Thrombolytic therapy for myocardial infarction.
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Cerebrovascular Disorders↗
Biomedical subjects
F Andreotti
Publications and source records attributed to F Andreotti.
Platelet and Thrombin Activity Following Cardiac Catheterization Despite Treatment with Aspirin.
Thromboembolic complications are reported to occur in up to 0.5-2% of left cardiac catheterizations and angiographies. Activation of the hemostatic system may contribute to their onset. To prevent platelet and thrombin activity during catheterization, aspirin or systemic heparin are often used in addition to heparinized flush solutions. We investigated whether aspirin alone can prevent platelet and thrombin activity induced by catheterization in ten consecutive patients (nine males, mean 50 +/- 8 years) undergoing elective left cardiac catheterization after at least 5 days of oral aspirin (75-300 mg/d). Anticoagulant drugs were not given. Peripheral venous samples were drawn before, immediately after (time 0), and at 15, 60, and 180 minutes after the procedure for measurement of thrombin-antithrombin (TAT), prothrombin fragment 1.2 (F 1.2), fibrinopeptide A (FPA), and beta-thromboglobulin (beta-TG). TAT, F1.2, and FPA increased significantly at time 0 compared with both before and 180 minutes after the procedure (P < 0.04); beta-TG values were higher at time 0 compared with 180 minutes later (P = 0.01). TAT levels were related to those of FPA (r = 0.66; P = 0.0003), F1.2 (r = 0.35; P = 0.01), and beta-TG (r = 0.37; p = 0.04). Thus, routine left cardiac catheterization is associated with transient, systematically detectable, activation of coagulation and platelets, despite aspirin therapy. Newer antiplatelet agents may be more effective in preventing hemostatic activation induced by catheterization.
Journal Article↗
[Pre-infarction angina and post-thrombolysis recanalization].
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Adenosine↗
[The absence of a procoagulant effect after TNK-t-PA: a comparison with streptokinase and rt-PA].
A limitation of current fibrinolytic drugs is the procoagulant activity induced by their administration. TNK is a mutant of tissue plasminogen activator (t-PA) with high fibrin specificity, resistance to plasminogen activator inhibitor-1 and slow plasma clearance, which is administered in a single intravenous bolus. In this study we investigated the procoagulant effect of TNK-t-PA compared to streptokinase, rt-PA or no thrombolysis. Twenty-nine patients with acute myocardial infarction, treated within 6 hours of symptom onset with 1.5 MU streptokinase over 1 hour (n = 12), 100 mg rt-PA in 1.5 hours (n = 12) or 30-40 mg TNK-t-PA in 15 s (n = 5), were studied and compared to 7 patients with contraindications to thrombolysis (control group). All patients received a similar i.v. heparin regimen for at least 24 hours. Blood samples were drawn before the start of treatment (time 0) and after 2 hours. Thrombin formation was assessed as plasma concentrations of thrombin-antithrombin complex (TAT). The four patient groups did not differ significantly in age, sex, time to treatment, infarct location, and TAT values at time 0 (mean value +/- standard error of the mean 9 +/- 2 micrograms/l). Mean TAT levels at 2 hours were 26 +/- 6 micrograms/l in streptokinase treated patients (p = 0.005 vs time 0), 21 +/- 4 micrograms/l in rt-PA treated patients (p < 0.05 vs time 0), 5 +/- 0.6 micrograms/l in TNK treated patients, and 4 +/- 0.4 micrograms/l in controls (NS vs time 0 for TNK and controls). In conclusion, our data suggest that, in patients with acute myocardial infarction, bolus TNK-t-PA, unlike streptokinase or rt-PA infusions, is devoid of procoagulant effects, evaluated 2 hours after its administration.
