PubMed Health⌕ Search

Biomedical subjects

Neal S Kleiman

Publications and source records attributed to Neal S Kleiman.

At least 55 records · Page 3Linked to original sources
PubMed2004

Dynamic prognostication in non-ST-elevation acute coronary syndromes: insights from GUSTO-IIb and PURSUIT.

BACKGROUND: Risk assessment in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) traditionally focuses on and is limited to admission findings. The objective of the current study was to develop an approach to predicting outcome in NSTE-ACS that could account for the changing nature of risk. METHODS: In 7294 of 8010 patients with NSTE-ACS and complete electrocardiographic data in the GUSTO-IIb trial, we predicted the mortality probability at days 0-2, 0-30, 3-30, 5-30, and 7-30 using multiple logistic regression. Resulting risk estimates were incorporated into a composite, dynamic model to estimate the effects of changing probabilities over time. These models were validated against an independent sample of 9461 patients from the PURSUIT trial. RESULTS: As time passed after admission, the risk of 30-day death declined in stable patients. This risk, which was 3.72% at baseline, declined to 1.92% in 6-day survivors, and the risk reduction was greatest for those with the highest baseline risk. Importantly, however, the development of inhospital complications modified these trends. The use of dynamic models not only allowed us to estimate early (<48 h) mortality with a high degree of accuracy (C-index of 0.87), but also to continuously update the longer-term prognosis with increasing accuracy: the C-index increased from 0.75 for the day 0-30 model to 0.81 and 0.82 for the composite and day 7-30 models, respectively. CONCLUSIONS: Dynamic risk assessment is feasible and reliable. This approach can improve risk assessment and provide valuable guidance for management of patients with NSTE-ACS.

Age Factors↗
PubMed2004

Coordinated series of studies to evaluate characteristics and mechanisms of acute coronary syndromes in high-risk patients randomly assigned to enoxaparin or unfractionated heparin: design and rationale of the SYNERGY Library.

Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

Angina, Unstable↗
PubMed2004

Abciximab pharmacodynamic model with neural networks used to integrate sources of patient variability.

OBJECTIVE: Our objective was to develop a computational model for predicting abciximab-induced inhibition of ex vivo platelet aggregation from the administered dose and readily available patient clinical characteristics by use of a neural network approach. METHODS: A back-propagation neural network was designed to establish the relationship between abciximab dosing, patient clinical history, and effect (inhibition of 20 micromol/L adenosine diphosphate-induced ex vivo platelet aggregation). The neural network was trained by use of data from 8 (out of 47) patients undergoing coronary angioplasty and 30 healthy individuals. Final neuron connection weights were used to evaluate significant patient covariates. The final neural network was validated via (1) predicting the effects of the validation database (remaining 39 patients) and (2) predicting the individual patient doses to achieve 20% of baseline platelet aggregation. RESULTS: The trained neural network successfully captured the complex pharmacodynamic profiles of abciximab without specifying a structural model and identified several patient covariates that significantly contribute to establishing the abciximab dose-effect relationship, including stable angina with nitrate treatment, previous myocardial infarction, and smoking. A wide distribution of individual bolus doses of abciximab was predicted, suggesting the potential for dosing individualization while improving the risk of adverse drug events. The mean predicted dose (16.9 mg) was in agreement with the results from a previously published concentration-effect relationship for abciximab (18.9 +/- 2.0 mg). CONCLUSIONS: These findings suggest the usefulness of neural network methods to individualize dosing for drugs with a narrow therapeutic index when real-time measures of drug concentration and effect are unavailable, but future clinical studies are required for prospective validation.

Abciximab↗
PubMed2004

Patient-specific antiplatelet therapy.

Platelets are key players in thrombosis, and have thus become the main targets in the acute treatment of, as well as in the primary and secondary prevention against, thrombotic cardiovascular diseases. Three main classes of anti-platelet agents are currently available for clinical use: aspirin, the thienopyridines, and the intravenous GPIIb/IIIa antagonists. While these therapies are beneficial in the mean patient population, they may produce adverse effects in selected patient subgroups. In this article, we review the three main classes of antiplatelet drugs, discussing them in terms of the patient characteristics that are likely to influence their overall efficacy and safety.

