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CLINICAL STUDY: MYOCARDIAL INFARCTION

Thrombin formation and fibrinolytic activity in patients with acute myocardial infarction or unstable angina: in-hospital course and relationship with recurrent angina at rest

^a Unitat Coronària, Servei de Cardiologia, Hospital General Vall d’Hebron, Barcelona, Spain
^b Unitat de Recerca d’Hemostàsia, Hospital General Vall d’Hebron, Barcelona, Spain

Manuscript received September 21, 1999; revised manuscript received July 5, 2000, accepted August 24, 2000.

Reprint requests and correspondence: Dr. Jaume Figueras, Unitat Coronària, Servei de Cardiologia, Hospital General Vall d’Hebron, Passeig Vall d’Hebron, 119-129, Barcelona 08035, Spain
j.figueras{at}jet.es

	Abstract

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OBJECTIVES

The goal of this study was to investigate possible differences in thrombin generation or fibrinolytic capacity in patients with unstable angina (UA) or acute myocardial infarction (AMI) with or without recurrent angina at rest.

BACKGROUND

Angina at rest in patients with AMI or UA is generally produced by a reduction in coronary flow, but it is unclear whether patients with or without this event differ in their thrombin generation or in their fibrinolytic capacities, which might influence the course of the culprit lesion.

METHODS

Thrombin-antithrombin complex (TAT), D-dimer, fibrinogen and plasminogen activator inhibitor (PAI-1) antigen plasma levels were determined in 40 patients with AMI and in 23 with UA on admission, at 10 days and at three months.

RESULTS

First day values for TAT, fibrinogen and D-dimer were comparable in patients with AMI and in those with UA. At 10 days they increased significantly in each group, and at 3 months they decreased to a similar extent. First day PAI-1 levels, however, were highest in both groups and declined in AMI patients at 10 days and at three months, whereas they also decreased at 10 days in UA patients but not any further at three months. Ten patients with AMI (25%) and 12 with UA (52%) developed in-hospital angina at rest. First day values for TAT, fibrinogen and D-dimer were similar in patients with or without angina, but PAI-1 levels were higher in the former subset (p < 0.008). At 10 days, however, TAT (p < 0.013) and D-dimer (p < 0.013) were higher in patients who developed angina than in those who did not.

CONCLUSIONS

The higher inhibition of fibrinolytic activity in the first day in patients with AMI or UA who will develop recurrent angina suggests that maintenance of a prothrombotic status may contribute to its mechanisms, perhaps by preventing passivation of the culprit thrombus/plaque. This is consistent with greater thrombin generation and greater levels of fibrynolitic products at 10 days observed in these patients compared with those who attain early stability.

Abbreviations and Acronyms   AMI = acute myocardial infarction   PAI-1 = plasminogen activator inhibitor, type 1   TAT = thrombin-antithrombin complex   UA = unstable angina

	Methods

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Patients.   The study population consisted of 77 patients admitted to our coronary care unit, 48 with AMI and 29 with UA. The clinical diagnosis of AMI was based on the concurrence of chest pain, elevated myocardial enzymes (total and MB creatine kinase above twice the upper normal limit) and electrographic changes (ST segment elevation or depression). Diagnosis of UA included the presence of typical angina at rest associated with acute and transient ST segment or T wave changes, with or without progressive exercise-induced angina without enzyme elevation. Exclusion criteria were: age >75 years, presence of Killip class III or IV, left bundle branch block, associated cardiac diseases, previous myocardial infarction, hospital admission for UA, coronary artery bypass grafting or coronary angioplasty. Twenty-six nonsmokers and healthy individuals, age 47 ± 5 years, constituted the control group.

Study protocol.   Patients were treated with intravenous heparin to maintain a partial thromboplastine time approximately twice the control value during the first 2 to 6 days and with aspirin, 250 mg orally. Those with UA and those with AMI who presented recurrent angina also received intravenous nitroglycerin and beta-adrenergic blocking agents. In patients with AMI beta-blockers were initiated during the first five days. Calcium antagonists were added if recurrent angina persisted. During the follow-up patients from both groups received aspirin 250 mg daily and most also received beta-blockers. Those with occasional angina also received nitrates or calcium antagonists. The protocol was approved by the Hospital ethics committee, and informed consent was obtained before entering the study.

