(Circulation. 1996;93:2121-2127.)
© 1996 American Heart Association, Inc.
Articles |
Temporal Relation Between Ischemic Episodes and Activation of the Coagulation System in Unstable Angina
From the Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy, and Prevention and Health–TNO Gaubius Laboratory, Leiden, Netherlands (C.K.).
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Abstract |
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Background Although a major role of coronary thrombosis in the pathogenesis of unstable angina has been demonstrated, the results of a series of studies have suggested that activation of the hemostatic system may not be confined to ischemic episodes. The purpose of this study was to investigate the temporal relation between ischemic episodes and activation of the coagulation system in unstable angina.
Methods and Results Thrombin–antithrombin III (TAT) and prothrombin fragment 1+2 (F1+2) levels were measured in 13 patients during spontaneous ischemic episodes (time 0, 5, and 15 minutes and 1 hour) to evaluate the time course of the activation of the coagulation system associated with the development of ischemia (protocol A). TAT and F1+2 levels were also measured in 28 patients with unstable angina on admission to hospital (every 6 hours for 24 hours and daily for 3 days) to assess their temporal relation with ischemic episodes (protocol B). In protocol A, TAT and F1+2 levels were elevated in 10 of 13 patients (77%) in at least 1 sample. The median value of TAT showed a peak at 5 minutes and returned to baseline within 15 minutes (P<.05), consistent with its plasma half-life of 5 minutes, whereas the median value of F1+2 showed no significant changes, possibly because of its longer half-life, which tends to dampen sudden bursts of thrombin production. In protocol B, activation of the clotting system was found in 10 of 33 samples (30%) temporally related to ischemia and also in 23 of 150 (15%, P=.07) of those not temporally related to ischemia.
Conclusions Our study demonstrates that patients with active unstable angina develop frequent bursts of thrombin production not necessarily associated with ischemic episodes and that, conversely, some ischemic episodes are not associated with evidence of thrombin activation.
Key Words: ischemia • coagulation • angina
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Introduction |
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Amajor role of coronary thrombosis in the pathogenesis of unstable angina has been demonstrated by postmortem, angiographic, angioscopic, and biochemical studies.1 2 3 4 The waxing and waning of symptoms over a period of up to 2 months5 and the very common multilayered appearance of coronary thrombi at postmortem examination6 indicate a recurrent episodic activation of the hemostatic system. However, the results of a series of studies suggest that such activation may not be confined to the timing of ischemic episodes. Elevated levels of FPA, TAT, and F1+2 for prolonged periods after ischemic episodes have been observed in unstable patients,3 7 8 9 which, given the short plasma half-life of these components, suggests that activation of the coagulation system, either continuously or intermittently, is not necessarily related to episodes of ischemia. Platelets are very strictly related to the process of thrombus formation,10 11 12 13 and a temporal dissociation between ischemic episodes and platelet activation in unstable angina was reported by Fitzgerald14 and confirmed by Vejar et al,15 who observed that only a minority of episodes of enhanced urinary excretion of 11-dehydrothromboxane B2 was related to ischemia.
A recurring activation of the clotting system and its possible dissociation from ischemic episodes would have important pathophysiological implications. To investigate their temporal relation with ischemic episodes in patients with unstable angina, we measured two markers of coagulation activation with different plasma half-lives: TAT (plasma half-life, 5 minutes)16 and F1+2 (plasma half-life, 90 minutes).17 Two different protocols were implemented: protocol A, with frequent sampling during and after spontaneous ischemic episodes, to assess the time course of hemostatic activation associated with the development of ischemia, and protocol B, with a fixed sampling schedule over the first 4 days of hospitalization, to follow the behavior of the coagulation system during the active phase of unstable angina and its temporal association with ischemic episodes.
Our results confirm an ongoing activation of the clotting system in unstable angina and demonstrate that bursts of thrombin production occurring during some but not all spontaneous ischemic episodes and also apparently unrelated to ischemia are a pathophysiological hallmark of this syndrome.
