RESUMO
BACKGROUND: Sodium arachidonate was used in this study to determine its capacity to generate thrombin through platelet activation. Whether aspirin prevent this effect was also investigated. METHODS AND RESULTS: Seventeen healthy volunteers without and after 160 mg/day aspirin intake for 3-5 days were studied. Lag-time and TG at basal condition and after platelet stimulation by sodium arachidonate (AA) were measured in normal non-aspirinated as well as "in vivo" aspirinated platelet rich plasma. (PRP). The lag-time was statistically significant shorter in non-aspirinated PRP activated with AA compared with non-activated PRP. This effect was inhibited by aspirin. In non-aspirinated PRP, there was an increase of TG at 4 and 6 min. incubation when platelets were activated with AA but the difference disappeared after 8 min. incubation, (84 +/- 71; 148 +/- 58 and 142 +/- 92 nmol/L respectively) compared with non-aspirinated. non-activated platelets (16 +/- 23; 55 +/- 56 and 111 +/- 76 nmol/L at 4,6 and 8 min, p < 0.0001, p < 0.0001 and p = 0.292, respectively). The AUCo-->22 min were 520.6 +/- 545.5 in non-aspirinated, non-stimulated PRP and 808.9 +/- 617, in non-aspirinated PRP activated with sodium arachidonate (p = 0.014). Aspirin administered in vivo produced a decrease of TG in PRP activated with AA. CONCLUSION: Platelet activated by AA trigged TG. This effect was inhibited by aspirin and could be an additional beneficial effect of aspirin in the prevention of thrombosis.
Assuntos
Ácido Araquidônico/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Trombina/agonistas , Adulto , Idoso , Área Sob a Curva , Aspirina/administração & dosagem , Aspirina/farmacologia , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Trombina/antagonistas & inibidores , Trombina/metabolismoRESUMO
To prevent arterial thrombosis, abciximab is administered together with aspirin. However, whether or not there are benefits to combine abciximab with aspirin is not yet well defined. Healthy volunteers were studied for the effect of aspirin + abciximab using sodium arachidonate and adenosine diphosphate (ADP) alone or in combination to induce platelet activation/aggregation. Abciximab produced complete inhibition of platelet aggregation induced with ADP but only 40% inhibition of aggregation induced by 0.75-mmol/l sodium arachidonate. Abciximab added in vitro to platelet-rich plasma (PRP) from platelets from aspirin-treated donors produced an almost complete inhibition of platelet aggregation. Aspirin, and abciximab alone, did not inhibit adenosine triphosphate (ATP) release as thoroughly as aspirin + abciximab did. Abciximab (3-5 microg/ml) produced inhibition of P-selectin expression induced with 5 (from 46.2 +/- 6.0% to 27.4 +/- 7.0%, P=0.002) and 20-micromol/l ADP (from 53.1 +/- 8.1% to 35.1 +/- 11.0%, P=0.019), but no effect was observed when 0.75-mmol/l sodium arachidonate was used (P=0.721). Aspirin diminished P-selectin expression in sodium arachidonate-stimulated platelets (from 77.7 +/- 11.8% to 40.2 +/- 3.6%, P<0.0001) in non-aspirinated and platelets from aspirin-treated donors, respectively. Abciximab (3, 4, and 5 microg/ml) added to platelets from aspirin-treated donors decreased P-selectin expression in platelets stimulated with sodium arachidonate from 40.2 +/- 8.6% to 25.6 +/- 11.5% (P=0.027), to 20.5 +/- 3.5% (P<0.0001), and to 22.5 +/- 1.8% (P<0.0001). We concluded that the antiplatelet effect of abciximab is greatly increased by aspirin.