Blood sampling.   All patients underwent venous blood sampling on the first 24 h after initiation of intravenous heparin and also on days 10 through 12 and at three months of follow-up. In patients who received thrombolytic therapy, the first sample was drawn before its administration. Samples were drawn between 8:30 and 9:30 AM in a fasting condition without vascular compression and with the patient lying in bed for at least the preceding 30 to 45 min. The first 3 ml of blood were discarded; then, 4.5 ml of blood and 0.5 ml of sodium citrate (0.13 M) for TAT, D-dimer and fibrinogen measurements were mixed, and 5 ml of blood were placed in a diatube for PAI-1 measurements. Samples were then centrifuged at 2,000 g for 20 min at 4°C, and the citrated tube was stored at –80°C until analyzed.

Laboratory methods.   Enzyme-linked immunosorbent assays were used to determine plasma concentrations of PAI antigen (Tintelize PAI-1, Biopool, Sweden), TAT (Enzysnost TAT Micro, Behring, Marbourg, Germany) and D-dimer (Fibrinostika FbDP, Organon Teknika, Boxtel, the Netherlands). Fibrinogen plasma levels were measured by the Von Clauss coagulative method. The lower limits of detection and the co-efficient of variation for PAI-I antigen were 0.5 ng/ml and 6%; for TAT they were 0.5 µg/l and 8.9%; for D-dimer they were 11 ng/ml and 14%, and for fibrinogen they were 0.2 g/l and 4.8%, respectively.

Coronary angiography.   Of the initial 77 patients, 14 were excluded because of lack of some blood samples (n = 4), inadequate sampling technique (n = 3) or need for coumadin therapy (n = 2) or coronary surgery (n = 5). Thus, a total of 63 patients, 23 with UA and 40 with AMI, were finally included. A coronary angiography was performed during hospitalization in 51, in 38 within the first 10 days and in 13 beyond day 10, and a contrast left ventriculogram was performed in 47. Technical restrains, or patient refusal prevented performance of cardiac catheterization in 12. A >70% stenosis of a major coronary vessel was considered significant.

Statistical analysis.   The chi-square test or the Fisher exact test was used to compare categoric variables. The intragroup and intergroup (interaction term) differences for continuous variables were assessed using analysis of two-way repeated measures, analysis of variance. The student t test for unpaired samples was used for intergroup differences between one time measurements. The data are expressed as mean ± standard deviation.

	Results

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Clinical and angiographic data.   Table 1 summarizes most relevant information. Fifteen patients with AMI received thrombolytic therapy, and 22 (34.9%), 10 with AMI and 12 with UA, developed angina at rest while in the hospital (1.9 ± 2.3 episodes for UA and 0.5 ± 0.9 for AMI). Patients with in-hospital angina were comparable to those without except for a lower incidence of smoking and a higher incidence of antecedent angina (>1 month). They also had a higher ejection fraction, in part accounted for by the lower proportion of patients with AMI (10/22, 45% vs. 30/41, 73%). The MB creatine kinase for AMI patients was 200 ± 129 IU/l (upper normal level, 25 IU/l). All 63 patients received intravenous heparin, mostly during the first two to four days and oral aspirin. Also, 45 (71.4%) received beta-blockers, 34 (54%) intravenous nitroglycerin, 32 (50.8%) oral or topical nitrates and 20 (31.7%) calcium antagonists. Sixteen patients, 5 with AMI and 11 with UA, underwent a coronary angioplasty, 11 within the first 7 days (day 3.3 ± 1.7) and 5 between day 10 and 20. Only two patients received a stent implantation. None of the patients died while in the hospital, but one from the group of patients with AMI had a reinfarction and another from the group of patients with UA had an AMI at one month of follow-up.

View larger version (33K): [in this window] [in a new window]   Figure 1 Thrombin-antithrombin complex (upper panel) and fibrinogen plasma levels (lower panel) (mean ± SEM) on days 1 and 10 and at 3 months in patients with unstable angina or acute myocardial infarction with (dashed bars) or without in-hospital angina (open bars). Also shown are values from a control group. Thrombin-antithrombin complex values at the three stages were higher in patients than they were in the control group (see text). There were significant (*) intragroup differences (ANOVA) in the two subsets as well as a trend towards intergroup differences (ANOVA, p < 0.077), mainly because of the higher values at 10 days in patients with in-hospital angina than in those without (p < 0.013). Fibrinogen levels were also higher in patients than they were in the control group and increased significantly at 10 days to a comparable extent in patients with or without in-hospital angina. Intragroup differences (ANOVA) were significant (*). ANOVA = analysis of variance.