Humans↗
PubMed2004

Pharmacokinetics and pharmacodynamics of argatroban in combination with a platelet glycoprotein IIB/IIIA receptor antagonist in patients undergoing percutaneous coronary intervention.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of argatroban, administered in combination with a platelet glycoprotein IIb/IIIa receptor antagonist, was characterized in patients undergoing percutaneous coronary intervention (PCI). Plasma argatroban and activated clotting times (ACTs) were assessed periprocedurally in 152 patients administered argatroban (250- or 300-microg/kg bolus, then 15-microg/kg/min infusion) in combination with abciximab or eptifibatide during PCI. The PK and PK-PD models were developed utilizing a sequential population approach in NONMEM. Population PK estimates for clearance, central volume, and peripheral volume were 22.0 L/h, 11.0 L, and 13.0 L, respectively (coefficients of variation [CVs] </= 10%). By covariate analysis, clearance increased linearly with body weight. Plasma argatroban and ACT effect were well described using a sigmoidal E(max) model. For argatroban in combination with platelet glycoprotein IIb/IIIa receptor blockade in patients undergoing PCI, population PK parameters are consistent with values reported for argatroban in healthy subjects. A predictable relationship exists between argatroban concentration and effect in this setting.

Aged↗
PubMed2004

Therapeutic use of intravenous eptifibatide in patients undergoing percutaneous coronary intervention: acute coronary syndromes and elective stenting.

Eptifibatide, a molecule isolated from the venom of the southeastern pygmy rattlesnake, selectively inhibits the platelet receptor IIb/IIIa. The safety and clinical efficacy of eptifibatide in patients undergoing percutaneous coronary intervention (PCI) was first evaluated in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) trial. In this study, the primary combined endpoint (composite of death, myocardial infarction [MI] or target vessel revascularization [TVR] at 30 days) occurred in 9.6% of the patients assigned to eptifibatide bolus followed by the 4-hour infusion versus 12.2% in the placebo group (p = 0.67). In the IMPACT-II trial, two different eptifibatide dosages were studied in 4011 patients undergoing elective PCI. The primary endpoint (death, MI, TVR or stent placement for threatened vessel closure at 30 days) occurred in 11.6% in the placebo group versus 9.1% in the 135/0.5 eptifibatide group (p = 0.035) and 10% in the 135/0.75 eptifibatide group (p = 0.18). The Enhanced Suppression of Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial studied a dose of eptifibatide 3- to 4-fold higher than that used in IMPACT II trial in patients undergoing non-emergent coronary artery stenting (two 180 microg/kg bolus doses 10 minutes apart). The 6-month composite endpoint (death, MI, TVR and 'bailout' eptifibatide use) occurred in 18.3% of patients in the placebo group versus 14.2% in the eptifibatide group (p = 0.008) and was maintained at 12 months (22.1% in the placebo group vs 17.5% in the eptifibatide group, p = 0.0068). The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) study in 10 948 patients was designed to study the effect of eptifibatide in the treatment of acute coronary syndromes (ACS) using two different dosages (180 microg/kg bolus followed by an infusion of either 1.3 microg/kg/min or 2 microg/kg/min. The primary endpoint, a composite of death or MI at 30 days, occurred in 15.7% of placebo-treated patients and 14.2% of eptifibatide-treated patients (p = 0.042). This difference was maintained at 7 days (11.6% in the placebo group vs 10.1% in the eptifibatide group, p = 0.016) and at 30 days (15.7% in the placebo group vs 14.2% in the eptifibatide group). In the eptifibatide studies, the rates of major bleeding were 0.7% (0.5% in the control group) in ESPRIT and 2.1% (1.3% in the placebo group) in PURSUIT. The incidence of intracranial bleeding was 0.2% in ESPRIT (0.1% in the placebo group) and 0.7% in PURSUIT (0.8% in the placebo group). Significant thrombocytopenia (platelet count <20 000/microL) was reported in 0.2% of the patients receiving eptifibatide in the ESPRIT trial (0% in the placebo group) and in <1% in PURSUIT (<1% in the placebo group). In summary, several clinical trials have demonstrated a clear-cut reduction in a variety of ischemic events in patients receiving eptifibatide as adjunctive pharmacotherapy during PCI.