Assuntos
Anticorpos Monoclonais/farmacologia , Aspirina/farmacologia , Fragmentos Fab das Imunoglobulinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Abciximab , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/biossíntese , Adulto , Ácido Araquidônico/farmacologia , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Selectina-P/biossíntese , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
BACKGROUND: Higher than normal serologic titers and the detection of bacteria within atheroma have suggested an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary heart disease (CHD), but the relationship has not been well established. HYPOTHESIS: The study was designed to establish a lack of relationship between chronic C. pneumoniae infection and CHD. METHODS: Chlamydia-specific IgG-antibody was assayed using an indirect immunofluorescence test in the serum of 159 patients with severe arterial disease and 203 patients with a heart valve prostheses and no demonstrable CHD. Fatal and nonfatal vascular events and systemic thromboembolism were recorded over a 2-year period. RESULTS: In the arterial group 107 patients (67.3%) and in the valvular group 120/203 (59.1%) were positive for C. pneumoniae antibody. The number of patients with fatal or nonfatal vascular events (double end point) in the arterial and valvular groups was 23 and 2, respectively (p < .0001). Triple end points (fatal plus nonfatal vascular events plus thromboembolism) were also more frequent in the arterial group (p < 0.002). The prevalence of chlamydia antibody positivity was the same in the arterial and valvular groups, and the occurrence of clinical events was also the same for chlamydia-positive (227 patients) as for chlamydia-negative (135 patients). After adjustment for confounding variables, only arterial disease was a predictive factor for double (OR 17.0; 95% CI 3.94-73.3) or triple (OR 3.12; 95% CI 1.56-6.25) end points. CONCLUSION: We find C. pneumoniae chronic infection not to be an independent risk factor for acute or chronic arterial disease.
Assuntos
Infecções por Chlamydia/complicações , Chlamydophila pneumoniae/imunologia , Doença das Coronárias/etiologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/análise , Infecções por Chlamydia/imunologia , Doença Crônica , Doença das Coronárias/imunologia , Feminino , Imunofluorescência , Seguimentos , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Aspirin and ticlopidine are used to prevent arterial thrombosis. In some clinical settings ticlopidine is administered with aspirin for improving antithrombotic effect. We administered aspirin (100 mg/day), ticlopidine (500 mg/day), or ticlopidine and aspirin for 7 days to healthy volunteers. Platelet aggregation and ATP release induced by sodium arachidonate, ADP, or a combination of both were measured. Sodium arachidonate (0.25 mmol/L), which produces no platelet aggregation, combined with adenosine diphosphate (1 mumol/L), which produced a reversible platelet aggregation of 20% after ticlopidine, resulted in a synergistic platelet aggregation response in normal (74.6 +/- 9.2%) and in ticlopidine platelet-rich plasma (59.1% +/- 14.9%, p < 0.0001). Synergism after sodium arachidonate (0.75 mmol/L) plus adenosine diphosphate (4 mumol/L) fell from 75.8% +/- 11.0% and 59.1% +/- 15.6% after ticlopidine or aspirin, respectively, to 14.8% +/- 18.0% (p < 0.0001) after ticlopidine plus aspirin. Aspirin and ticlopidine alone did not inhibit adenosine triphosphate release as thoroughly as did aspirin plus ticlopidine. Aspirin or ticlopidine does not adequately prevent platelet activity as ticlopidine plus aspirin do. Addition of aspirin to treatment with ticlopidine improves their antiplatelet activity and better results could be obtained in arterial thrombotic prevention strategies.
Assuntos
Trifosfato de Adenosina/sangue , Aspirina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/farmacologia , Sinergismo Farmacológico , HumanosRESUMO
Unfractionated heparin (UFH) exerts its anticoagulant properties by increasing the inactivation of thrombin and activated factor X by antithrombin III. Apart from this main action release of tissue factor pathway inhibitor (TFPI) from endothelial cells could also be important for the antithrombotic activity of heparins. Four different heparin preparations were injected subcutaneously into 5 healthy volunteers 1 week apart: (1) UFH 2,500 IU fix dose (FixUFH), (2) 1 mg/kg body weight of low molecular weight heparin (LMWH), (3) the combined LMWH-adjusted dose plus UFH 2,500 IU fix dose (ComHep) and (4) UFH 2,500 IU/10 kg body weight (UFHvar). Plasma samples were drawn before and 1, 2, 4, 6, 12 and 24 h afterwards. FixUFH did not affect the concentration of total and free TFPI. Total TFPI increased in the 1st hour after LMWH injection from 74 to 124 ng/ml (p < 0.01), after ComHep from 82 to 144 ng/ml (p < 0.01), and after UFHvar from 91 to 113 ng/ml (p < 0.05). All observed elevations were significant at the peak value (+/- 2 h, p < 0.01 compared with baselines). The increase of free TFPI produced by UFHvar (74.5 and 70.5 ng/ml) was significantly higher than with LMWH (42.8 and 38.0 ng/ml) at 2 and 4 h (p < 0.001 and p < 0.01, respectively). UFHvar and ComHep but not LMWH produced a statistically significant increase of free TFPI compared with FixUFH at 2, 4 and 6 h (p < 0. 01). We concluded that at comparable therapeutic doses, subcutaneous UFHvar released more free TFPI than LMWH and ComHep. A synergism between LMWH and low dose of UFH was found in 4-, 6- and 12-hour blood samples.