In patients with AMI measurements of PAI-1 were highest on the first day, and a similar trend was observed in those with UA. First day and 10 day levels were comparable in the two subsets (Tables 2 and 3). For all 63 patients (Fig. 2), as well as for each of the two subsets (Tables 2 and 3), those with in-hospital angina had higher first day values than those who remained asymptomatic. Intergroup analysis revealed a significant difference for the overall group (p < 0.029, Fig. 2). Also, first day values of PAI-1 were >50 ng/ml in 16 of 22 patients with in-hospital angina (72.7%) and in 14 of 41 without (34.1%, p < 0.01) and were significantly higher than those in the control group (27.3 ± 24.2, p < 0.001).

View larger version (31K): [in this window] [in a new window]   Figure 2 D-dimer (upper panel) and PAI-1 plasma levels (lower panel) (mean ± SEM) on days 1 and 10 and at 3 months in patients with unstable angina or acute myocardial infarction with (dashed bars) or without in-hospital angina (open bars) and in those from a control group. D-dimer values at the three stages were higher in patients than they were in the control group (see text). There were significant intragroup differences (*) (ANOVA) in the two subsets as well as intergroup differences (ANOVA, p < 0.029). At 10 days values were significantly higher in patients with in-hospital angina than they were in those without (p < 0.004). Plasminogen activator inhibitor, type 1 levels were also higher in patients than they were in the control group, and there were significant (*) intragroup (ANOVA) as well as intergroup differences (ANOVA, p < 0.029). The latter were mainly related to the particularly higher PAI-1 levels on day one in patients who developed in-hospital angina than in those who did not (p < 0.008). ANOVA = analysis of variance; PAI-1 = plasminogen activator inhibitor, type 1.

In 54 of 63 patients (83.7%) the 10th day sample was taken either before coronary angiography or 4 days after the procedure, whereas in the remaining nine sampling was performed 24 to 72 h after the procedure. Thus, in the 38 patients who underwent catheterization within the first 10 days, the interval between catheterization and the 10th day sampling was 5.0 ± 2.3 days. Moreover, at 10 days patients were no longer receiving heparin, which had been discontinued within the first four to five days in most of them.

	Discussion

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Fibrinogen and TAT measurements.   Consistent with previous observations (14–16) patients with AMI or UA had higher fibrinogen levels on the first day than did a control population. In addition we noted a further increase at 10 days similar to that reported by Aznar et al. (17), and that might be attributable to an acute phase reaction (18–20). More specifically, however, we demonstrated that these values were comparable in the two subsets. We also observed that TAT levels increased during hospitalization to a similar extent in the two groups. The results in patients with UA are in line with those reported by Hoffmeister et al. (21), Al-Nozha et al. (22) and Biasucci et al. (23), who also found increases in TAT levels during hospitalization. These investigators (21–23), however, limited their measurements to the first days, had no early follow-up data and did not compare the results of UA patients with the results of patients with AMI (22,23). In our study the increases in thrombin generation at 10 days corresponding to the increases in TAT declined at three months but remained higher than they did in control subjects. Similarly, Merlini et al. (24) documented that patients with UA or AMI had a persistent hypercoagulable state at six months of follow-up.

PAI-1 and D-dimer measurements.   Another observation of interest was the higher PAI-1 levels found on day one than at 10 days or at the three months of follow-up. Even though this was more apparent in patients with AMI, those with UA also had higher first day than 10 day values, indicating that both groups had a reduced PAI-1 related fibrinolytic activity during at least the first 24 h. In patients with UA, Hoffmeister et al. (21) also found increased levels of PAI-1 but did not document a decline at 10 days and Al-Nozha et al. (22) also observed increased levels during the first five days but did not examine possible changes later on. Moreover, these authors did not investigate possible differences between patients with or without recurrent angina (21,22). In contrast with these studies Alexopoulos et al. (25) found no change in PAI-1 levels within first 24 h to 48 h in similar patients. In patients with AMI Sakamoto et al. (26) observed, as in our study, a transiently reduced fibrinolytic capacity that became normal a few weeks after discharge, but the study did not assess possible changes during the hospital course or differences between patients with or without recurrent angina.

