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Biomedical subjects

P A Merlini

Publications and source records attributed to P A Merlini.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tissue-factor antigen and activity in human coronary atherosclerotic plaques.

BACKGROUND: Coronary atherosclerotic-plaque thrombosis is a key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque rupture or fissuring frequently occurs in atherosclerosis, only a small proportion of ruptured plaques develop thromboses. METHODS: Tissue-factor antigen and activity were measured in atherectomy samples from 50 consecutive patients with coronary artery disease (stable angina n = 19, unstable angina n = 24, and myocardial infarction n = 7). FINDINGS: Median tissue-factor antigen and activity concentrations were significantly higher in plaques from patients with unstable angina and myocardial infarction than in those from patients with stable angina (antigen: 66.1 pg/mg [interquartile range 43.8-82.5] vs 32.4 pg/mg [9.8-43.4], p = 0.0001; activity: 0.22 mU/mg [0.17-0.41] vs 0.13 mU/mg [0.05-0.16], p = 0.0004). INTERPRETATION: Tissue-factor, an initiator of the coagulation cascade, may account for the different thrombotic responses to the rupture of human coronary atherosclerotic plaques.

Angina Pectoris↗
PubMed1997

Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris.

OBJECTIVES: This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris. BACKGROUND: Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina. METHODS: We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months. RESULTS: Outcome events--death, myocardial infarction or refractory angina requiring revascularization--occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone. CONCLUSIONS: The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.

Acetylcysteine↗
PubMed1997

Persistent thrombin generation during heparin therapy in patients with acute coronary syndromes.

Intravenous heparin, a fundamental therapy in the treatment of patients with acute coronary syndromes, acts by inhibiting thrombin and activated factors X, IX, XI, and XII. It has also been demonstrated that heparin reduces plasma fibrinopeptide A, a marker of thrombin activity, but it is unknown whether it decreases prothrombin fragment 1+2, an indirect marker of thrombin generation. We measured the plasma levels of prothrombin fragment 1+2, fibrinopeptide A, and antithrombin III in 64 consecutive patients with unstable angina or myocardial infarction receiving intravenous heparin. Blood samples were obtained at baseline (before any treatment) and then at 90 minutes and 24 and 48 hours after the administration of an intravenous bolus of heparin (5000 IU) followed by a continuous infusion of 1000 IU per hour to maintain activated partial thromboplastin time at more than double its baseline levels. In comparison with baseline, there was a significant decrease in fibrinopeptide A at 90 minutes and at 24 and 48 hours (baseline, 2.3 nmol/L; 90 minutes, 1.15 nmol/L; 24 hours, 1.4 nmol/L; 48 hours, 1.2 nmol/L; P < .0001) but no change in prothrombin fragment 1+2 levels (baseline, 1.27 nmol/L; 90 minutes, 1.3 nmol/L; 24 hours, 1.33 nmol/L; 48 hours, 1.29 nmol/L; P = NS). Antithrombin III activity decreased at 24 and 48 hours (baseline, 108%; 24 hours, 97%; 48 hours, 95%; P < .0001). Hence, in patients with acute coronary syndromes, intravenous heparin at a dose reaching an activated partial thromboplastin time that adequately suppresses thrombin activity does not suppress increased thrombin generation.

Acute Disease↗
PubMed1996

Thrombin activity and early outcome in unstable angina pectoris.

BACKGROUND: The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome. METHODS AND RESULTS: Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2 patients died. Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiac events in patients with abnormal rather than normal plasma levels of fibrinopeptide A (P<.01), whereas no difference in outcome was observed between patients with normal and those with abnormal 24-hour urinary excretion. Cox regression analysis showed that the only variables independently related to an early unfavorable outcome were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of intracoronary thrombosis at angiography (P=.016), and abnormal fibrinopeptide A plasma levels (P=.038). CONCLUSIONS: Patients with unstable angina pectoris and abnormal fibrinopeptide A plasma levels are at increased risk for an early unfavorable outcome.

