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Effects of Reteplase and Alteplase on Platelet Aggregation and Major Receptor Expression During the First 24 Hours of Acute Myocardial Infarction Treatment

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Effects of Reteplase and Alteplase on Platelet Aggregation and Major Receptor Expression During the First 24 Hours of Acute Myocardial Infarction Treatment View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 1466 JACC Vol. 31, No. 7 June 1998:1466–73 Effects of Reteplase and Alteplase on Platelet Aggregation and Major Receptor Expression During the First 24 Hours of Acute Myocardial Infarction Treatment PAUL A. GURBEL, MD, FACC, VICTOR L. SEREBRUANY, MD, PHD, ANDREW R. SHUSTOV, MD, RAYMOND D. BAHR, MD, FACC, CYNTHIA CARPO, MD, E. MAGNUS OHMAN, MD, FACC,* ERIC J. TOPOL, MD, FACC,† FOR THE GUSTO-III INVESTIGATORS‡ Baltimore, Maryland; Durham, North Carolina; and Cleveland, Ohio Objectives. We sought to compare platelet characteristics after molecule-1 (p 5 0.002) expression at 24 h. Trends toward reteplase and alteplase therapy in the setting of the Global Use of decreased receptor expression early (3 to 6 h), followed by a Strategies to Open Occluded Coronary Arteries (GUSTO)-III trial. progressive increase at 12 h and especially at 24 h occurred after Background. Platelet function may be impaired during throm- both agents. bolysis in patients with an acute myocardial infarction. The effects Conclusions. In this prospective clinical ex vivo platelet study, of reteplase and alteplase on platelet aggregation and major similar patterns of platelet aggregation and surface receptor surface antigen expression during the first 24 h of infarction expression occurred during the first 24 h of coronary thrombolysis therapy are unknown. with reteplase and alteplase. However, after reteplase, indicators Methods. Platelet aggregation and receptor expression by flow of platelet activity were higher at 24 h after thrombolysis than cytometry were determined in 23 patients before thrombolysis and after alteplase. These data suggest that GP IIb/IIIa inhibitors or thereafter at 3, 6, 12 and 24 h. other antiplatelet strategies may be particularly advantageous Results. Aggregation was higher after reteplase at 24 h when when used 12 to 24 h after thrombolysis, especially after reteplase induced by 5 mmol/liter adenosine diphosphate (ADP) (p 5 therapy. It is at this time point during the first day of coronary 0.007), 10 mmol/liter ADP (p 5 0.02), collagen (p 5 0.003) and thrombolysis that GP IIb/IIIa is markedly expressed and platelets thrombin (p 5 0.009) than after alteplase. Reteplase therapy are most active. exhibited greater glycoprotein (GP) IIb/IIIa (p 5 0.04), very late (J Am Coll Cardiol 1998;31:1466–73) antigen-2 (p 5 0.04) and platelet/endothelial cell adhesion ©1998 by the American College of Cardiology Thrombolytic therapy is the standard treatment for patients (9–11), combined with thrombolytic agents, have been shown with acute myocardial infarction (AMI). Whereas streptoki- in animal studies and clinical trials to improve reperfusion. nase and alteplase are established agents, the clinical efficacy The attempt to determine the platelet-related properties of of reteplase is evolving. Platelets play an important role in the thrombolytic agents is not new. There is substantial evidence natural history of AMI. Intravascular platelet activation may from in vitro (12–14) and animal studies (15,16) that impaired limit reperfusion or cause reocclusion of the recanalized platelet function occurs after thrombolytic therapy. Although infarct-related arteries, thus resulting in an overall decreased there is agreement that concentrations of substances released effectiveness of thrombolytic therapy (1,2). Glycoprotein (GP) by platelets are elevated after thrombolysis (17–20), there is IIb/IIIa receptor antagonists (3–8) and monoclonal antibodies no consensus about the dynamics of ex vivo platelet status in this setting (21–24). Such discrepancies could relate partly to the particular thrombolytic agent, limitations of the techniques to assess platelet function, the lack of a standard From the Union Memorial Hospital and St. Agnes Hospital, Baltimore, method to sample blood and no specified time course to Maryland; *Duke Clinical Research Institute, Durham, North Carolina; and handle samples. Indeed, the majority of human myocardial †Department of Cardiology, Cleveland Clinic, Cleveland, Ohio. ‡A complete list of the GUSTO-III Investigators appears in reference 27. This study was infarction (MI) studies lack a careful, precise description of supported in part by Boehringer Mannheim GmbH, Mannheim, Germany and by the time course of platelet monitoring. The random mea- Medtronic, Inc., San Diego, California and was presented in part at the 70th surement of platelet function, outside strict time intervals Scientific Sessions of the American Heart Association, Orlando, Florida, No- vember 1997. during MI, has revealed very limited information about Manuscript received September 22, 1997; revised manuscript received March arterial patency, thrombolytic success and possible platelet 2, 1998, accepted March 5, 1998. involvement in reocclusion, reinfarction and bleeding. Many Address