Also worthwhile was the significant in-hospital increase in plasma D-dimer levels in patients with AMI or UA. Similar increases had been previously reported by some investigators in patients with AMI (27,28) or UA (21,28) but not by others (25,29). Although Kruskhal et al. (28) performed only a single measurement and within 1 h of chest pain in patients with UA or AMI, they showed similar levels of D-dimer as our first day values (28). Moreover, we observed a further increase at 10 days that was not documented by Hoffmeister et al. (21). Among patients with AMI, increases in D-dimer are known to occur (28,29) and appear to be particularly elevated in those with heart failure or ventricular arrhythmias (30). Of interest is that Takano et al. (31) observed that, in patients with atherothrombotic strokes, D-dimer values were significantly higher at seven days than on day one, as in our patients with AMI or UA.

Influence of clinical instability.   Previous investigations that have analyzed TAT (21–23), PAI-1 (21,22) or D-dimer levels (21) in patients with UA have not evaluated possible differences between those with or without recurrent in-hospital angina. This is relevant because our patients who experienced episodes of angina at rest despite full medical therapy differed in these parameters from those who remained stable. Thus, even though both subsets, stable and unstable, presented an increased rate of thrombin formation at 10 days as indicated by the higher levels of TAT and D-dimer, which are probably associated with increases in other markers of acute phase reactants such as fibrinogen—seen in this study and by others (17)—C-reactive protein (32–34) or von Willebrand factor (34,35), the change was more remarkable in the unstable group. This group also had higher levels of PAI-1 on the first day than those who remained asymptomatic, and they had a greater fall on day 10. The difference between these findings and those of Hoffmeister et al. (21) who failed to find a decline of PAI-1 at 10 days may possibly lie in the differences in the clinical course because they excluded patients with recurrent angina. At variance with these studies, however, Alexopoulos et al. (25) found no change in PAI-1 levels within first 24 h to 48 h and failed also to find differences between patients with or without recurrent angina. Although it is unclear why our results differ from theirs, for one thing the population and study design were different (25). In fact, their patients were older, had more women, some had had previous coronary events, and the analysis of the recurrence of angina was limited to the first 48 h (25). Moreover, PAI-1 antigen was measured by a different technique, samples were not systematically obtained at the same hour and, as opposed to previous observations (36), they encountered no circadian differences in PAI-1 levels. As indicated, failure to note further increases in D-dimer at 10 days by Hoffmeister et al. (21) could presumably be attributed to the exclusion of patients with recurrent angina. Thus, their results in stable "unstable" patients would be in agreement with those of our stabilized patients who showed lower values of D-dimer at 10 days than those who remained unstable.

Hypothetically, the increased in-hospital thrombin generation and D-dimer levels seen in patients with recurrent angina could possibly be linked, in part, to coincidental episodes of silent ischemia, like the changes in TAT levels documented by Biassucci et al. (37). However, at 10 days the majority of our patients with recurrent angina had already attained a stable course. Therefore, in view of the consistent increases in TAT and D-dimer levels at 10 days on one hand and of their short plasma half-life (5 min for TAT [38] and 4 to 8 h for D-dimer [28,39]) on the other, we are more inclined to interpret these changes as originating from a steady source, such as the inflammatory reaction that accompanies this unstable condition (16,40,41) than to an unpredictable source such as asymptomatic episodes of ischemia.

Another reliable marker of thrombin activity in plasma, the fibrinopeptide A, has also been shown to increase in patients with UA who experience in-hospital angina associated with ST segment changes (29) or intracoronary thrombus (42). Moreover, increased fibrinopeptide A levels have been documented in patients with UA who developed an AMI during the hospitalization (43).

It is unclear why our patients with AMI and recurrent angina had a lower initial fibrinolytic activity than those who remained stable since, apparently, the former subset would tend to have a less occlusive thrombus. Thus, it is conceivable that the observed systemic alterations in thrombin formation and in fybrinolitic status would be independent of the characteristics of the thrombus of the culprit artery and might be secondary to a more generalized response, such as the alluded systemic inflammatory reaction. Accordingly, it is possible that unstable patients after an AMI would present a greater inflammatory response than the stable ones, as in patients with UA who remain symptomatic (33). Moreover, our patients with AMI and recurrent angina had a larger incidence of preinfarction angina than those without angina, which is in agreement with previous reports (3,44). In this regard, it is of interest that tissue factor plasma levels, which are a primary initiator of the extrinsic coagulation cascade, have been shown to be higher in patients with AMI who experienced UA previously as compared with those who did not (45).