Aged↗
PubMed1996

Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study.

OBJECTIVES: This study was designed to investigate whether combination therapy with metoprolol and nifedipine provides a greater anti-ischemic effect than does monotherapy in individual patients with stable angina pectoris. BACKGROUND: Combination therapy with a beta-adrenergic blocking agent (which reduces myocardial oxygen consumption) and a dihydropyridine calcium antagonist (which increases coronary blood flow) is a logical approach to the treatment of stable angina pectoris. However, it is not clear whether, in individual patients, this combined therapy is more effective than monotherapy. METHODS: Two hundred eighty patients with stable angina pectoris were enrolled in a double-blind trial in 25 European centers. Patients were randomized (week 0) to metoprolol (controlled release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) for 6 weeks; placebo or the alternative drug was then added for a further 4 weeks. Exercise tests were performed at weeks 0, 6 and 10. RESULTS: At week 6, both metoprolol and nifedipine increased the mean exercise time to 1-mm ST segment depression in comparison with week 0 (both p < 0.01); metoprolol was more effective than nifedipine (p < 0.05). At week 10, the groups randomized to combination therapy had a further increase in time to 1-mm ST segment depression (p < 0.05 vs. placebo). Analysis of the results in individual patients revealed that 7 (11%) of 63 patients adding nifedipine to metoprolol and 17 (29%) of 59 patients (p < 0.0001) adding metoprolol to nifedipine showed an increase in exercise tolerance that was greater than the 90th percentile of the distribution of the changes observed in the corresponding monotherapy + placebo groups. However, among these patients, an additive effect was observed only in 1 (14%) of the 7 patients treated with metoprolol + nifedipine and in 4 (24%) of the 17 treated with nifedipine + metoprolol. CONCLUSIONS: The mean additive anti-ischemic effect shown by combination therapy with metoprolol and nifedipine in patients with stable angina pectoris is not the result of an additive effect in individual patients. Rather, it may be attributed to the recruitment by the second drug of patients not responding to monotherapy.

Adrenergic beta-Antagonists↗
PubMed1996

Prolonged streptokinase infusion in patients with unstable angina: results of a randomized, placebo-controlled clinical trial.

BACKGROUND: The purpose of this study was to assess the efficacy both of prolonged (48 h) and of short-duration (1 h) administrations of streptokinase in patients with unstable angina. In unstable angina, thrombosis is a dynamic process that waxes and wanes for hours and even days. The majority of previous studies have investigated the efficacy of short-duration thrombolytic regimens. METHODS: One hundred patients with acute unstable angina were randomly allocated to receive placebo, 1,500,000 U streptokinase during 1 h or 250,000 U streptokinase during 1 h and then a prolonged infusion of 100,000 U for the next 48 h. All of the treatments included intravenous heparin administration for 72 h. RESULTS: No death occurred in the study population. One of 34 patients treated with placebo (2.9%), three of 33 treated with streptokinase during 1 h (9.0%) and three of 33 treated with streptokinase during 48 h (9.0%) had a myocardial infarction. Refractory angina occurred in nine, three and seven patients receiving placebo, streptokinase during 1 h and streptokinase during 48 h, respectively. Kaplan-Meier analysis showed that the total probability for a patient to be free of cumulative events did not differ among the three groups of patients (NS). Fourteen patients (41%) receiving placebo, 15 patients (45%) receiving streptokinase during 1 h and 14 patients (42%) receiving streptokinase during 48 h had ischaemic episodes detected by Holter monitoring during the first 72 h after hospital admission (NS). Two patients receiving streptokinase during 48 h required blood transfusion, and a greater incidence of minor bleeding (P < 0.05) and adverse events (P < 0.02) was observed in patients receiving prolonged streptokinase administration than in those receiving streptokinase during 1 h or placebo. CONCLUSIONS: In patients with acute unstable angina, the administration of two different regimens of streptokinase significantly reduces the probability neither of developing cardiac events during hospitalization nor of ischaemia detected by Holter monitoring in the early phase after hospital admission. Although the sample size of the study provided sufficient power to exclude only a large difference in effect size, it did allow us to detect a significantly higher incidence of bleeding in the group of patients treated with prolonged streptokinase infusion.

