain population.

Aged↗
PubMed2000

Moderate alcohol consumption is associated with decreased platelet activity in patients presenting with acute myocardial infarction.

Moderate alcohol consumption (MAC) and platelet inhibition have been independently associated with a reduced risk for the development of acute myocardial infarction (AMI). The effects of MAC on the initial platelet status in patients presenting with AMI are not elucidated. Here we sought to define the effects of MAC on platelet characteristics in AMI patients before applying any reperfusion strategies. The study was designed as an analysis within the cohort study in 23 patients with AMI enrolled in the GUSTO-III. Platelets were investigated by different techniques, including aggregometry, flow cytometry, and ELISA. MAC patients exhibited mild, but consistent, inhibition of platelet aggregability, surface receptor expression, and released substances as compared to non-alcohol consuming patients. These differences were significant for 5 microM ADP (p = 0.04), 10 microM ADP-induced aggregation (p = 0.02); P-selectin (p = 0.01), and PECAM-1 (p = 0.02) platelet-bound expression. Our study confirms that moderate alcohol consumption is associated with diminished platelet activation in patients presenting with AMI. The ability of MAC to favorably modulate the pre-reperfusion platelet status in such patients is of clinical importance, and further investigation in large-scale clinical trials seem warranted.

Aged↗