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Methods |
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Patient Population
The original study group was composed of 41 consecutive patients (32 men) 55±12 years old (range, 42 to 79 years) admitted to our CCU for the severity of their unstable angina. However, 3 patients were subsequently withdrawn because of the demonstration of angiographically normal coronary arteries with spasm diagnostic of variant angina. Thus, 38 patients formed the study group. The inclusion criteria were angina at rest, with at least 2 ischemic episodes or 1 episode lasting more than 20 minutes during the previous 24 hours, with diagnostic ST-segment shift and no evidence of myocardial infarction detected by enzymatic techniques. The exclusion criteria were left bundle-branch block, dilated cardiomyopathy, valvular heart disease, previous myocardial infarction with ejection fraction <40% or with evidence of left ventricular aneurysm, previous myocardial infarction within 4 weeks or treatment with heparin within the previous 24 hours, atrial fibrillation, the presence of a pacemaker, or any other ECG abnormality that would invalidate ST-segment analysis. Major surgery or trauma within the previous month, known thrombotic disorders, malignancy, and inflammatory diseases were also excluded to avoid inclusion of patients with increased clotting tendency. Patients with poor peripheral veins were also excluded because of the difficulties in obtaining repeated clear venipuncture. Between October 1992 and October 1993, 138 patients were admitted to our CCU with a diagnosis of unstable angina: 23 patients were excluded because they had experienced no ischemic episodes during the previous 24 hours, 14 were already on heparin, 10 had an increase in total creatine kinase within 6 hours of admission, 20 had suffered a recent myocardial infarction, and 11 had poor peripheral veins. In addition, 19 patients were excluded because of neoplastic disease (2), inflammatory diseases (9), severe anemia (2), left bundle-branch block (3), Wolff-Parkinson-White syndrome (1), abdominal aortic aneurysm (1), and left ventricular pseudoaneurysm with thrombi (1). The onset of instability ranged from 1 to 20 days (5.6±6.3 days). Nineteen of the 38 patients were secondary referrals to our center. All patients were treated with various combinations of calcium antagonists, intavenous nitrates, and/or ß-blockers; aspirin (100 mg) was also prescribed, with a loading dose of 325 mg when necessary. Heparin was not used as a first-step treatment and was added to the standard therapy only in cases of worsening symptoms, in which case blood sampling was discontinued. All admission samples were taken under aspirin cover.
The study was approved by the Ethics Committee of the Catholic University, and all patients gave their signed informed consent.
Study Design
To assess the temporal relation between activation of the
hemostatic system and ischemic episodes, we designed two
different protocols. Protocol A, with frequent sampling during
spontaneous ischemic episodes, was designed to assess the time
course of hemostatic activation during and after an ischemic
episode. This was assessed in 13 patients by taking blood samples as
soon as possible after the onset of ST-segment changes, with or without
chest pain, and subsequently at 5, 15, and 60 minutes from the onset.
At the onset of ST-segment changes, a diagnostic 12-lead
ECG was recorded and the amount of ST-segment shift measured.
Protocol B, with a fixed sampling schedule over the first 4 days of
hospitalization in the CCU, was designed to follow the behavior of the
coagulation system during the active phase of unstable angina and to
evaluate its temporal relation with ischemia. Twenty-eight
patients were assessed by blood samples, taken from separate clean
venipunctures, as soon as possible after admission and
subsequently every 6 hours for the first 24 hours, between 8 and
10 AM on days 2 (48 hours), 3 (72 hours), and 4 (96 hours),
and before hospital discharge. Sampling was discontinued when the
addition of heparin or urgent revascularization
(coronary angioplasty or bypass) was clinically indicated. All
patients had Holter monitoring for 24 hours and remained in the CCU,
under ECG monitoring of the lead with the most striking
ischemic ST changes, until completion of the study. The nurses
were instructed to recognize and annotate each ST-segment change from
the monitors. The results of samples taken in the absence of
ischemia were analyzed separately from those taken
within 3 half-lives of an ischemic episode for each of the
investigated markers (ie, a period during which TAT and
F1+2 could reasonably still be elevated, as defined in the
study): within 15 minutes for TAT (n=17 episodes) and within 4.5 hours
for F1+2 (n=33 episodes).
Coronary angiography was performed within 5 days of admission in 26 patients because of the severity of symptoms and within days 5 to 9 in 7 other patients. In 5 patients, angiography was not performed: in 3 because of waning of symptoms and a negative exercise stress test and in 2 because of death. The angiograms were reviewed by an expert angiographer (G.S.) who was unaware of the patients' clinical and analytical data.
Blood Sampling and Laboratory Assays
Blood was always withdrawn through a clean
venipuncture with minimal venostasis via a 19-gauge needle.