Aged↗
PubMed1996

Factor V (Arg 506-->Gln) mutation in young survivors of myocardial infarction.

Many young patients with venous thromboembolic disease are partially resistant to the anticoagulant action of activated protein C as a result of factor V (Arg 506 --> Gln) mutation. The frequency of this mutation in young patients with arterial thrombotic diseases, such as myocardial infarction, is less well established. We studied 100 young patients with myocardial infarction and 100 age- and sex-matched controls. One patient (1%; 95% CL 0.05-6.2) and two controls (2%; 95% CL 0.3-7.7) were heterozygotes for the mutation; there was no homozygote in either group. Hence, premature myocardial infarction is not associated with heterozygosity for factor V (Arg 506 --> Gln) mutation.

Adult↗
PubMed1996

Non neutralizing antibodies to tissue type plasminogen activator in the serum of acute myocardial infarction patients treated with the recombinant protein.

Recombinant tissue-type plasminogen activator (rt PA) is currently used as a thrombolytic agent in the management of acute myocardial infarction (AMI). Since it is known that other recombinant proteins induce antibody formation when administered to humans, we determined the presence of anti-rt-PA antibodies in serial blood samples from 60 AMI patients (43 treated with and 17 without rt-PA). Blood samples were taken upon hospital admission, 15 days and 1, 3, 6 months thereafter. A blood sample was also collected from 200 healthy subjects. Using an ELISA, anti-rt-PA antibodies were detected as serum immunoglobulins specifically binding immobilized rt-PA, AMI patients before treatment and normal subjects exhibited negligible levels of anti-rt-PA antibodies; both groups had only one outlier value. Fifteen days after rt-PA treatment, 2 AMI patients showed an increase in antibody titer beyond the highest normal value. This titer progressively decreased during the following 6 months. The antibodies from these two patients bound rt-PA both in a solid and fluid phase. They bound melanoma t-PA to a lower degree and did not bind urokinase type plasminogen activator at all, indicating specificity for t-PA. The marked temporal relationship between rt-PA infusion and antibody appearance indicated that antibody formation had been elicited by the infusion of rt-PA. Nevertheless, the lack of anti-rt-PA antibody interference with rt-PA function in vitro, along with the favourable clinical outcome of those patients having such antibodies would indicate that the appearance of anti-rt-PA antibodies does not interfere with the physiological fibrinolytic activity.

Adult↗
PubMed1995

Activation of the hemostatic mechanism during thrombolysis in patients with unstable angina pectoris.

In patients with myocardial infarction, thrombolytic therapy induces a paradoxical activation of the hemostatic mechanism. In patients with unstable angina, the effect of thrombolysis on the coagulation cascade is unknown. We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A in consecutive patients with unstable angina randomized to receive placebo alone (n = 23), streptokinase 1,500,000 IU over 1 hour followed by a 48-hour placebo infusion (n = 21), or streptokinase 250,000 over 1 hour followed by a continuous infusion of 100,000 IU per hour over 48 hours (n = 20). All the patients received intravenous heparin for 72 hours. The plasma levels of the different markers were measured at baseline, 90 minutes, 24 hours, and 48 hours after the start of therapy. The median baseline plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A were similar in the three treatment groups. In comparison with placebo, an increase in plasma prothrombin fragment 1 + 2 and fibrinopeptide A, was observed after 90 minutes in the two groups receiving thrombolysis. After 24 and 48 hours, the prothrombin fragment 1 + 2 levels remained significantly higher only in the patients receiving the 48-hour streptokinase infusion. In patients with unstable angina, thrombolytic therapy induces an activation of the hemostatic mechanism, despite concomitant heparin administration; in those receiving a prolonged streptokinase infusion, the activation of coagulation persists for as long as the drug is administered.

