(Circulation. 1995;91:2520-2527.)
© 1995 American Heart Association, Inc.
Articles |
Alterations of Coagulation and Fibrinolytic and Kallikrein-Kinin Systems in the Acute and Postacute Phases in Patients With Unstable Angina Pectoris
Presented in part at the 1992 annual Scientific Sessions of the American Heart Association, New Orleans, La.
From the Medizinische Klinik (H.M.H., M.J., L.S.), Abt. III and Abt. für Thorax-, Herz- und Gefäßchirurgie (H.P.W., W.H.), Eberhard-Karls-Universität Tübingen, Germany.
Correspondence to Priv-Doz Dr Hans Martin Hoffmeister, Medizinische Universitätsklinik, Abt. III, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
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Abstract |
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Background Unstable angina pectoris is frequently associated with intracoronary thrombus formation. In a prospective study, we investigated in 35 patients with unstable angina pectoris markers of coagulation and the kallikrein-kinin and fibrinolytic systems in the acute and postacute phases.
Methods and Results We determined serially in the patients up to 10 days after admission factor XII and the ß–factor XIIa inhibition, kallikrein-like activity, prekallikrein, C1-esterase inhibitor, kallikrein inhibition, high molecular weight kininogen as indicators of the contact phase and bradykinin generation, thrombin–antithrombin III (TAT) complex as marker of the activated coagulation cascade, fibrinogen, plasminogen, plasminogen activator inhibitor–1 (PAI-1), tissue-type plasminogen activator (TPA), and D-dimers as indicators of the fibrinolytic system. Data were compared with those from control subjects (n=25) and from patients with stable angina pectoris (n=25). In patients with unstable angina pectoris, initially the contact phase and the kallikrein-kinin system were markedly elevated (factor XII, 96±5% versus 117±5%; kallikrein-like activity, 35.7±2.9 versus 27.4±1.3 U/L; high molecular weight kininogen, 52.7±5.2% versus 87.7±3.9%; P<.01 versus control subjects). Contact-phase activation persisted for the following 10 days, whereas the initially enhanced bradykinin generation normalized after 2 days. Furthermore, we had evidence of a hypercoagulative state (TAT, 10.9±3.1 versus 4.5±0.7 µg/L, P<.05; D-dimer, 474±81 versus 272±71 ng/mL) persisting longer than the clinically symptomatic period in association with disturbed fibrinolysis (TPA, 15.9±1.9 versus 5.1±0.4 ng/mL; P<.01; PAI-1, 9.9±2.6 versus 4.6±1.6 AU/mL; P=NS) in the presence of elevated fibrinogen levels.
Conclusions Our data indicate that in patients with unstable angina pectoris, intracoronary thrombus formation is associated with a hypercoagulative state, including activation of the contact phase and of the kallikrein system and increased bradykinin generation. The persistence of this hypercoagulative state, together with a disturbed fibrinolysis, might indicate an increased risk for further coronary events.
Key Words: angina pectoris • kallikrein-kinin system • fibrinolysis • coagulation
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Introduction |
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Recurrent periods of angina pectoris at rest without development of myocardial necrosis characterize unstable angina pectoris in patients with coronary artery disease. A clinically oriented classification for these patients was proposed by Braunwald.1 From angiographic studies, it is known that intracoronary thrombus formation is frequently present.2 3 4 The pathophysiology of this acute coronary syndrome is characterized by dynamic interaction at a coronary stenosis among the vessel wall, corpuscular elements of the blood, coagulation, fibrinolysis, and other related systems.5 6 The local thrombogenicity depends on the activation, adhesion, and aggregation of platelets due to plasmatic as well as cellular regulator and feedback mechanisms. Activation of the intrinsic pathway of the coagulation occurs via activation of factor XII by
–factor XIIa and subsequent
activation of factor XII, the production of thrombin, and, finally,
polymeric cross-linked fibrin, which, together with activated
platelets, lead to the formation of a thrombus. Regarding the
fibrinolytic system, reduced activity of the tissue-type plasminogen
activator (TPA) was described in patients with unstable angina pectoris
as well as an elevated level of the plasminogen activator inhibitor–1
(PAI-1), especially in patients at risk of developing myocardial
infarction.7 In contrast, other authors described a TPA
activity identical to that of patients with stable angina pectoris or
of control subjects but confirmed the elevation of PAI in patients with
unstable angina pectoris.3 Increased breakdown of fibrin
indicated by elevated D-dimer levels was described in those
patients,8 but contradictory data were also
reported.9 Regarding coagulation, Rennie and
Ogston10 found no significant alterations in the factor
XII system in a small number of patients with unstable angina pectoris
in contrast to those with myocardial infarction; similarly, Munkvad et
al11 observed no reduction in factor XII–dependent
fibrinolytic activity. In a study on a smaller number of patients with
unstable angina pectoris, including some with minor nontransmural
myocardial infarctions, a reduction in the kallikrein precursor
prekallikrein was observed, indicating activation of the
kallikrein-kinin system and probably of the related contact phase of
the coagulation,12 whereas Rennie and
Ogston10 did not observe activation of the contact phase
in patients with unstable angina pectoris. Some of the controversial
findings might result from the fact that unstable angina pectoris is a
condition with wide variability in severity, duration, and frequency of
ischemia in the patients included in the cited studies. Thus,
measurements only at one point or at a few points in time may lead to
different results, especially if there is a variant period of time to
the last ischemic episode. Furthermore, coagulation/thrombin
generation, factor XII–kallikrein-kinin system, and fibrinolysis are
interactively coupled by many autoregulative activators and inhibitors.
