Thrombin: Structure, Biochemistry, Measurement, and Status in Clinical Medicine.

Thrombin remains a molecule of great interest to scientists and clinicians alike because of its important role in hemostasis, thrombosis, inflammation and vascular remodeling. Yet one of the great challenges has been the inhibition of thrombin generation to a degree that minimizes intravascular thrombosis while preserving physiologic hemostasis. It has become increasingly clear that high levels of anticoagulation with either direct or indirect thrombin antagonists are not beneficial and, in fact, are quite detrimental. Despite the overwhelming shift of interest toward the platelet in clinical trials of acute coronary syndromes, much can be gained through further investigation of coagulation processes responsible for thrombin generation and activity.

Anticoagulation in Congestive Cardiomyopathy: Steps Toward Defining the Great Unknown.

It is generally agreed that congestive cardiomyopathy predisposes to the formation of cardiac thrombus and in turn systemic thromboembolism. Several uncontrolled studies have confirmed this association and have prompted wide-scale recommendations for long-term anticoagulation in these patients. Clinical studies have also attempted to identify patients at high risk for embolic events. The presence of cardiac thrombus, its topographic characteristics, the severity of left ventricular dysfunction, and decreased apical flow velocities may each represent markers of increased risk.Driven by the lack of definitive data addressing this issue, several pleas from the medical community have come forth for a large, randomized controlled trial of anticoagulation in congestive cardiomyopathy. Accordingly, a multicenter trial comparing aspirin, warfarin, or placebo as prophylaxis against thromboembolism has been proposed and if conducted will provide valuable information regarding the management of patients with congestive cardiomyopathy.

Improving the Efficacy and Stability of Coronary Reperfusion Following Thrombolysis: Exploring the Thrombin Hypothesis.

A major assumption in the treatment of patients with acute myocardial infarction (MI) implies that the speed of coronary arterial reperfusion correlates directly with the overall extent of myocardial salvage, and that the extent of mycardial salvage, in turn, determines the absolute reduction in patient mortality. While a growing experience has made it clear that myocardial salvage-independent (time-independent) mechanisms of benefit also exist, few would argue with the hypothesis that the greatest benefit derived from coronary thrombolysis occurs with early (time-dependent) treatment. Thus, improvements in the efficacy of reperfusion and the stability of reperfusion are likely to have considerable impact on patient outcome.

Clinical Experience with Routine Activated Coagulation Time Monitoring During Elective PTCA.

Background: Intracoronary thrombosis is an important factor in the pathogenesis of acute complications during percutaneous coronary interventions. The activated coagulation time (ACT) is a simple, reproducible bedside test that has become standard as the means of monitoring the anticoagulant effect of heparin during these procedures. To determine if ACT-adjusted heparin dosing reduces the procedure-related complications of elective PTCA, 1200 patients who underwent nomemergent percutancous transluminal coronary angioplasty (PTCA) between January 1, 1988 and February 26, 1992 were studied. MethodslResults: Two groups were identified based on the use of empirical heparin dosage (group 1, before July 1, 1990) vs. ACT-guided heparin administration strategies (group 2, after July 1, 1990). Group 2 patients were older, had worse left ventricular function, and were more likely to have experienced a prior myocardial infarction than patients in group 1. Patients in group 1 were more likely to have chronic stable angina and a positive exercise test, while group 2 patients were more likely to be undergoing PTCA for post-myocardial infarction (MI) angina. Angiographic characteristics were also consistent with a higher risk profile in group 2 than in group 1 (92.7% vs. 83.4%, p < 0.001). Postprocedural complications, including abrupt closure and late closure, were lower in group 2 patients. The incidence of abrupt vessel closure was decreased by approximately 50% (6.9% vs. 3.5%, p < 0.025), and delayed vessel closure was significantly reduced by over 6017,(3.2% vs. 1.0%, p < 0.05). There were no differences in femoral artery complications between the two specified groups. Conclusion: ACT-guided heparin therapy during percutaneous coronary interventions decreases acute and delayed vessel closure, even in the presence of clinical and angiographic characteristics that would predict a higher incidence of these events.

Achieving Optimal Reperfusion without Adjunctive Antithrombotic Therapy: Novel Thrombolytic Dosing Strategies.

There is firm evidence that reperfusion therapy, to be effective must establish and maintain coronary arterial blood flow at a level sufficient to allow myocardial perfusion. However, current thrombolytic regimens have clear limitations, including a relatively low capacity to achieve TIMI Grade 3 blood flow and an unacceptable incidence of coronary reocclusion. Although it has been assumed that the key to achieving optimal reperfusion lies with adjunctive antithrombotic therapy, it may be that novel thrombolytics and dosing strategies can address the problem adequately. This possibility is attractive and requires careful consideration.

Plasma Markers of Procoagulant Activity Among Individuals with Coronary Artery Disease.

Background: There is compelling evidence that coronary atherosclerosis represents a chronic active process characterized by inflammation, impaired fibrinolysis, intermittent plaque rupture, and luminal thrombosis. Identifying readily measurable plasma markers of procoagulant activity may have an important role in both tracking and understanding the natural history, as well as in defining the ideal treatment, of patients with coronary artery disease. Methods/Results: A total of 30 men and women with suspected coronary artery disease who underwent outpatient cardiac catheterization were sampled for evidence of thrombin generation and fibrin formation in plasma. Compared with healthy controls, patients had significantly increased concentrations of fibrinopeptide A (18.8 +/- 10.8 ng/ml vs. 2.5 +/- 2.3, p < 0.001), thrombin-antithrombin complexes (8.13 +/- 4.56 ng/ml vs. 3.4 +/- 3.0, p < 0.001), and prothrombin activation fragment 1.2 (0.15 +/- 0.09 ng/ml vs. 0.12 +/- 0.19, p = 0.01). There was a statistically insignificant trend toward increased thrombin-antithrombin complex concentrations in patients with hypercholesterolemia (p = 0.10). Patients with angiographically defined coronary artery disease involving two or more vessels were found to have heightened thrombin generation and fibrin formation compared with those with single vessel disease. Conclusions: Patients with atherosclerotic coronary artery disease exhibit evidence of heightened procoagulant activity, including thrombin generation and fibrin formation. This observation, coupled with those derived from other recent studies, support the hypothesis that coronary atherosclerosis represents a chronic active process typified by vessel wall inflammation and recurrent thrombosis. Future efforts in disease prevention and treatment must consider these fundamental pathobiologic properties.