Study limitations.   The use of heparin during first day samples may be considered as a limitation to assess coagulation alterations. However, we deemed it of interest since it is a widely used treatment, and, hence, the potential prognostic implications derived from these initial findings could be applicable to patients with standard therapy. In previous studies, Hoffmeister et al. (21) and Al-Nozah et al. (22) also included patients treated with heparin and assumed, as we did, that TAT levels could have been somewhat higher without this antithrombin therapy. This effect, however, would be similar in all our subsets of patients. In addition, and while heparin reduces thrombin formation and fibrinopeptide A levels—which is a specific product of fibrinogen cleavage by thrombin—its effects on D-dimer levels seem to be negligible (27). On the other hand, 10 day TAT values could have been influenced by heparin discontinuation for this is a condition associated with a rapid increase in fibrinopeptide A (46) and thrombin generation. However, this is a short duration phenomenon with a return to baseline values at 24 h (47), and, consequently, it is unlikely to have altered our 10 day samples because they were taken at an average of five days after heparin cessation.

Another potential limitation is the possible interference by the catheterization and angioplasty procedures with the natural evolution of thrombin generation and fibrinolytic activity. Indeed, the higher need for catheterization or angioplasty in the unstable group and the possible link between these procedures and the activation of thrombin formation (48,49) could have partly accounted for their higher values. However, it was precisely to circumvent this interference and that of the variable use of heparin during the first days that the second samples were drawn at 10 days, which is a time when most patients have already stabilized. Although there are no studies analyzing the changes in the parameters herein reported after catheterization, there appears to be a striking increase in C-reactive protein and interleukin 6 after percutaneous transluminal coronary angioplasty or coronary angiography, but only in UA patients with high levels of C-reactive protein and interleukin 6 before the procedures and not in those with normal levels or those with stable angina (49). These values, however, return to baseline in 72 h (49). Among our patients only nine (14%) had their angiography/percutaneous transluminal coronary angioplasty performed between the 24 h to 72 h before the 10th day sample, and five of them belong to the stable subset. Moreover, since TAT and D-dimer have a much shorter half-life than C-reactive protein, 5 min (38) and 5 h to 8 h (28,39) versus 19 h (49), it seems improbable that catheterization procedures could have significantly influenced the changes observed in most of our patients.

Admittedly, the fact that our group of healthy controls was younger than our patients subsets constitutes a limitation. Thus, even though other groups have found similar differences between patients and controls (14–16,21), it is possible that the magnitude of our differences might not be comparable with those of age-matched control studies. Hence, our data need to be interpreted with caution. Moreover, the relevance of our results with respect to the incidence of infarction is very limited since the number of patients studied is reduced. Nevertheless, there might be a link with our findings because recurrence of angina appears to be a good predictor of subsequent infarction (2–4,44,50). Finally, we evaluated only symptomatic recurrent ischemia and provided no information about silent ischemia. Thus, theoretically, there is a possibility that, by analyzing asymptomatic rather than symptomatic ischemia, the results could have been different. However, silent ischemia is much more likely to occur among patients with recurrent angina than it would in those who remain asymptomatic (2,5,51).

Clinical implications.   Our study extends previous observations on the persistence of a hypercoagulative state in patients with UA or AMI. It adds, however, that this becomes more apparent among patients with either UA or AMI who remain unstable in the hospital. This subset, moreover, already shows a particularly reduced fibrinolytic capacity on admission. These findings, therefore, may shed further light into the mechanisms of angina at rest in the context of UA or AMI. They may suggest that the persistence of a hypercoagulative condition may perhaps limit the ability to reduce the size of the thrombi at the culprit lesion and, hence, may facilitate additional deposition of fibrin or platelet aggregates. The association with transient increases in coronary tone, which seem to follow a circadian pattern (8), would further reduce coronary flow leading to myocardial ischemia. Our results, therefore, would be in concert with the concept that a better control of thrombin generation, and possibly of platelet aggregation, will eventually contribute to a better prevention of recurrent angina in at least a number of these patients.

	Footnotes

 
Supported, in part, by the grant PRHG-14/97 from the Hospital General Vall d’Hebron, Barcelona, Spain.

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