for correspondence: Dr. Paul A. Gurbel, Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Research clinical studies have examined platelets at unspecified times Building, R202, Baltimore, Maryland 21215. E-mail: [email protected]. or even days after thrombolysis (17,20,22–25), when the ©1998 by the American College of Cardiology 0735-1097/98/$19.00 Published by Elsevier Science Inc. PII S0735-1097(98)00172-7 JACC Vol. 31, No. 7 GURBEL ET AL. 1467 June 1998:1466–73 PLATELETS DURING THROMBOLYSIS IN AMI infusion of heparin for the first 24 h after thrombolysis, as Abbreviations and Acronyms recommended in the GUSTO-III protocol. Eighteen patients ADP 5 adenosine diphosphate had successful reperfusion and remained free of recurrent AMI 5 acute myocardial infarction ischemia in the first 24 h of their hospital stay. Three patients 5 FITC fluorescein isothiocyanate (two with reteplase, one with alteplase) had persistent chest GP 5 glycoprotein GUSTO 5 Global Use of Strategies to Open Occluded Coronary pain and ST elevation and underwent immediate angiography, Arteries which revealed the absence of reperfusion. Two patients (one MI 5 myocardial infarction with reteplase, one with alteplase) developed recurrent isch- PAI-1 5 plasminogen activator inhibitor-1 emia in the first 24 h and also underwent emergency angiog- 5 PECAM-1 platelet/endothelial cell adhesion molecule-1 raphy. TBS 5 Tris-buffered saline VLA-2 5 very late antigen-2 Time course and exclusion of blood samples. The sched- ules for blood drawing, sample preparation and processing were critical issues of the study design and were monitored by an independent observer (A.R.S.). The actual timing of blood effects of adjunctive therapy cannot be excluded (26). collection for the baseline sample was 9.5 6 1.4 min (mean 6 Moreover, our knowledge of the status of platelets during SD) before the start of thrombolytic therapy, 174.6 6 21.8 min the first 24 h after thrombolysis is very limited, especially for the 3-h sample, 371.1 6 24.2 min for the 6-h sample, from controlled clinical trials. 709.4 6 17.8 min for the 12-h sample and 1,402.9 6 18.8 min The purpose of the present study was to define the imme- for the 24-h sample. Samples were processed within 1 h after diate and early platelet-related effects of reteplase and alte- blood drawing. Four patients (three in the reteplase group, one plase in AMI. We assessed platelet aggregation in response to in the alteplase group) did not complete the protocol at all multiple agonists and determined major surface receptor ex- time points. The reasons for early termination were patient pression with flow cytometry at specified times after thrombol- transfer for emergency angioplasty (n 5 3) and inability to ysis in patients enrolled in the randomized Global Use of obtain a blood sample (n 5 1). Twenty-three baseline samples, Strategies to Open Occluded Coronary Arteries (GUSTO-III) 22 samples collected at 3 h, 20 samples collected at 6 h, 20 trial. samples collected at 12 h and 19 samples collected at 24 h were included in the analysis. Platelet aggregation. Blood samples for platelet aggrega- Methods tion and flow cytometric studies were taken at specified The study was approved by the Institutional Review Board intervals: in the emergency department immediately before of St. Agnes Hospital and Union Memorial Hospital (Balti- administration of the thrombolytic therapy and in the coronary more, Maryland). Written informed consent was obtained care unit at 3, 6, 12 and 24 h after thrombolytic therapy began. from all study participants. Citrate and whole blood were immediately mixed in a 1:9 Patients. Twenty-three consecutive patients admitted to ratio and centrifuged at 1,200 3 g for 2.5 min. The resulting the emergency departments of St. Agnes Hospital or Union platelet-rich plasma was kept at room temperature for use Memorial Hospital between July and December 1996 with a within 1 h. Platelet counts were determined for each plasma diagnosis of AMI were included. All patients were enrolled in sample with a Coulter counter ZM. Platelet numbers were the GUSTO-III trial of reteplase versus accelerated alteplase adjusted to 3.50 3 108/ml with homologous platelet-poor treatment for AMI. The inclusion criteria have been reported plasma. Platelet aggregation was induced by 5 and 10 mmol/ elsewhere (27). In summary, patients of any age who presented liter adenosine diphosphate (ADP), 1 mg/ml of collagen, 1 within6hofsymptom onset with .30 min of continuous mg/ml of thrombin and 1.25 mg/ml of ristocetin. All agonists symptoms of AMI and had $1-mm ST segment elevation in were obtained from Chronolog Corporation. Aggregation two or more limb leads, $2-mm ST segment elevation in two studies were performed with a Chronolog Whole Blood Lumi- or more contiguous precordial leads or bundle branch block on Aggregometer (Model 560-Ca). Aggregation was expressed as the 12-lead electrocardiogram were eligible for enrollment. the maximal percent change in light transmittance from base- Patients were excluded for bleeding diathesis; previous stroke, line, using platelet-poor plasma as a reference at the end of the major operation or significant trauma in the past 6 weeks; or recording time.
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