Assuntos
Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina/uso terapêutico , Lipoproteínas/metabolismo , Adulto , Análise de Variância , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Injeções Subcutâneas , Masculino , Nadroparina/uso terapêutico , Valores de ReferênciaRESUMO
BACKGROUND: There are no reported studies on the safety and efficacy of low-dose aspirin with low-intensity oral anticoagulation in patients with heart valve replacement. In this study, we compared the use of 100 mg/d aspirin with 650 mg/d aspirin in the prevention of systemic embolism and vascular death in patients with heart valve replacement who were being treated with oral anticoagulants with a target international normalized ratio (INR) of 2.0 to 3.0. METHODS AND RESULTS: Four hundred nine of 416 consecutive patients who had cardiac valve replacement were randomized in open allocation into one of two groups; both groups were treated with oral anticoagulant therapy with a target INR of 2.0 to 3.0. Two hundred seven patients who received 100 mg/d aspirin for an average of 24.1 months were compared with 202 patients who received 650 mg/d aspirin for an average of 21.7 months in a randomized-treatment, open-allocation study. There were no significant differences in systemic embolism, vascular death, or total death rates between the low- and high-dose aspirin treatment groups (0.5 and 1.1, 1.2 and 0.5, and 4.6 and 2.5 per 100 patients/y, respectively). The total number of hemorrhagic events was 13.4 per 100 patients/y in the high-dose aspirin group and 7.9 per 100 patients/y in the low-dose aspirin group (P = .035), but the rate of bleeding was influenced by dipyridamole in the 650-mg aspirin group. CONCLUSIONS: In patients with mechanical heart valve replacements, low-dose aspirin (100 mg/d) in conjunction with oral anticoagulants at an INR of 2.0 to 3.0 is as effective as the use of high-dose aspirin (650 mg/d) in the prevention of systemic embolism.
Assuntos
Aspirina/administração & dosagem , Próteses Valvulares Cardíacas , Inibidores da Agregação Plaquetária/administração & dosagem , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Tromboembolia/tratamento farmacológico , Tromboembolia/mortalidade , Tromboembolia/prevenção & controle , Resultado do TratamentoRESUMO
BACKGROUND: Vascular endothelium reacts to various pathophysiologic stimuli by releasing several autocoids and cytokines that can be used along with the coagulation and fibrinolytic markers for the diagnosis of hemostatic alterations. Several newer markers for vascular distress, such as tissue plasminogen activator (TPA), tissue plasminogen activator inhibitor-1 (PAI-1), TPA/PAI-1 complex, and the newly reported inhibitor of the coagulation process, namely, tissue factor pathway inhibitor (TFPI), have been implicated in the pathogenesis of pulmonary hypertension. METHODS: To investigate the behavior of endothelial cells at basal and time-dependent venous stasis-induced changes, various markers were measured in patients with primary and secondary pulmonary hypertension and compared with healthy human volunteers (controls) without any family history of thromboembolism or history of hypertensive disorders. The right atrial pressure (RAP) and pulmonary arterial pressure were measured and the hemostatic parameters were correlated to determine the relevance of these parameters with the alterations in the present indices. RESULTS: A fibrinolytic deficit exists in patients with pulmonary hypertension, indicated by the prolongation of the euglobulin clot lysis time at basal conditions and after the venous occlusion test. This defect was mainly due to increased production of PAI-1 by endothelium (patients 59.8 +/- 22.3 AU/ml; controls 30.3 +/- 14.5 AU/ml; p = 0.005). We also report for the first time that a decrease in tissue factor pathway inhibitor antigen was also observed in these patients when RAP was > 9 mmHg [controls 95.6 +/- 61.6 ng/ml; patients with RAP > 9 mmHg 47.2 +/- 19.2 ng/ml (p = 0.044); patients with RAP > 9 mmHg 96.6 +/- 32.4 ng/ml (p = 0.002 compared with patients with RAP > 9 mmHg)], indicating endothelial cell and hemostatic disturbances. CONCLUSIONS: We conclude that the euglobulin clot lysis time was prolonged in patients with pulmonary hypertension compared with controls. The impairment of the fibrinolytic system was due to an elevated concentration of PAI-1. In RAP > 9 mmHg, an additional prothrombotic factor is the decrease in plasma tissue factor pathway inhibitor antigen. It appears from this study that antithrombotic treatment is indicated in these patients.