Aged↗
PubMed1995

Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction.

OBJECTIVES: This prospective study investigated the behavior of thrombin generation and activity during thrombolysis and concomitant heparin administration. BACKGROUND: It has been shown that during thrombolytic therapy there is an increase in thrombin generation and activity. Increased thrombin activity is suppressed by concomitant intravenous heparin, but it is unknown whether thrombin generation is also affected. METHODS: Thrombin generation was assessed by measuring prothrombin fragment 1 + 2 and thrombin-antithrombin complex plasma levels and thrombin activity by measuring fibrinopeptide A plasma levels. Serial blood samples were obtained before and at 90 min and 24 and 48 h after the administration of streptokinase (15 patients), recombinant tissue-type plasminogen activator (15 patients) or anistreplase (13 patients). An intravenous bolus of heparin (5,000 IU) was administered before the start of thrombolytic therapy, followed by an infusion of 1,000 U/h to maintain an activated partial thromboplastin time > 1.5 times baseline. RESULTS: During thrombolytic and concomitant heparin therapy, there was an increase in the plasma levels of prothrombin fragment 1 + 2 (baseline 1.08 vs. 2.73 nmol/liter, p < 0.001) and thrombin-antithrombin complex (baseline 6.5 vs. 17.1 micrograms/ml, p < 0.01) at 90 min, whereas no change was observed in fibrinopeptide A at 90 min (baseline 2.8 vs. 3.0 nmol/liter, p = NS). CONCLUSIONS: During thrombolytic therapy with both fibrin-specific and non-fibrin-specific drugs, there is an increase in thrombin generation despite concomitant administration of intravenous heparin.

Aged↗
PubMed1995

Selection of medical treatment in stable angina pectoris: results of the International Multicenter Angina Exercise (IMAGE) Study.

OBJECTIVES: The present study was designed to investigate which characteristics of anginal symptoms or exercise test results could predict the favorable anti-ischemic effect of the beta-adrenergic blocking agent metoprolol and the calcium antagonist nifedipine in patients with stable angina pectoris. BACKGROUND: The characteristics of anginal symptoms and the results of exercise testing are considered of great importance for selecting medical treatment in patients with chronic stable angina pectoris. However, little information is available on how this first evaluation may be used to select the best pharmacologic approach in individual patients. METHODS: In this prospective multicenter study, 280 patients with stable angina pectoris were enrolled in 25 European centers. After baseline evaluation, consisting of an exercise test and a questionnaire investigating patients' anginal symptoms, the patients were randomly allocated to double-blind treatment for 6 weeks with either metoprolol (Controlled Release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) according to a parallel group design. At the end of this period, exercise tests were repeated 1 to 4 h after drug intake. RESULTS: Both metoprolol and nifedipine prolonged exercise tolerance over baseline levels; the improvement was greater in the patients receiving metoprolol (p < 0.05). Multivariate analysis revealed that low exercise tolerance was the only variable associated with a more favorable effect within each treatment group. Metoprolol was more effective than nifedipine in patients with a lower exercise tolerance or with a higher rate-pressure product at rest and at ischemic threshold. None of the characteristics of anginal symptoms or exercise test results predicted a greater efficacy of nifedipine over metoprolol. CONCLUSIONS: The results of a baseline exercise test, but not the characteristics of anginal symptoms, may offer useful information for selecting medical treatment in stable angina pectoris.

Angina Pectoris↗
PubMed1995

Heightened thrombin formation but normal plasma levels of activated factor VII in patients with acute coronary syndromes.