Repeated venipunctures were always performed in different
veins or in different and progressively more distal segments of the
same vein. A 4.5-mL sample was immediately transferred into precooled
tubes containing 0.5 mL citrate, theophylline, adenosine, and
dipyridamole (CTAD tubes, Behring Werke). The tubes
were centrifuged at 2000g and at 4°C for 20
minutes. Plasma aliquots of 500 µL were pipetted into appropriate
tubes, snap-frozen, and stored at -80°C within 1 hour of
venipuncture, according to the method previously described
by our group and by others.16 17 18 All samples were taken by
the investigators only. The aliquots were assayed for TAT and
F1+2 by use of commercially available ELISAs (Enzygnost
thrombin–antithrombin III complex and Enzygnost Micro
F1+2 ELISA test kit, Behring Werke).16 17 The
assays were performed at the end of each protocol by one of the
investigators (W.v.d.G.), who was unaware of the patients' clinical
data.
Since measurement of products of thrombin generation can be biased by in vivo and in vitro artifacts and since our control group consisted of only normal subjects who had low baseline levels of TAT and F1+2,3 we considered it reasonable to adopt rather conservative limits for the definition of abnormal elevation in our study. We arbitrarily chose as a value of definitely elevated TAT and F1+2 the maximum level in normal subjects (volunteer staff members) +2 SDs, ie, 6 µg/L and 1.3 nmol/L, respectively. In addition, we excluded from further analysis TAT and F1+2 values above the detection limit of the assays (ie, 60 µg/L and 8 nmol/L), because they were considered to be likely artifacts. Of a total of 291 samples, 6 (2%) were excluded.
Reproducibility of Repeated Venipuncture
We tested the long-term reproducibility of our measurements
during serial venipunctures by determining TAT levels in 5
normal volunteers in whom blood was collected every 6 hours for 24
hours and then once a day for 3 days. TAT levels remained stable
throughout the study, and no significant increases were observed with
repeated venipuncture, with an average intersample CV of
25%. In 4 volunteers, samples at times 0, 5, 15, and 60 minutes, as in
protocol A, were taken, with a CV of 27%. To exclude interoperator or
technical variabilities, single samples were taken from 5 patients at
the same time, from different veins, by two different investigators.
The average CV between different arms was 22%. Interassay and
intra-assay CVs were 3% and 6%, respectively.
Statistical Analysis
Since F1+2 and TAT were not distributed normally,
nonparametric tests were used. The results are expressed as
median and range; the Mann-Whitney U test was used to
evaluate differences between individual groups. Discontinuous
variables were tested by contingency 
2 test.
Continuous variables containing clinical data are expressed as
mean±SD and were evaluated by unpaired t test. A
probability of P<.05 was assumed to be significant. All
tests are two-tailed.
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Results |
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In our laboratory, normal values of TAT and F1+2 ranged from 1 to 4.2 µg/L and from 0.4 to 0.9 nmol/L, respectively. We considered arbitrarily a cutoff point of 6 µg/L for TAT and of 1.3 nmol/L for F1+2 (ie, the maximum of normal values +2 SDs) as indicative of a detectable activation of the clotting system.
Protocol A
Clinical characteristics are reported in Table 1
.
TAT and F1+2 levels were found to be elevated in 10 of 13
patients (77%) in at least 1 of the 4 samples taken over a period of 1
hour after the onset of the spontaneous ischemic episodes. In
all episodes, ECG changes diagnostic of ischemia
were observed on the 12-lead ECG: ST-segment depression in 6 patients,
ST-segment elevation in 3, and pseudonormalization of previously
negative T waves in 4. No significant increases in heart rate or blood
pressure were observed during any of these episodes. Signs of
ischemia never lasted longer than 15 minutes and were always
relieved promptly by nitrates (Table 1).
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In 9 patients, TAT levels were >6 µg/L in at least 1 sample (16 of
52, 31% of the samples taken), and the elevation exhibited a
characteristic time course (Fig 1). At time 0, all but 1
patient had normal TAT levels; at 5 minutes, values had increased in 6
patients, in 4 of whom it represented the peak (median,
22.8 µg/L and range, 6.1 to 41.3 for the 6 patients; median, 6.1
µg/L and range, 0.3 to 41.3 for all 13 patients). In other patients,
the peak was reached at 15 minutes, at which time 3 patients continued
to have elevated levels. In all but 2 patients, TAT levels returned to
baseline at 1 hour; in one patient, levels increased further, and in
another, TAT levels increased weakly only at 1 hour (Fig 1). The median
value of TAT in the 13 patients showed a typical dome-shaped
curve with a peak increase at 5 minutes and a return to baseline at 15
minutes (P<.05). The same curve is more sharply defined
when only the patients with elevated values of TAT are considered (Fig 2).