Acute Disease↗
PubMed2004

Acute myocardial infarction: clinical characteristics, management and outcome in a university medical centre in a developing Middle Eastern country.

BACKGROUND: The management and outcome of acute myocardial infarction (AMI) have not been well studied in developing countries, although demographic data from the World Health Organization indicate that developing countries contribute a major share to the global burden of cardiovascular disease. OBJECTIVES: To analyze the clinical characteristics, management and outcome of patients hospitalized with AMI in a university medical centre in a developing Middle Eastern country. METHODS: The study population comprised all patients hospitalized with AMI at the American University of Beirut between January 1, 1997, and December 30, 1998. The medical records of the patients were reviewed to determine their clinical characteristics, the diagnostic and invasive procedures used during the hospitalization, and any in-hospital complications, including death. RESULTS: The population comprised 184 patients with a mean age of 60+/-13 years. Fifty-two per cent of the infarcts were anterior and 76% developed Q waves. Fifty-one per cent of the patients received thrombolytic therapy. At discharge, 80% of the patients were given acetylsalicylic acid, 35% were given beta-blockers, 34% were given angiotensin-converting enzyme inhibitors and 30% were given statins. Seventy-two per cent of the patients underwent coronary angiography, 23% underwent percutaneous transluminal coronary angioplasty and 13% had coronary artery bypass grafting. The in-hospital mortality was 13%. The predictors of in-hospital mortality were advanced age (over 60 years), diabetes, prior AMI, Killip class greater than I and ejection fraction less that 40%. In contrast, the predictors of coronary angiography were younger age (less than 60 years), absence of diabetes or no history of AMI, Killip class I and ejection fraction greater than 40%. CONCLUSIONS: Coronary angiography after AMI was performed more frequently than expected in a university medical centre in a developing country, and it seemed to be selectively used in the low- risk patients rather than the high-risk ones. Furthermore, the underuse of medical therapy with beta-blockers and statins was evident. These findings should prompt cardiac societies in these countries to initiate educational campaigns focusing on the cost-effectiveness of therapy in AMI to optimize the use of their limited resources.

Cardiovascular Agents↗
PubMed2004

Six-month outcomes of percutaneous coronary balloon angioplasty in acute coronary syndromes: Results from the PURSUIT trial.

BACKGROUND: Potent inhibition of the platelet glycoprotein IIb/IIIa receptor has improved the acute outcome of patients presenting with acute coronary syndromes (ACS). For patients with ACS undergoing percutaneous balloon angioplasty without coronary stenting in the era of platelet glycoprotein IIb/IIIa blockade, the long-term prognosis is less clear. OBJECTIVE: To examine the six-month outcome of patients who received eptifibatide within a randomized clinical trial and subsequently underwent balloon angioplasty. METHODS: Patients included in this substudy were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized study evaluating the efficacy of eptifibatide in reducing the incidence of death or nonfatal myocardial infarction (MI) in non-ST segment elevation ACS. During the index hospitalization, 1151 (12.2%) of the PURSUIT patients underwent percutaneous balloon angioplasty without coronary stenting. RESULTS: Eptifibatide was associated with a significant reduction in the adjudicated composite end point of death or MI at six months after randomization in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) (P=0.037). A trend toward a beneficial effect was evident before the procedure (4.7% versus 6.9%; P=0.13) and at 30 days (12.1% versus 15.3%; P=0.12). The incidence of repeat revascularization was relatively low for patients undergoing PTCA, with no difference observed between the eptifibatide and placebo groups (16.3% versus 14.8%; P=0.51). CONCLUSIONS: Eptifibatide was associated with a sustained beneficial effect to six months in patients with ACS undergoing PTCA. It reduced the incidence of preprocedural MI. The rate of repeat revascularization at six months was low and was not significantly altered by eptifibatide.

Acute Disease↗
PubMed2003

Evolving revascularization approaches for myocardial ischemia.