Plaque rupture with the exposure of a tissue factor-rich procoagulant surface is considered the common pathogenetic mechanism of unstable angina and myocardial infarction. Activated factor VII, the key enzyme for initiating blood coagulation under resting conditions, is increased in pathological situations associated with tissue factor exposure. We measured the plasma levels of activated factor VII and studied their relation with signs of coagulation enzyme activity in patients with acute coronary syndromes. The plasma levels of activated factor VII, prothrombin fragment 1 + 2, and fibrinopeptide A were measured on admission in consecutive patients presenting with acute myocardial infarction (n = 28), unstable angina (n = 32), and stable angina (n = 17) and in age- and sex-matched healthy individuals (n = 33). Plasma determinations of the same markers were also repeated at 15 days and 3 and 6 months. On admission, the patients with unstable angina or myocardial infarction had significantly higher plasma levels of prothrombin fragment 1 + 2 (P < .0001) and fibrinopeptide A (P < .0001) than those with stable angina or healthy individuals, whereas no differences were detected in the plasma levels of activated factor VII. During follow-up there was a significant decrease in the plasma levels of fibrinopeptide A both in patients with unstable angina (P < .001) and in those with myocardial infarction (P < .001), whereas no changes in plasma prothrombin fragment 1 + 2 or activated factor VII levels were observed. Hence, in the acute and chronic phases of myocardial infarction and unstable angina, heightened coagulation enzyme activity is not accompanied by an increase in activated factor VII.

Acute Disease↗
PubMed1994

Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty.

OBJECTIVES: The aim of this study was to investigate the relation between coronary atherosclerotic plaque injury and activation of the coagulation cascade. BACKGROUND: Thrombus formation after atherosclerotic plaque disruption has been implicated in the pathogenesis of atherosclerosis, unstable angina and myocardial infarction. METHODS: Biochemical markers of thrombin generation (prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A) were measured in coronary blood before, during and immediately after percutaneous transluminal coronary angioplasty. After demonstrating that blood withdrawal through an angioplasty catheter does not artifactually elevate the plasma levels of these markers in patients after heparinization, coronary artery samples were collected proximal and distal to the lesion before and distal to the lesion after balloon inflation in 26 patients. RESULTS: Plasma levels of F1+2 measured proximal to the lesion before angioplasty (median 0.47 nmol/liter, 95% confidence interval [CI] 0.40 to 0.50) were significantly elevated after angioplasty (median 0.55 nmol/liter, 95% CI 0.46 to 0.72, p = 0.001). In contrast, plasma fibrinopeptide A levels measured proximal to the lesion before angioplasty (median 2.0 ng/ml, 95% CI 1.3 to 2.2) were similar to those measured after angioplasty (median 1.8 ng/ml, 95% CI 1.3 to 3.0, p = NS). After we defined a normal range of interassay variability on the basis of values obtained from samples drawn proximal and distal to the lesion before angioplasty, seven patients (27%) had a significant increase in F1+2 plasma levels. A significant increase in plasma fibrinopeptide A occurred in five of these seven patients. Lesions with dissection, filling defects or haziness on postangioplasty angiography were associated with more thrombin generation than lesions without these features. CONCLUSIONS: Markers of thrombin generation and activity can be collected safely and assayed accurately in heparinized blood withdrawn through an angioplasty catheter. Balloon dilation of coronary stenoses increases thrombin generation and activity within the coronary artery in a substantial subgroup of patients undergoing angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1994

Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.

BACKGROUND: The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization. METHODS AND RESULTS: We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028). CONCLUSIONS: During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.

Adult↗
PubMed1993

Activation of the hemostatic system during thrombolytic therapy.

Activation of the hemostatic mechanism has been described during thrombolytic therapy. This phenomenon has been detected by new methods of assessing hemostatic system function, based on immunoenzymatic or radioimmunoassays. However, these methods are extremely sensitive and, unless they are performed in expert laboratories, carefully following the recommended procedures, they generate in vitro artifacts. A description of these methods is provided, as well as a critical review of the available studies. The correct use of these methods will provide us with an understanding of the complex response of the hemostatic system to pharmacologic thrombolysis.

Animals↗