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), in the 9 patients with elevated levels of TAT
(
), and in the 4 patients without any increase in TAT (
): a
typical dome-shaped curve with a significant peak increase at 5
minutes (P=.05) and a return to baseline at 15 minutes can
be observed in the overall population and, more clearly, in patients
with elevated values of TAT. This pattern is consistent with
the 5-minute half-life of TAT.
F1+2 levels were higher than 1.3 nmol/L in 10 of 13
patients in at least 1 sample (28 of 52, 54% of the samples taken),
but the elevation exhibited a time course different from that of TAT:
F1+2 was elevated in 5 patients at time 0, in 7 at 5
minutes (peak median value), in 5 at 15 minutes, and after 1 hour in 7
patients (Fig 3). The median value of F1+2
for the 13 patients showed a "flat" curve, which exhibited no
significant differences over the 60 minutes (Fig 4).
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In 1 patient, only F1+2 levels were elevated, despite the
presence of chest pain with ischemic ECG changes. No increases
in either TAT or F1+2 were detected in 3 patients, 2 of
whom presented ST-segment elevation during the ischemic
event (Table 1
).
Protocol B
Episodic elevation of TAT and F1+2 associated with
ischemic episodes. During the study, 87 ischemic
episodes were observed (67 symptomatic, 20
asymptomatic), and blood samples were taken within 4.5
hours (3 half-lives of F1+2) in 33 episodes (38%) and
within 3 half-lives of TAT (15 minutes) in 17 episodes.
Twenty-seven of the 33 episodes were observed in the first 24 hours
during Holter monitoring. F1+2 levels were >1.3 nmol/L in
8 of 33 episodes (24%; median, 1.77 nmol/L; range, 1.33 to 6.42) but
were <1.3 nmol/L in 25 episodes (median, 0.85 nmol/L; range, 0.24 to
1.28; Fig 5). TAT levels were >6 µg/L in 9 of the 17
episodes (53%; median, 17.9 µg/L; range, 12 to 51) but in 8 were <6
µg/L (47%; median, 2.3 µL; range, 1.3 to 4.1; Fig 6). Overall, 10 of 33 (30%) were associated with
activation of the clotting system. The mean time from onset of
ischemia to blood sampling was 8 minutes (range, 2 to 15
minutes) for TAT and 47 minutes (range, 2 to 270 minutes) for
F1+2. The mean duration of ischemia was 20±18
minutes (range, 5 to 60 minutes; Table 2).
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Episodic elevation of TAT and F1+2 not associated with
ischemia. An episodic activation of the clotting system
was observed in most but not all patients: in 22 of 28 patients (80%),
at least one increase in either TAT or F1+2 levels was
detected, but in 6 of 28 patients, no such activation was observed.
During the study, 150 samples were taken during periods free of
ischemia (ie, not taken within 3 half-lives of
F1+2 from an ischemic episode), but in 23 samples
(15%), activation of the clotting system was observed: In 17 samples
(11%) and in 19 samples (13%), levels of F1+2 and TAT,
respectively, were elevated (Figs 5 and 6). Median levels of TAT were
2.3 µg/L (range, 0.1 to 60) in the 150 samples and 23.6 µg/L
(range, 6 to 60, P=NS versus elevated TAT during
ischemia) in the 19 samples with elevated levels. Median levels
of F1+2 were 0.9 nmol/L in the 150 samples (range, 0.1 to
6.48) and 1.7 nmol/L (range, 1.3 to 6.48, P=NS versus
elevated F1+2 during ischemia) in the 17 samples
with elevated levels.
Elevated TAT or F1+2 levels showed no correlation with the interval between sampling and occurrence of the last ischemic episode or with the duration of the episode.
Thus, overall, 33 episodes of activation of the clotting system were
detected in protocol B, but only 10 (30%) were temporally related to
ischemia (Figs 5 and 6). Moreover, peak values of TAT and
F1+2 associated with ischemic episodes did not
differ significantly from peak values not associated with
ischemia.
Had we considered TAT and F1+2 levels of 4 µg/L and 1 nmol/L (mean+2 SDs), respectively, as cutoff points, activation of the coagulation system would have been observed in 19 of 33 samples temporally related to ischemia (58% instead of 30%) and in 57 of 150 samples not temporally related to ischemic episodes (38% instead of 15%, P=.06).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our findings demonstrate the occurrence of bursts of thrombin production in unstable angina consistent with an ongoing waxing and waning activation of the coagulation system, as suggested by previous studies.3 19 We have also demonstrated that this activation is not necessarily temporally related to detectable ischemic episodes, because about one fourth of ischemic episodes in protocol A were not associated with detectable activation of the clotting system and, conversely, from about one half to two thirds of all episodes of activation in protocol B were unrelated to detectable ischemic episodes.