Stable angina pectoris secondary to ischemic heart disease is a common and disabling condition. Medical therapy aims to relieve symptoms, improve exercise capacity, and decrease cardiac events by reducing myocardial oxygen demand or improving coronary blood supply to the ischemic myocardium. If medical treatment is inadequate, invasive revascularization procedures to improve coronary perfusion are considered. Percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery are well-established and widely used myocardial revascularization techniques. Recent advances in PTCA have attempted to address the problem of restenosis, initially through the deployment of bare metal intracoronary stents and, more recently, with drug-eluting stents. Developments in CABG have focused on reducing the invasiveness of the procedure and minimizing the incidence of serious complications. Refinements include the use of mechanical stabilizers, endoscopic harvesting of conduit vessels, robotic telemanipulation systems, and fully automated anastomotic devices. Surgical laser transmyocardial revascularization and therapeutic angiogenesis represent newer approaches to coronary revascularization. Therapeutic angiogenesis aims to deliver an angiogenic growth factor or cytokine to the myocardium to stimulate collateral blood vessel growth throughout the ischemic tissue. The angiogenic factor may be administered as a recombinant protein or as a transgene within a plasmid or gene-transfer vector. Ongoing angiogenic gene therapy clinical trials are evaluating which factors, vectors, and delivery techniques hold the greatest promise for management of patients with chronic stable angina.

Angiogenesis Inducing Agents↗
PubMed2003

Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease.

Angiogenic gene therapy for stable angina is aimed at promoting new blood vessel formation in the heart, thus providing enhanced cardiac perfusion, symptom relief, increased exercise capacity, improved quality of life, and reduced risk of coronary events. Ad5FGF-4 is a replication-deficient serotype 5 adenovirus encoding the gene for fibroblast growth factor-4 (FGF-4) driven by a cytomegalovirus promoter. In preclinical studies using a pig model of myocardial ischemia, a single intracoronary infusion of Ad5FGF-4 improved cardiac contractile function and regional blood flow in the ischemic region during stress. These effects were apparent after 2 weeks and maintained for > or =12 weeks. Histologic evidence of capillary angiogenesis was observed. FGF-4 gene expression was detected in the heart but not at extracardiac sites. Placebo-controlled trials in humans with chronic stable angina indicate that Ad5FGF-4 increases treadmill exercise duration and improves stress-related ischemia measured by perfusion sestamibi single-photon emission computed tomography. More patients receiving Ad5FGF-4 than placebo reported complete resolution of their angina and no nitroglycerin use. Ad5FGF-4 gene therapy was well tolerated. The administration procedure did not cause any adverse events, although mild, transient fever, a transient modest fall in platelet count, and a transient mild elevation in hepatic enzymes and uric acid levels occurred in a few patients. This adverse event profile concurs with other adenoviral gene trials. There was no evidence of myocarditis, retinal neovascularization, or angioma formation. FGF-4 was not detected in venous blood. Larger clinical trials will assess Ad5FGF-4 with regard to cardiovascular prognosis, symptom relief, and safety profile in patients with chronic stable angina.

Adenoviridae↗
PubMed2003

Simultaneous modeling of abciximab plasma concentrations and ex vivo pharmacodynamics in patients undergoing coronary angioplasty.

An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 microM adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg (n = 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 microg/kg/min (n = 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (Emax = 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds.

Abciximab↗
PubMed2003

A novel point-of-care enoxaparin monitor for use during percutaneous coronary intervention. Results of the Evaluating Enoxaparin Clotting Times (ELECT) Study.

OBJECTIVES: The aim of this study was to discern a target range of anticoagulation for enoxaparin during percutaneous coronary intervention (PCI) as measured by the Rapidpoint ENOX (Pharmanetics Inc., Morrisville, North Carolina), a new point-of-care test. BACKGROUND: In the U.S., enoxaparin has been used in only a small proportion of PCI procedures, partly because a rapid enoxaparin-specific assay was unavailable. METHODS: We analyzed data from 445 enrolled patients receiving subcutaneous or intravenous enoxaparin in a prospective, multicenter study. Serial anticoagulation measurements and clinical outcomes were recorded. RESULTS: The in-hospital composite occurrence of death, myocardial infarction, and urgent target vessel revascularization was 5.4%, and Thrombolysis In Myocardial Infarction (TIMI) major bleeding, minor bleeding, and any reported bleeding occurred in 0.2%, 1.3%, and 7.9% of patients, respectively. No significant association between procedural ENOX times and ischemic events was observed (p = 0.222), although the event rate was 4.0% among those with ENOX times between 250 to 450 s versus 7.2% for those outside this range (p = 0.134). Increasing ENOX time at sheath removal was correlated with any bleeding (p = 0.010) with a 1% increase for every approximately 30-s rise. CONCLUSIONS: Ischemic events were infrequent, and the rate appeared lowest in the mid-range of ENOX times. Bleeding events increased with increasing ENOX times. These observations, combined with a suggested procedural anti-Xa level of 0.8 to 1.8 IU/ml, translate into a recommended ENOX time range of 250 to 450 s for PCI and <200 to 250 s for sheath removal.