Aged↗
The TIMI 9b and GUSTO IIb Trials and the "Thrombin Hypothesis"
The "thrombin hypothesis" proposes that the clinical outcome of patients with unstable angina or acute myocardial infarction (MI) is related to the degree of thrombin inhibition, with greater inhibition resulting in improved outcome. Two recent trials (TIMI 9b and GUSTO IIb) tried to test this hypothesis by randomizing 15,000 patients with MI or unstable angina to a 3-to-5 day intravenous administration of either the powerful thrombin inhibitor hirudin, or standard heparin. In both studies, after 30 days, there was no significant difference in the rates of death or nonfatal infarction between the 2 treatment arms. More than one reason may explain these findings. In both trials the anticoagulant regimens were carefully tailored to prevent excessive bleeding complications and to achieve a predetermined level of efficacy, as measure by aPTT. It is possible that similar aPTTs and similar bleeding rates will result in similar clinical outcomes, regardless of the anticoagulant agent used. It is also possible that patients already receiving fibrinolytic drugs and aspirin did not derive such additional thrombolytic benefit from anticoagulants to compensate for the increased bleeding risk associated with their use. Finally, thrombin may not always play the crucial role that has been attibuted to it: marked thrombin generation may occur only in subgroups of patients, or as a secondary response to a primary trigger that fails to be antagonized by antithrombin therapy or that re-emerges after stopping treatment. The true role played by anticoagulants in the management of acute coronary syndromes is not clear from TIMI 9b or GUSTO IIb because neither study included a control group not receiving anticoagulants. These trials, however, raise important issues that deserve further investigation: for example, the definition of what drives thrombin generation in patients with acute coronary syndromes and the identification of possible subgroups of patients deriving true clinical benefit from anticoagulant therapy.
Journal Article↗
Targeting new thrombolytic regimens at specific patient groups: implications for research and cost-containment.
Fibrinolytic drugs and aspirin, compared with placebo, have reduced the 35-day mortality of patients with acute myocardial infarction from approximately 12% to about 8%. The mortality reduction with active treatment is most evident in high risk groups of patients. Moreover, mortality with a fully patent infarct-related artery at 90 min from the start of thrombolytic treatment is half that found with an occluded artery. Yet more than 50% of acute infarct patients receiving thrombolysis fail to achieve complete early coronary patency or develop re-occlusion. Although thrombolytic strategies are continually evolving to try to further reduce early mortality and increase coronary reperfusion rates, new regimens, when tested in unselected patients against successful active treatments, such as streptokinase and aspirin, are likely to show no, or only small, average benefits, even when applied to tens of thousands of patients. In contrast, the effect of a new thrombolytic regimen is likely to be most evident is selected patients showing large areas of potentially salvageable ischaemic myocardium, as these patients have a higher absolute risk of premature death than patients with smaller infarcts and therefore should gain greater benefit from successful reperfusion. Since the effect of the new treatment, if present, would be greatest in this group, a smaller number of patients would be needed to show an effect; moreover, the risk of the new treatment would be justified against the larger potential benefit to be gained. We propose to target future thrombolytic regimens, in the first instance, at homogenous groups of high-risk patients; for example, those with large areas of potentially salvageable myocardium. This approach seems a rational and cost-effective way to invest limited amounts of medical resources and offers patients the greatest potential benefit of the new therapy, while restricting possible complications to a smaller number. Continued clinical research aimed at identifying possibly different causes of coronary occlusion and the reasons for worse outcomes is also essential to assign the most appropriate treatments to selected groups of patients.
Clinical Trials as Topic↗
Serum lipoprotein(a) level is related to thrombin generation and spontaneous intermittent coronary occlusion in patients with acute myocardial infarction.
BACKGROUND: Thrombotic occlusion of the infarct-related coronary artery is often intermittent in the early, evolving phase of acute myocardial infarction. To assess their relationship to this pattern of coronary occlusion, serum or plasma concentrations of cholesterol, triglyceride, lipoprotein(a), and coagulation and fibrinolytic factors were measured in venous blood before the initiation of thrombolytic therapy. METHODS AND RESULTS: Thirty-two patients (23 men, 9 women: age, 30 to 70 years) with acute myocardial infarction received intravenous recombinant tissue plasminogen activator (20 to 60 megaunits) within 6 hours of the onset of symptoms. Continuous ECG ST-segment recording demonstrated intermittent occlusion of the infarct-related coronary artery in 12 patients (group 1) before the start of thrombolytic treatment and persistent occlusion in 20 patients (group 2). Groups 1 and 2 were similar in age, sex, race, duration of symptoms, blood sample collection time, location of the infarct-related coronary artery, and extent of coronary artery disease. The serum level (median [interquartile range]) of lipoprotein(a) was 34 (13 to 47) mg/dL versus 11.5 (5 to 27) mg/dL (P = .02), and the plasma level (median [interquartile range]) of thrombin-antithrombin III complex was 10.85 (6.4 to 21.5) versus 6.8 (4.2 to 8.7) micrograms/L-1 (P < .04) in groups 1 and 2, respectively. The levels of the other factors were similar in both groups. CONCLUSIONS: The phenomenon of spontaneous intermittent closure and reopening of coronary arteries early during acute myocardial infarction in humans is associated with a higher level of lipoprotein(a) and of a marker of thrombin generation, suggesting that lipoprotein(a) and thrombin are closely related to coronary patency in these patients.