Temporal Relation Between Thrombin Formation and
Ischemic Episodes
An ongoing activation of the clotting system in unstable angina
was suggested by Neri Serneri et al20 and Theroux et
al8 on the basis of elevated plasma levels of FPA.
Elevated levels of FPA and F1+2 on admission to hospital
and of F1+2 at 6 months after discharge have recently been
reported in unstable angina,3 and raised levels of FPA
have been described in association with angiographic evidence of
thrombosis21 and related to ST-segment
shifts,22 although the latter was not confirmed in a
recent study.23 Because of the short half-life of FPA
and F1+2, it is not clear whether such elevated
levels of FPA and F1+2 represent the tail of acute
bursts of thrombin generation or a persistent low-grade
activation of thrombin. A dissociation between platelet
activation and spontaneous myocardial ischemia was
reported by Vejar et al,15 who reported that 60% of
episodes with enhanced urinary excretion of
11-dehydrothromboxane B2 in patients with
unstable angina occurred in the absence of ST-segment changes or chest
pain. A similar finding was also observed by Fitzgerald,14
who interpreted the dissociation as being due, most likely, to episodes
of silent ischemia, although Holter monitoring was not included
in their study. Thus, the results of previous studies based on
products of platelet activation show a dissociation between
ischemic episodes and platelet activation. This similarity
to our findings is not surprising, since platelets are a
fundamental component of the clotting cascade (especially at the site
of a stenosis),10 are activated by
thrombin, enhance the process of thrombin formation, and lead to
vasoconstriction by the release of such products as
thromboxane A2,
serotonin, ADP, and platelet-activating
factor.12 13 24 25
At variance with previous studies that considered only one22 or two3 20 time points (entry plus discharge or follow-up), we systematically monitored the activation of the coagulation system during 4 days of hospitalization in the CCU under ECG cover. Such a protocol allowed us to investigate specifically the temporal relation between activation of the coagulation system and ischemic episodes. Thus, we were able to demonstrate a temporal relation between bursts of thrombin formation and at least some ischemic episodes in both protocols. We also observed bursts of thrombin generation that were unrelated to ischemic episodes. In protocol A, 3 of 13 patients (23%) had no increase in the levels of TAT or F1+2 associated with ischemia during 1 hour of follow-up, and in protocol B, activation of the coagulation system, temporally related to ischemia, was observed in 9 of 17 samples (53%) for TAT and in 8 of 33 samples (24%) for F1+2. In protocol A, the sharp increase in TAT over 5 minutes and its return to normal median values within 15 minutes suggest that a very brief burst of thrombin production is often associated with an ischemic episode; however, we were unable to assess whether these bursts are a cause or a consequence of ischemia. In protocol B, an episodic activation of the coagulation system was observed in 18% of samples (33 of 183) taken over 4 days; in 6 of 28 patients (21%), no activation of the coagulation system was observed, but, intriguingly, activation was also observed in 15% of samples (23 of 150) taken during periods free of ischemia, suggesting a dissociation between thrombin formation and ischemic events. Although in vivo and in vitro artifacts represent a possible bias in studies involving proteases of the coagulation system, our findings are unlikely to be due to artifacts, because great care was taken over sampling procedures. Moreover, to reduce the possibility of artifacts and to increase specificity, we also excluded very high levels of TAT and F1+2 and accepted as elevated only those that were higher than the maximum levels in normal subjects +2 SDs. Had we had adopted lower values of TAT and F1+2 as cutoff points for activation of the coagulation system, we would have detected not only more episodes of activation associated with ischemic episodes (30% with cutoff at 6 µg/mL and 58% with cutoff at 4 µg/mL) but also more episodes unrelated to ischemic events (15% and 38%, respectively).
The difference between the behavior of TAT and that of F1+2 may be explained on the basis of the nearly 20 times longer half-life of F1+2, which tends to dampen the peaks and troughs related to episodic bursts of activation and to give persistently slightly elevated levels of F1+2. Conversely, the sharp rise and fall in TAT are in agreement with its short half-life.