Assuntos
Coagulação Sanguínea , Endotélio Vascular/fisiopatologia , Fibrinólise , Hipertensão Pulmonar/fisiopatologia , Adolescente , Adulto , Idoso , Feminino , Hemostasia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangueRESUMO
For preventing thromboembolic events, the concurrent use of oral anticoagulant and antiplatelet drugs has been proposed. In prosthetic heart valves the use of moderate intensity anticoagulants [International Normalized Ratio (INR) 2-3] plus aspirin (100 mg/day) decreases the amount and severity of embolic episodes. The possibility that the same regimen could provide benefit in the prevention of thrombotic events in other arterial diseases is also indicated by the ATACS trial in unstable angina. The ongoing studies in ischemic heart diseases will also give the answer to this possibility.
Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tromboflebite/tratamento farmacológico , Administração Oral , Angina Instável/tratamento farmacológico , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Ensaios Clínicos como Assunto , Dipiridamol/administração & dosagem , Dipiridamol/efeitos adversos , Dipiridamol/uso terapêutico , Embolia/tratamento farmacológico , Embolia/epidemiologia , Embolia/etiologia , Embolia/prevenção & controle , Seguimentos , Próteses Valvulares Cardíacas/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Incidência , Metanálise como Assunto , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Recidiva , Tromboembolia/tratamento farmacológico , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Tromboflebite/etiologia , Tromboflebite/prevenção & controleRESUMO
In this pilot study the combined use of desmopressin, which releases tissue plasminogen activator from vascular endothelium, and a low dose of streptokinase as a new thrombolytic regimen for acute myocardial infarction is proposed. Eighteen patients with acute myocardial infarction were treated intravenously with 150,000 U (4 patients) or 250,000 U (14 patients) of streptokinase infused over 10 minutes, followed by 24 µg of desmopressin infused over 5-10 minutes. Aspirin and beta-blockers were administered at admission, and heparin and oral anticoagulants were started at the end of the thrombolytic regimen. Hemostatic parameters were studied before and 30, 60, 120, and 240 minutes after starting thrombolytic therapy. Fifteen patients (83.3%) had evidence of clinical reperfusion. Angiography was performed with a mean delay of 8.8 hours (range 1.5-22 hours) from the start of thrombolytic therapy. Fourteen patients (77.8%) had patency of the infarct-related artery: 10 patients (55.6%) achieved TIMI grade 3, and 4 patients (22%) achieved TIMI grade 2. Two patients (one TIMI grade 1 and one TIMI grade 2) underwent coronary angioplasty. No patient died during the in-hospital period. At 18 months follow-up, all patients are alive. No major or minor bleeding was detected. The significant decline in plasma fibrinogen and in the euglobulin lysis time, and the increase in fibrinogen/fibrin degradation products, indicate a plasma lytic state. Crosslinked fibrin degradation products increased from 310 +/- 120 ng/ml to 670 +/- 310 ng/ml (p = 0.009), suggesting that fibrin digestion occurred in vivo. This pilot study provides data supporting the feasibility and efficacy of a new and more economic thrombolytic treatment of acute myocardial infarction without hemorrhagic complications.
