ABSTRACT
Thrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications. Methods: Fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet alpha-granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial. Results: Thrombin generation (TAT 12.1 +/- 17.8 ng/ml vs. 3.4 +/- 1.0 ng/ml; F1.2 0.19 +/- 0.14 nmol/l vs. 0.12 +/- 0.8 nmol/l), fibrin formation (FPA 15.8 +/- 23.5 ng/ml vs. 7.5 +/- 2.3 ng/ml), and platelet activation) 10.6 +/- 2.4% vs. 2.5 +/- 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r = -.10, p = 0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r =.42, p = 0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold. Conclusions: Thrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of di sease and response to treatment observed commonly in clinical practice.
ABSTRACT
Background: Systemic hypotension, at times transient while in other instances more prolonged, is common among patients with myocardial infarction (MI). It also is a characteristic feature for patients experiencing either advanced congestive heart failure or cardiogenic shock. In this group of patients, thrombolytic therapy has failed to exert. favorable impact on their high in-hospital mortality. Although it has been postulated that the success of thrombolytic therapy is directly linked to systemic blood pressure' there is little information available in human subjects. Methods and Results: In a University of Massachusetts Thrombolysis Data Bank Study, 127 patients with MI who were given intravenous thrombolytic therapy (tPA or streptokinase) within 6 hours from symptom onset (4.2 +/- 1.5 hours) had serial systemic blood pressure measurements (at the time of hospital arrival, treatment initiation, and every 30 minutes during the thrombolytic infusion) and underwent coronary angiography within 120 minutes of treatment initiation. All patients received intravenous heparin and oral aspirin. By univariate analysis, disastolic blood pressure below 80 mmHg at the time of treatment initiation was associated with a reduced angiographic coronary perfusion grade [Thrombolysis in Myocardial Infarction (TIMI) flow grade; p + 0.02]. A correlation analysis of tPA-treated patients indicated that a greater maximum change in diastolic blood pressure during treatment correlated inversely with coronary perfusion (r +.24, p < 0.05). By multivariate regression analysis, however, only shorter time to treatment (p + 0.001) and thrombolysis with tPA (p + 0.02) were independent predictors of coronary arterial perfusion grade. Conclusion: Systemic blood pressure (and presumably proximal coronary arterial perfusion pressure) in the ranges investigated in this study is not an independent predictor of coronary reperfusion following intravenous thrombolytic therapy with either tPA or streptokinase. It seems likely, therefore, that properties intrinsic to the ruptured plaque and occlusive thrombus, and potentially the local metabolic environment, either alone or acting synergistically with perfusion pressure, are determinants of thrombolytic success. Further investigation of factors influencing the efficacy of thrombolysis should be undertaken.
ABSTRACT
Background: Current strategies in the treatment of patients with acute coronary syndromes include antiplatelet agents and thrombin antagonists, most commonly aspirin and heparin, respectively. Cardiac events, however, occur despite what is considered to be maximal medical treatment. Methods: We determined the percentage of activated platelets in whole blood samples taken from 22 patients with unstable angina and non-Q-wave myocardial infarection participating in the TIMI III B trial. Platelet activation was assessed using a monoclonal antibody to the surface-expressed alpha-granule protein, P-selectin, and flow cytometry. All patients received a full complement of antiischemic medications as well as intravenous heparin and oral aspirin, and were then randomized to tissue plasminogen activator or placebo. Results: Platelet activation prior to randomization was increased threefold to fourfold compared with healthy volunteers (11.4 +/- 11.4% vs. 2.0%; p < 0.01). Serial measurements performed 12, 24, 48, and 96 hours after treatment initiation revealed that platelet activation persisted. No differences in patients experiencing recurrent ischomic events (n = 9) or those randomized to a 90-minute, accelerated infusion of tissue plasminogen activator (n = 12) were observed. Conclusions: A modest degree of platelet activation is seen for at least 96 hours and possibly longer in patients with unstable angina and non-Q-wave myocardial infarction, despite being treated with intravenous heparin and oral aspirin. These findings support current efforts to identify more potent and selective antithrombotic treatment strategies.
ABSTRACT
Background: Myocardial ischemia at rest is typically associated with atherosclerotic coronary artery disease, atherommous plaque rupture, and intracoronary thrombosis. In areas of advanced disease and vascular injury, the extent of thrombus is influenced largely by a delicate balance of procoagulant factors, favoring thrombus initiation, growth, and development, and anticoagulant factors, attempting to limit potentially flow-limiting coronary thrombosis. Thrombin, a 308 amino acid serine pretense, is considered the most patent procoagulant factor in the setting of acute vessel wall injury, playing an essential role in the conversion of fibrinogen to fibrin, accelerating the prothrombinase complex, activating platelets, and stabilizing fibrin polymers. The purpose of this study was to determine the relationship between electrocardiographic abnormalities and markers of thrombin activity and generation among patients with unstable angina and non-Q.wave myocardial infarction. Mehtods and Results: In a study of 36 patients (59.1+/- 11.0 years) with myocardial ischemia at rest participating in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB trial, thrombin activity in plasma, as determined by fibrinopeptide A (FPA), prothrombin fragment 1.2 (F 1.2), and thrombin-antithrombin III complexes (TAT) concentrations, were found to be increased significantly when compared with healthy volunteers (p < 0.004). Thrombin generation was also increased modestly compared with age-matched patients with stable coronary artery disease undergoing elective cardiac catheterization. Given that,he surface 12-lead electrocardiogram (ECG) is frequently abnormal in patients with ischemic chest pain at rest and represents a readily available, first-line diagnostic test for assessing disease activity and treatment response, we investigated whether ECG abnormalities and thrombin activity/generation in plasma were correlated. Twenty-six patients (72%) had ECG changes compatible with myocardial ischemia at the time of study entry, including 18 (50%) with newly inverted T waves (or pseudonormalization), 14 (39%) with reversible ST-segment depression, and 4 (11%) with transient (<30 minutes) ST-segment elevation. Within the predefined ECG groups there were no differences in plasma thrombin activity between patients with and those without confirmed abnormalities. Similarly, there were no differences in either plasma thrombin activity or generation between the predefined ECG groups. Conclusion: Although ECG abnormalities supporting the presence of myocardial ischemia occur commonly in patients with chest pain at rest, they do not correlate closely with markers of thrombin activity and generation in plasma. The diagnostic and prognostic capabilities of these diagnostic tools, considered either alone or together, require further investigation.