Pathophysiological
Implications
The lack of evidence of thrombin formation in one fourth of the
ischemic episodes cannot be explained by episodic increases in
myocardial demand (which was not detectable in our study); it may,
therefore, be explained by coronary constriction. Conversely,
the bursts of thrombin formation observed during periods free of
ischemia may be explained either by antithrombotic mechanisms,
which may have prevented the formation of a coronary
flow-limiting thrombus, or by episodic thrombin formation unrelated
to coronary thrombosis.
F1+2 and TAT complexes are related to the amount of formed and circulating thrombin, respectively, and provide indications of the activity of factor Xa but not of actual fibrin formation. Since our study addressed the mechanisms underlying the activation of the coagulation system in unstable angina rather than the mechanisms responsible for ischemia, markers of fibrin production, such as FPA, were not measured. Another potential limitation of our study is that the roles of tissue factor26 and of platelet activation,10 11 12 13 24 25 26 which may be responsible for thrombin activation, were not assessed.
The commonly held hypothesis that coronary thrombosis is just the result of a purely mechanical plaque fissure does not, by itself, explain the recurrent activation of the coagulation system that we recorded even in patients with a 2-week history of unstable angina.
Given the short plasma half-life of TAT and F1+2, the fact that 30% of all samples taken during the 4 days of the study had elevated levels of these markers suggests a very frequent activation of the coagulation system. However, the presence of powerful stimuli that maintain the system either activated or in a hyperreactive state for prolonged periods of time, rather than during occasional bursts, cannot be excluded.
The finding of elevated levels of TAT and F1+2 in the peripheral blood in response to a localized coronary thrombotic process is also intriguing, because a critical mass of thrombus may be necessary to detect activation of the coagulation system in the peripheral blood.27 Although we have no definite explanation for this enigma, we must stress that a number of authors have also reported this finding3 7 8 9 20 21 22 23 and that, intriguingly, increased levels of FPA have been reported within 5 minutes of the start of episodes of vasospastic angina.28 29 Explanations for this latter finding include the possibility that the coagulation cascade may hyperreact to localized stimuli, producing either a detectable response in the periphery or a washout of thrombin formation products from the site of a thrombus after restoration of flow. The peak values of TAT and F1+2 associated with ischemic episodes were comparable to those unrelated to ischemic episodes and also to those found in cases of deep vein thrombosis and pulmonary embolism, when the actual amount of thrombus is several times greater than that present in the coronary arteries.30
Alternatively, activation of the coagulation cascade in unstable angina may not necessarily be localized at the site of a single unstable coronary atherosclerotic plaque, because occasional bursts of systemic production of thrombin might also be caused by circulating activated monocytes31 or be diffused within the coronary tree.32 33 This possibility would be compatible with the increased urinary excretion of 11-dehydrothromboxane B2 unrelated to ischemic episodes,15 even in the presence of platelet cyclooxygenase 1 blockade.34 The growing evidence of an important inflammatory component in unstable angina,33 35 36 37 38 39 together with the multiple links between inflammation and the coagulation system, might help explain the persistent recurrence of bursts of activation of the hemostatic system over periods of days and weeks. The relation between inflammation and activation of coagulation in unstable angina, therefore, deserves further study.
Conclusions
Our study demonstrates ongoing bursts of thrombin
production in unstable angina not necessarily related to
ischemic episodes. While confirming the frequently increased
generation of thrombin in unstable angina, our findings also suggest
that the mechanisms responsible for instability may be more complex
than a simple mechanical fissure of an atherosclerotic plaque and may
possibly be related to recurrent production of inflammatory
cytokines.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the National Research Council (CNR), targeted project "Prevention and Control Disease Factors," Progetto FAT.MA, Rome, Italy (research grant 94.00518.PF41). We are indebted to the nurses of the CCU at Policlinico Gemelli for their assistance and to V. Perrin for her assistance in the preparation of the manuscript.
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Footnotes |
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Reprint requests to Luigi M. Biasucci, MD, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo F Vito, 00168 Rome, Italy.
Received October 3, 1995; revision received December 20, 1995; accepted December 21, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis: evolving concepts. Circulation. 1990;83(suppl II):II-47-II-59.
2. Mizuno K, Miyamoto A, Satomura K, Kurita A, Arai T, Sakurada M, Yanagida S, Nakamura H. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet. 1991;337:809-812. [Medline] [Order article via Infotrieve]
3.
Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo
M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of
coagulation mechanism in unstable angina and myocardial
infarction. Circulation. 1994;90:61-68.