Acute Disease↗
Temporal relation between ischemic episodes and activation of the coagulation system in unstable angina.
BACKGROUND: Although a major role of coronary thrombosis in the pathogenesis of unstable angina has been demonstrated, the results of a series of studies have suggested that activation of the hemostatic system may not be confined to ischemic episodes. The purpose of this study was to investigate the temporal relation between ischemic episodes and activation of the coagulation system in unstable angina. METHODS AND RESULTS: Thrombin-antithrombin III (TAT) and prothrombin fragment 1 + 2 (F1 + 2) levels were measured in 13 patients during spontaneous ischemic episodes (time 0, 5, and 15 minutes and 1 hour) to evaluate the time course of the activation of the coagulation system associated with the development of ischemia (protocol A). TAT and F1 + 2 levels were also measured in 28 patients with unstable angina on admission to hospital (every 6 hours for 24 hours and daily for 3 days) to assess their temporal relation with ischemic episodes (protocol B). In protocol A, TAT and F1 + 2 levels were elevated in 10 of 13 patients (77%) in at least 1 sample. The median value of TAT showed a peak at 5 minutes and returned to baseline within 15 minutes (P < .05), consistent with its plasma half-life of 5 minutes, whereas the median value of F1 + 2 showed no significant changes, possibly because of its longer half-life, which tends to dampen sudden bursts of thrombin production. In protocol B, activation of the clotting system was found in 10 of 33 samples (30%) temporally related to ischemia and also in 23 of 150 (15%, P = .07) of those not temporally related to ischemia. CONCLUSIONS: Our study demonstrates that patients with active unstable angina develop frequent bursts of thrombin production not necessarily associated with ischemic episodes and that, conversely, some ischemic episodes are not associated with evidence of thrombin activation.
Adult↗
Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction.
BACKGROUND: When a myocardial infarction is preceded by angina, the infarct tends to be smaller than when there is no preinfarction angina. Prompt recanalization of the occluded infarct-related artery is crucial in limiting the size of the infarct. We prospectively studied the relation among preinfarction unstable angina, the speed of coronary reperfusion, and the size of the infarct in patients with acute myocardial infarction receiving thrombolytic therapy. METHODS: We compared 14 patients who had unstable angina during the week before myocardial infarction with 9 patients who had no preinfarction angina. Coronary arteriograms were obtained at base line and 15, 35, 55, and 90 minutes and 24 hours after the start of thrombolytic therapy. The size of the infarct was estimated on the basis of creatine kinase and creatine kinase MB levels, which were measured every 4 hours during the first 24 hours. RESULTS: Complete reperfusion (a flow of grade 3 according to the Thrombolysis in Myocardial Infarction classification) was achieved at 35 minutes in 64 percent of the patients with preinfarction angina but in none of those without preinfarction angina (P = 0.006); at 55 minutes in 86 percent and 38 percent, respectively (P = 0.05); and at 90 minutes in 86 percent and 50 percent, respectively (P = 0.14). The mean (+/- SD) time to reperfusion was 27 +/- 16 minutes in the group with preinfarction angina and 48 +/- 17 minutes in the group without preinfarction angina (P = 0.04); the peak creatine kinase levels were 1118 +/- 783 and 2395 +/- 1615 U per liter, respectively (P = 0.03); the peak creatine kinase MB levels were 102 +/- 67 and 251 +/- 186 U per liter, respectively (P = 0.009); and the 24-hour integrated creatine kinase MB levels were 1716 +/- 1171 and 4267 +/- 3252 U.liter-1 x 24 hours, respectively (P = 0.009). The time to reperfusion was positively correlated with the indexes of infarct size (r > or = 0.53, P < or = 0.02). CONCLUSIONS: In patients with acute myocardial infarction preceded by unstable angina, as compared with those without preinfarction angina, thrombolytic therapy resulted in more rapid reperfusion and smaller infarcts. Earlier myocardial reperfusion may thus account for the smaller infarct size in patients with preinfarction angina.
Adult↗
Different Effects of Lipopolysaccharide on Plasminogen Activator Inhibitor-1 Production in Aortic Media in Vivo and in Culture.