Angioplasty, Balloon, Coronary↗
PubMed2003

Acute myocardial infarction and cardiac arrest in a patient receiving paclitaxel.

A 68-year-old man suffered an acute myocardial infarction while receiving an intravenous infusion of paclitaxel. Coronary angiograms revealed only mild plaquing of the infarct-related artery without significant angiographic obstructions. The authors postulate that paclitaxel may have caused coronary vasospasm and myocardial infarction.

Aged↗
PubMed2003

Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial.

CONTEXT: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI). OBJECTIVE: To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications. DESIGN, SETTING, AND PARTICIPANTS: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002. INTERVENTIONS: Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. MAIN OUTCOME MEASURES: The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization. RESULTS: Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P =.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P =.40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001). CONCLUSIONS: Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.

Abciximab↗
PubMed2003

Arterial thrombosis for the interventional cardiologist: from adhesion molecules and coagulation factors to clinical therapeutics.

Arterial thrombosis is the result of a complex and well-orchestrated set of events where interactions between platelets and leukocytes are intertwined with enzymatic reactions of the coagulation system. Here, we present a contemporary panorama of arterial thrombosis and provide a framework the interventionalist can use to understand the current antithrombotic pharmacotherapies and recognize the role of therapies that have yet to be developed. We analyze thrombosis in the context of plaque rupture and vascular injury and describe the interactions between platelets and the subendothelium. We then discuss platelet-leukocyte interactions, emphasizing the inflammatory nature of thrombosis and how this relates to vessel restenosis following angioplasty. The different reactions of the coagulation system are described not from an isolated perspective, but are integrated into the sequence of cell-cell interactions that parallel them. Finally, we describe the mechanisms that terminate the thrombotic response.

Arterial Occlusive Diseases↗
PubMed2003

Platelet-monocyte complex formation: effect of blocking PSGL-1 alone, and in combination with alphaIIbbeta3 and alphaMbeta2, in coronary stenting.

BACKGROUND: Binding of platelet P-selectin to P-selectin glycoprotein ligand 1 (PSGL-1) is an initial event in the interactions between platelets and monocytes. Platelet-monocyte complexes (PMCs) have been implicated in several vascular disease processes, including acute coronary syndromes (ACS) and complications after percutaneous coronary intervention (PCI). We investigated the effect of ex vivo blockade of PSGL-1, alone and in combination with blockade of the alphaMbeta(2) (Mac-1) and alpha(IIb)beta(3) (GP IIb/IIIa) integrins, on PMC formation. METHODS AND RESULTS: Dual-label flow cytometry was used to detect PMCs in the blood of 10 volunteers and 10 patients undergoing PCI who received intravenous GP IIb/IIIa antagonists. PSGL-1 blockade, both prior to and after platelet stimulation, markedly reduced the formation of PMCs. Concomitant ex vivo blockade of the alphaMbeta(2) and alpha(IIb)beta(3) integrins did not result in further decreases of PMCs compared to PSGL-1 blockade alone. Antagonism of PSGL-1 also led to near elimination of leukocyte-platelet interactions under flowing conditions. CONCLUSION: Blockade of PSGL-1 alone is sufficient to inhibit and reverse the formation of PMCs following platelet stimulation. Concurrent antagonism of PSGL-1 and the alpha(IIb)beta(3) and alphaMbeta(2) integrins was not more effective than inhibition of PSGL-1 alone. These results suggest that platelet-monocyte complex formation is mostly dependent on PSGL-1.

Adult↗