4.
Fuster V, Frye RL, Connolly DC, Damelson MA, Eweback
LR, Kurland LT. Arteriographic patterns early in the onset of
coronary syndromes. Br Heart J. 1975;37:1250-1259.
5.
Braunwald E. Unstable angina: a
classification. Circulation. 1989;80:410-414.
6. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation. 1985;4:699-708.
7. Ardissino D, Gamba G, Merlini PA, Rolla A, Barberis P, Demicheli G, Testa S, Bruno N, Specchia G. Fibrinopeptide A excretion in urine: a marker of the cumulative thrombin activity in stable versus unstable angina patients. Am J Cardiol. 1991;68:58B-63B.[Medline] [Order article via Infotrieve]
8.
Theroux P, Latour JG, Leger-Gauthier C, De Lara
J. Fibrinopeptide A and platelet factor
levels in unstable angina pectoris.
Circulation. 1987;75:156-162.
9. Wilensky RL, Zeller JA, Wish M, Tulchinsky M. Urinary fibrinopeptide A levels in ischemic heart disease. J Am Coll Cardiol. 1989;14:597-603. [Abstract]
10.
Folts JD, Crowell EB, Rowe GG. Platelet
aggregation in partially obstructed vessels and its elimination with
aspirin. Circulation. 1976;54:365-370.
11.
Willerson JT, Yao SK, McNatt J, Cui K, Anderson HV,
Swensen MO, Buja LM. Liposome-bound
prostaglandin E1 often prevents cyclic flow
variations in stenosed and endothelium-injured
canine coronary arteries.
Circulation. 1994;89:1786-1791.
12.
Schmitz JM, Apprill PG, Buja M, Willerson JT, Campbell
WB. Vascular prostaglandin and
thromboxane production in a canine model of
myocardial ischemia. Circ Res. 1985;57:223-231.
13.
Golino P, Buja M, Ashton JH, Kulkarni P, Taylor A,
Willerson JT. Effect of thromboxane and
serotonin receptor antagonists of
intracoronary platelet deposition in dogs with
experimentally stenosed coronary arteries.
Circulation. 1988;78:701-711.
14. Fitzgerald DJ. Platelet activation in the pathogenesis of unstable angina: importance in determining the response to plasminogen activators. Am J Cardiol. 1991;68:51B-57B. [Medline] [Order article via Infotrieve]
15. Vejar M, Fragasso G, Hackett D, Lipkin DP, Maseri A, Born GVR, Ciabattoni G, Patrono C. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost. 1990;63:163-168.[Medline] [Order article via Infotrieve]
16. Pelzer H, Schwarz A, Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemost. 1988;59:101-106. [Medline] [Order article via Infotrieve]
17. Pelzer H, Schwarz A, Stuber W. Determination of human prothrombotic activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost. 1991;65:153-159. [Medline] [Order article via Infotrieve]
18. Biasucci LM, Liuzzo G, Caligiuri G, Monaco C, Quaranta G, Sperti G, van de Greef W, Maseri A. Frequent sampling by clear venipuncture in unstable angina is a reliable method to assess hemostatic system activity. Fibrinolysis. 1994;8:142-144.
19. Fuster V, Badimon L, Badimon J, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:310-318. [Medline] [Order article via Infotrieve]
20. Neri Serneri GG, Gensini GF, Carnovali M, Prisco D, Rogasi PG, Casolo GC, Fazi A, Abbate R. Association between time of increased fibrinopeptide A levels in plasma and episodes of spontaneous angina: a controlled prospective study. Am Heart J. 1987;113:672-678. [Medline] [Order article via Infotrieve]
21. Wilensky RL, Bourdillon PD, Vix VA, Zeller JA. Intracoronary artery thrombus formation in unstable angina: a clinical, biochemical and angiographic correlation. J Am Coll Cardiol. 1993;21:692-699. [Abstract]
22. Eisenberg PR, Kenzora JL, Sobel BE, Ludbrook PA, Jaffe AS. Relation between ST segment shift during ischemia and thrombin activity in patients with unstable angina. J Am Coll Cardiol. 1991;18:898-903. [Abstract]
23. Becker RC, Tracy RP, Bovill EG, Corrao JM, Baker S, Ball SP, Mann KG. Surface 12-lead electrocardiographic findings and plasma markers of thrombin activity and generation in patients with myocardial ischemia at rest. J Thromb Thrombol. 1994;1:101-107. [Medline] [Order article via Infotrieve]
24. Ashton JH, Golino P, McNatt JM, Buja LM, Willerson JT. Serotonin S2 and thromboxane A2-prostaglandin H2 receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries. J Am Coll Cardiol. 1989;13:755-763. [Abstract]
25.