Background: Lipopolysaccharide (endotoxin) has been shown to increase the expression of plasminogen activator inhibitor type-1 (PAI-1) in the vessel wall. Endotoxin is known to increase PAI-1 production in endothelial cells, but its action on smooth muscle cells (SMCs) is presently not clear. In this study we determined the effect of endotoxin on PAI-1 and tissue plasminogen activator (t-PA) production by aortic SMCs in vivo in two animal species, and in culture. Methods: The aortas of Sprague Dawley rats and of New Zealand White rabbits were rapidly excised after parenteral administration of endotoxin. Total RNA was extracted from the aortic media, and PAI-1 and t-PA mRNA levels were quantified after Northern blotting. In addition, cultured rat aortic SMCs were treated with endotoxin. PAI activity in the conditioned medium was determined with a spectrophotometric assay, and total RNA was extracted from the cells and analyzed. Results: A rapid and strong induction in the aortic medi a of PAI-1 mRNA was observed by endotoxin in both rat (50 mg/kg) and rabbit (1 mg/kg). t-PA mRNA was barely detectable and was not increased by endotoxin. Studies in cultured SMCs showed low expression of PAI-1 mRNA under serum-free conditions and little PAI activity in the cell-conditioned medium. Endotoxin did not increase the levels of PAI-1 mRNA nor PAI activity under serum-free conditions. The effect of endotoxin (10 mg/ml) in the presence of 10% (v/v) newborn calf serum on PAI-1 mRNA was negligible; PAI activity, however, increased by 50.3 +/- 7.3% compared with controls. mRNA levels of t-PA and low-density lipoprotein/receptor-related protein/alpha2-macroglobulin receptor also increased after endotoxin administration. PAI activity was identified as PAI-1 by immunoblotting. Fibrin zymography showed that t-PA was present only in complex with PAI-1. Conclusions: A strong increase in PAI-1 gene expression by endotoxin was observed in aortic SMCs in vivo but not in culture. Th is suggests that the effect of endotoxin on SMCs is indirect. The fibrinolytic/proteolytic potential of the SMCs in the vessel wall is likely to have important implications for the migration of cells during vessel wall remodeling, such as neointima formation, during tumor cell metastasis, and for the fate of intramural thrombi.
Journal Article↗
Clinical markers of thrombolytic success.
Although a number of markers of successful coronary thrombolysis have been proposed, only a few of these have the two necessary features of a clinically useful marker: (1) widespread early availability and (2) good predictive value. The reduction in ST-segment elevation on the standard 12 lead electrocardiogram 1-4 h after initiation of thrombolysis may be the simplest and most useful clinical 'tool' to gauge the effectiveness of thrombolytic therapy. The predictive value of this single marker might be further improved by combining it with assessment of the rate of increase of serum myoglobin and of troponin T, provided these determinations were rapidly available.
Biomarkers↗
Is the benefit of preinfarction angina on infarct size due to faster coronary recanalization?
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Aged↗
1994 Joint European and World Congress of Cardiology: An Overview in the Field of Thrombosis and Thrombolysis.
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Journal Article↗
Early spontaneous intermittent myocardial reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less myocardial damage.
OBJECTIVES: This study investigated the influence of early spontaneous intermittent reperfusion on the extent of myocardial damage and its relation to endogenous hemostatic activity. BACKGROUND: In the early phase of acute myocardial infarction coronary occlusion is often intermittent, even before thrombolytic therapy is administered. The relation between this phenomenon, myocardial damage and hemostatic activity is unknown. METHODS: Holter ST segment recording and pretreatment plasma tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, prothrombin fragment F1 + 2 and soluble fibrin levels were measured in 57 patients with acute evolving myocardial infarction. Spontaneous intermittent myocardial reperfusion, defined as two or more episodes of transient resolution of ST segment elevation to within 0.05 mV of baseline, lasting > or = 1 min, before the start of recombinant t-PA (rt-PA) treatment was present in 28 patients (group 1) and absent in 29 (group 2). Left ventriculography and coronary angiography were performed 90 min after intravenous rt-PA administration. Plasma creatine kinase-MB fraction (CK-MB) levels were measured every 6 h for 24 h, and C-reactive protein levels were measured daily for 3 days. RESULTS: Group 1 had lower peak plasma CK-MB (141.9 +/- 28.3 vs. 203.8 +/- 23.3 IU/liter [mean +/- SEM], p < 0.014) and C-reactive protein levels (16 +/- 4 vs. 28 +/- 4 mg/liter on day 1; 26.6 +/- 5.5 vs. 61.8 +/- 14.4 mg/liter on day 2; 19.6 +/- 4.2 vs. 40.6 +/- 6.5 mg/liter on day 3, p < 0.012) and a higher left ventricular ejection fraction (62.9 +/- 4% vs. 51.1 +/- 5%, p < 0.04) than group 2. Group 1 had lower plasma t-PA antigen levels (15.6 vs. 27 micrograms/liter, p < 0.006) but higher prothrombin fragment F1 + 2 (1.8 vs. 1.1 nmol/liter, p < 0.003) and soluble fibrin levels (66.8 vs. 31 nmol/liter, p < 0.01). Coronary patency at 90 min was similar. CONCLUSIONS: Early spontaneous intermittent reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less subsequent myocardial damage. This finding is consistent with a protective effect of intermittency on the myocardium and a procoagulant effect of spontaneous lysis on blood. It may also reflect a different rate of evolution of coronary thrombosis and myocardial infarction in patients with and those without spontaneous intermittent myocardial reperfusion.