Association Between Body Weight and In-Hospital Clinical Outcome Following Thrombolytic Therapy: A Report from the National Registry of Myocardial Infarction.

Background: In epidemiologic studies, excessive body weight, independent of other risk factors, portends a poor prognosis among patients with coronary artery disease experiencing acute myocardial infarction (MI). At least one recent study has suggested that patients of excessive body weight when receiving thrombolytic therapy are often under-dosed, potentially reducing early coronary arterial patency and adversely affecting in-hospital clinical outcome. Concern has also been raised that body weight may influence treatment utilization, delays, and complication rates. Despite these concerns, the association between body weight and patient outcome following coronary thrombolysis has received limited attention. Methods/Results: Demographic, procedural, and outcome data from patients with MI were collected at 1073 United States hospitals participating in The National Registry of Myocardial Infarction from 1990 through 1994. Among 350,755 patients with MI enrolled, 87,688 (25.1%) were treated with tissue plasminogen activator (t-PA). Divided into body weight tertiles, 23.5% of patients were less than 70 kg (low weight), 36.8% were 70-85 kg (moderate weight), and 37.5% were greater than 85 kg (high weight). Patients of low weight were older (p < 0.001), received treatment later (p < 0.001), and were less likely to undergo cardiac catheterization, coronary angioplasty, or bypass surgery (p < 0.001) than moderate- or high-weight patients. Low-weight patients also experienced minor bleeding, major bleeding, recurrent MI, and death more often (p < 0.001). Adjusted for age, low body weight was independently associated with in-hospital mortality. Despite receiving a lower dose of t-PA per kg body weight, high-weight patients had a low incidence of cardiogenic shock, recurrent MI, death, and hemorrhagic complications.When high-weight women and men were compared, several interesting observations emerged. Mortality was increased twofold in women (6.8% vs. 3.0; p < 0.001), even adjusting for their older age. Despite being at increased risk, women were less likely than their male counterparts to undergo cardiac catheterization (p = 0.001) or bypass surgery (p = 0.008). Conclusions: The National Registry of Myocardial Infarction provides a unique resource for assessing health care trends in the United States. Our findings suggest that low body weight is associated with increased in-hospital morbidity and mortality. They also suggest that current dosing strategies for t-PA administration are probably adequate for high-weight patients. The excessive mortality and limited use of in-hospital interventions among high-weight women deserve further study to address gender-related differences in disease processes, as well as potential bias or discrimination.

Clinical Utility of Electrocardiographic ST-Segment Area for Predicting Unsatisfactory Outcomes Following Thrombolytic Therapy.

The bedside surface 12-lead electrocardiogram is a mainstay in the early diagnostic evaluation of patients with suspected acute myocardial infarction. The presence of ST-segment elevation exceeding 1.0 mm in two or more anatomically associated leads is a reliable marker of myocardial injury and, when considered along with concomitant ST-segment depression, reflects the extent of myocardial injury. Mounting evidence also suggests that prolonged repolarization is a marker of injury and predicts the likelihood of malignant ventricular arrhythmias. We questioned whether a measure of both ST-segment duration and deviation (ST-deviation area) would offer additional prognostic information. Methods/Results: Admission electrocardiograms from 200 consecutive patients with ischemic chest pain accompanied by ST-segment elevation in whom thrombolytic therapy was given within 6 hours from symptom onset were analyzed. The sum of ST-segment elevation (Sigma ST elevation) and ST-segment deviation (Sigma ST deviation) were calculated, as was the sum of ST-segment deviation area (Sigma ST deviation area). All ST measurements were performed 60 msec after the J point. Computerized planimetry was used to calculate ST-segment area. Sigma ST deviation and Sigma ST deviation area remained constant over time. Patients with large deviations (Sigma ST elevation > 20 mm (odds ratio 2.14, p = 0.02) and Sigma ST deviation area > 150 (odds ratio 1.92, p = 0.02) had a higher incidence of in-hospital unsatisfactory clinical outcome (defined as death, congestive heart failure, cardiogenic shock, recurrent myocardial infarction, or the need for coronary revascularization). These relationships were present for both inferior and anterior infarctions. Sigma ST deviation area correlated closely with Sigma ST elevation (r = 0.92; p = 0.0001) and significantly but much less strongly with the sum of Q waves (r = 0.18; p = 0.01). By univariate analysis, only site of infarction (p = 0.01), Sigma ST deviation area (p = 0.04), and the sum of Q waves (p = 0.005) were identified as predictors of a poor clinical outcome. The sum of Q waves was identified by multivariate analysis as the best independent predictor of an unsatisfactory clinical outcome. Conclusions: A clinician's ability to provide optimal care is influenced strongly by the availability of diagnostic and prognostic information. In the evaluation of patients with acute myocardial infarction, ST-segment deviation area derived from the admission surface electrocardiogram can be used to risk-stratify patients. The full clinical potential of this measure is unknown and will require further evaluation.