RESUMO
OBJECTIVE: To investigate whether plaque rupture and thrombosis have a role in silent ischaemia as well as in unstable angina. DESIGN: Prospective analysis of the results of haemostatic diagnostic tests at the moment of developing silent ischaemia at rest. SETTING: Coronary care unit. PATIENTS: 22 patients with acute myocardial infarction, 12 patients with symptomatic angina (unstable angina), and 10 normal volunteers (control group). INTERVENTIONS: Continuous cardiac monitoring detected 15 asymptomatic episodes (silent ischaemia) in 6 patients with unstable angina. Blood samples were obtained at admission and when an asymptomatic alteration was detected and 10 minutes later. MAIN OUTCOME MEASURES: Comparisons of concentrations of tissue plasminogen activator, urokinase type plasminogen activator, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation products, von Willebrand factor, and thrombin-antithrombin III complexes in patients and controls at admission; same comparisons in patients with silent ischaemia at the start of an episode and 10 minutes later. RESULTS: Tissue plasminogen activator concentrations were raised at admission in patients with acute myocardial infarction (mean (SD) 14.2 (6) ng/ml) and in patients with unstable angina (10.1 (2.5) ng/ml) in comparison with controls (5.1 (2.7) ng/ml, p < 0.01 and < 0.05 respectively). There was no differences between the two groups of patients, however. Similar results were observed at the start of a silent ischaemic episode (9.8 (1.9) ng/ml) and 10 minutes later (10.5 (2.9) ng/ml) compared with controls (p < 0.05). Tissue plasminogen activator inhibitor-1 concentrations were raised in patients with acute myocardial infarction (45.1 (15) ng/ml) compared with volunteers (20.6 (16) ng/ml, p < 0.01). In patients with silent ischaemia tissue plasminogen activator inhibitor-1 concentrations were slightly but not significantly increased. Concentrations of cross-linked fibrin degradation products (D dimer) increased during unstable angina (2150 (350) ng/ml) and silent ischaemia (2270 (450) ng/ml) compared with the concentrations in volunteers (340 (80) ng/ml) and patients with acute myocardial infarction (310 (120) ng/ml; p < 0.01). CONCLUSIONS: The results suggest that thrombosis mediates the pathophysiological mechanisms of silent ischaemia and unstable angina.
Assuntos
Angina Instável/etiologia , Infarto do Miocárdio/etiologia , Isquemia Miocárdica/etiologia , Trombose/complicações , Angina Instável/sangue , Eletrocardiografia Ambulatorial , Feminino , Fibrinólise/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Isquemia Miocárdica/sangue , Isquemia Miocárdica/diagnóstico , Inibidor 1 de Ativador de Plasminogênio/sangue , Estudos Prospectivos , Trombose/sangue , Ativador de Plasminogênio Tecidual/sangueRESUMO
After cardiac valve replacement patients were blindly randomized into two groups, both receiving aspirin (330 mg) and dipyridamole (75 mg) twice daily and the oral anticoagulant acenocoumarol (Sintrom). An international normalized ratio of 2.0 to 2.99 was assigned to group A and 3.0 to 4.5 to group B; both groups were subsequently analyzed for thromboembolic and hemorrhagic complications. Final evaluation included 51 and 48 patients, respectively. The follow-up was 626 months for group A (12.3 months/patient) and 486 months for group B (10.1 months/patient). The frequency of thromboembolism was equal in both groups: one transient ischemic attack in group A (a rate of 1.92/100 patient-years) and two transient ischemic attacks in group B (a rate of 4.94/100 patient-years). There was, however, a statistical difference in bleeding complications between the two groups (p less than 0.02). Two patients bled in group A, a rate of 3.9% (3.8/100 patient-years), which represents an incidence of one episode each 25.6 years of treatment; 10 patients bled in group B, a rate of 20.8% (24.7/100 patient-years) representing an incidence of one episode each 4 years of treatment. We conclude that an international normalized ratio of 2 to 3 is safer than a ratio of 3 to 4.5 and confers good protection from thromboembolism when oral anticoagulant therapy is used conjointly with platelet function-inhibiting drugs in patients with mechanical substitute heart valves.