Yao SK, Ober J, McNatt J, Benedict CR, Rosolowsky M,
Anderson HV, Cui K, Maffrand JP, Campbell WB, Buja LM, Willerson
JT. ADP plays an important role in mediating platelet
aggregation and cyclic flow variations in vivo in stenosed and
endothelium-injured canine coronary
arteries. Circ Res. 1992;70:39-48.
26. Bevilacqua MP, Gimbrone MA Jr. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost. 1987;13:425-433. [Medline] [Order article via Infotrieve]
27. Alexopoulos D, Ambrose JA, Stump D, Borrico S, Gorlin R, Deshmukh P, Fisher EA. Thrombosis related markers in unstable angina pectoris. J Am Coll Cardiol. 1991;17:866-871. [Abstract]
28. Irie T, Imaizumi T, Matuguchi T, Koyanagi S, Kanaide H, Takeshita A, Nakamura M. Increased fibrinopeptide A during anginal attacks in patients with variant angina. J Am Coll Cardiol. 1989;14:589-594. [Abstract]
29. Oshima S, Ogawa H, Yasue H, Okumura K, Matsuyama K, Miyagi H. Increased plasma fibrinopeptide A levels during attacks induced by hyperventilation in patients with coronary vasospastic angina. J Am Coll Cardiol. 1989;14:150-154. [Abstract]
30. Estivals M, Pelzer H, Sie P, Pichon J, Boccalon H, Boneau B. Prothrombin fragment 1+2, thrombin-antithrombin III complexes and D-dimers in acute vein thrombosis: effects of heparin treatment. Br J Haematol. 1991;78:421-424. [Medline] [Order article via Infotrieve]
31.
Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I,
Fossati G, Pasotti D, Bramucci E, Angoli L, Marsico F, Specchia G,
Notario A. Increased expression of neutrophil and monocyte
adhesion molecules in unstable coronary artery disease.
Circulation. 1993;88:358-363.
32. DiSciascio G, Cowley MJ, Goudreau E, Vetrovec GW, Johnson DE. Histopathologic correlates of unstable ischemic syndromes in patients undergoing directional coronary atherectomy: in vivo evidence of thrombosis, ulceration, and inflammation. Am Heart J. 1994;128:419-426. [Medline] [Order article via Infotrieve]
33.
Van der Wal AC, Becker AE, van der Loos CM, Das
PK. Site of intimal rupture or erosion of thrombosed
coronary atherosclerotic plaques is characterized by an
inflammatory process irrespective of the dominant plaque
morphology. Circulation. 1994;89:36-44.
34. Ciabattoni G, Ujang S, Sritar P, Andreotti F, Davies G, Simonetti BM, Patrono C, Maseri A. Aspirin, but not heparin, suppresses the transient increase in thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty. J Am Coll Cardiol. 1993;21:1377-1381. [Abstract]
35.
Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V,
Fallon JT. Macrophage infiltration in acute
coronary syndromes: implication for plaque rupture.
Circulation. 1994;90:775-778.
36.
Liuzzo G, Biasucci LM, Gallimore RJ, Grillo RL, Rebuzzi
AG, Pepys MB, Maseri A. Prognostic value of C-reactive protein
and serum amyloid a protein in severe unstable angina.
N Engl J Med. 1994;331:417-425.
37. Biasucci LM, D'Onofrio G, Liuzzo G, Zini G, Monaco C, Caligiuri G, Tommasi M, Rebuzzi AG, Maseri A. Intracellular neutrophil myeloperoxidase is reduced in unstable angina and myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol. 1996;27:611-616. [Abstract]
38.
Neri Serneri GG, Abbate R, Gori AM, Attanasio M,
Martini F, Giusti B, Dabizzi P, Poggesi L, Modesti PA, Trotta F,
Rostagno C, Boddi M, Gensini GF. Transient intermittent
lymphocyte activation is responsible for the instability of
angina. Circulation. 1992;86:790-797.
39.
Carry M, Korley V, Willerson JT, Weigelt L,
Ford-Hutchinson AW, Tagari F. Increased urinary
leukotriene excretion in patients with cardiac
ischemia: in vivo evidence for
5-lipoxygenase activation.
Circulation. 1992;85:230-236.
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