Analysis of Variance↗
Endothelium-derived haemostatic factors and the antiphospholipid syndrome.
The cause of thrombosis in the antiphospholipid syndrome (APS) is unknown. There have been reports of abnormalities in the antigenic levels or activity of endothelium-derived haemostatic factors, such as tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1); however the data from these studies are conflicting. We studied plasma from nine patients with APS; seven of them had a history of thrombosis, and three had systemic lupus erythematosus (SLE). We also studied nine matched control patients who had SLE without APS, and 14 healthy individuals. We measured t-PA, von Willebrand factor (vWF), anticardiolipin antibody (ACA) and anti-endothelial cell antibody (AECA) levels by enzyme-linked immunoassay (ELISA), PAI-1 activity by a parabolic-rate chromogenic assay, and lupus anticoagulant (LA) activity by a standard mixing test. For t-PA and PAI-1, measurements were made on morning and evening plasma samples. The two groups of patients did not differ significantly with respect to age, sex, plasma lipids or anti-inflammatory drugs. Most APS patients (7/9) but none of the controls were taking warfarin. Between the APS and the control patients no significant differences were detected in t-PA, PAI-1, vWF or AECA levels. When APS patients were considered alone, vWF levels correlated positively with IgG ACA levels (r = 0.81, P < 0.01) and negatively with platelet count (r = -0.68, P < 0.05). There was no correlation between levels of ACA or LA activity and t-PA, PAI-1 or AECA. Compared with healthy volunteers, the diurnal variation of t-PA and PAI-1 was blunted in the two patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Early remodelling of coronary stenoses after thrombolytic treatment in patients with acute myocardial infarction.
OBJECTIVE: To assess the frequency of early remodelling of coronary stenosis morphology after thrombolytic treatment in patients with acute myocardial infarction. DESIGN: Coronary angiograms were analysed by a computerised edge detection analysis system. Coronary stenosis severity was measured and morphology classified as smooth or complex. PATIENTS: Coronary arteriograms were obtained approximately 90 min and 24 h after thrombolytic treatment from 40 patients with acute myocardial infarction. MAIN RESULTS: Stenosis morphology was complex in 22 patients (65%) and smooth in 11 (32%) 90 min after thrombolysis. The morphology of 11 (50%) complex coronary stenoses and three (27%) smooth stenoses had changed at 24 h (P < 0.05). The transition from complex to smooth was associated with a reduction in stenosis severity from 65 (4)% to 51 (5)% (P < 0.05). The stenosis severity was 63 (4)% and 60 (5)% in those with persistently complex morphology, and 56 (7)% and 50 (5)% in those with persistently smooth morphology at 90 min and 24 h respectively (NS). CONCLUSIONS: Transition of morphology from complex to smooth within 24 h is common. This transition is associated with a reduction in stenosis severity of a degree greater than that found in persistently smooth stenoses over the same interval. 50% of stenoses are smooth at 24 h.
Adult↗
Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure.
Thromboembolism is an important complication of heart failure. To test the hypothesis that heart failure may be associated with hemostatic dysfunction, we studied hemostatic function in 21 patients with stable chronic heart failure and related these measures to the severity of heart failure as assessed by clinical evaluation, neuroendocrine activation, radionuclide ventriculography, and cardiopulmonary exercise testing. Plasma and blood viscosity were elevated; all patients showed evidence of platelet activation, and many had elevated plasma concentrations of fibrinopeptide A, D-dimer, and von Willebrand factor. The plasma concentrations of these variables were poorly interrelated and related poorly to the severity of heart failure. Plasma concentrations of angiotensin II and endothelin were correlated, and the latter was also correlated with the plasma concentration of von Willebrand factor. Patients with chronic heart failure have hemostatic abnormalities that may predispose them to thromboembolic events and may be in part due to neuroendocrine activation.
Adult↗