Determination of only one or a few markers might thus miss some of the
possible interrelated alterations. The aim of the present study was therefore to characterize comprehensively the changes and their time courses (1) of the thrombin generation and of the coagulation, including the related kallikrein-kinin system, and (2) of the fibrinolytic system in the acute and postacute phases in patients with unstable angina pectoris compared with those with stable exertional angina pectoris.
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Methods |
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Patients and Protocol
Thirty-five patients with unstable angina pectoris were included in the study. All patients were admitted to our institution because of repeated symptoms of angina pectoris at rest, and due to the severity of their symptoms all of them were treated initially in the intensive care unit. The mean age of the patients was 59±2 years (range, 31 to 78 years); 30 men and 5 women were included. All except 3 patients (who refused) had coronary angiography. Forty-six percent had one-vessel disease, 34% had two-vessel disease, and 11% had three-vessel disease. Eleven percent of the patients had diabetes mellitus. Also, 29% were smokers, 26% were ex-smokers, and 45% were nonsmokers. Twenty-four patients had a history of a prior myocardial infarction (including 2 patients who were not catheterized). Thirty of the patients were classified as IIIB and 5 patients were classified as IIIC according to Braunwald.1
All patients received treatment that included, if appropriate, intravenous therapy with nitrates, calcium antagonists, and ß-blockers. Twenty-one patients received aspirin (100 to 300 mg/d). All patients were treated with intravenous heparin (1000 IU/h) adjusted by repeated measurements of the activated partial thromboplastin time (aPTT) to have twice the normal aPTT. Intravenous heparin was administered for 24 to 48 hours and was stopped 24 hours after stabilization of the symptoms. The mean duration of intravenous heparinization was 32 hours. Mean aPTT of the patients in the follow-up study therefore was significantly prolonged until the second day. In a prestudy, we measured heparin plasma levels during this regimen in a subgroup of patients with a chromogenic substrate test (Chromogenix) and obtained levels of <0.5 U/mL. These low levels of heparin do not interfere with the analytical methods used in the study.13 The patients then received 7500 IU heparin BID SC.
In 14 of the 35 patients, unstable angina pectoris could not be controlled by intensive drug treatment; therefore, percutaneous transluminal coronary angioplasty (PTCA) was performed. These patients were included only in the first sampling time at admission but were excluded from the follow-up study despite the finding that we could not detect a difference in the parameters investigated between patients with and those without early PTCA. Patients who had early PTCA were excluded so we could cope with possible alterations in these patients due to the procedure and the additional heparin administration given routinely during this procedure. Blood samples thus could be obtained from 21 patients without PTCA for 10 days after admission. In all patients, serial creatine kinase (including CK-MB) and ECG (12-lead) monitoring were performed. Seventeen of the 35 patients had either transient ST-segment elevation or depression; 8 of them were in the group of patients who needed early revascularization and thus were not included in the follow-up study. The other 9 patients (6 with ST-segment depression and 3 with ST-segment elevation) did not show any significant difference in the parameters investigated compared with the other patients of the follow-up study. Patients with a significant increase in CK (>150% normal range) or persisting ECG alterations indicating development of myocardial infarction (new Q waves, R-wave reduction >30% in two or more chest leads) were excluded from the study. The highest mean CK value of the patients was 34±5 U/L. After verbal information, all patients gave their informed consent for additional blood sampling. The protocol of the study was approved by the ethical committee of the University of Tübingen.
For comparison, plasma levels were determined in a control group consisting of healthy volunteers, none of whom had a history or symptoms of cardiac diseases. None of them experienced cardiovascular disease during a 2-year follow-up. The age in the control group ranged from 21 to 83 years; the mean age was 38±4 years. There were 12 women and 13 men in this group, and all were nonsmokers.
For examination of plasma levels in the patients with stable exertional angina pectoris, a group of 25 patients with proven coronary heart disease was investigated. These patients were admitted for cardiac catheterization, and all had coronary angiography. Eight had one-vessel disease, 11 had two-vessel disease, and 6 had three-vessel disease. The distribution of smoking, diabetes mellitus, and prior myocardial infarction (56%) was not different from the incidence found in patients with unstable angina pectoris. The mean age of this group was 55±2 years, with a range of 34 to 72 years. There were 22 men and 3 women in this group. Nineteen of them had received treatment with aspirin (100 to 300 mg/d). These patients had treatment with nitrates, ß-blockers, or calcium antagonists in various combinations to control their stable exertional angina pectoris.
To investigate whether the setting of an intensive care unit, including intravenous lines, monitoring, and intravenous heparin, might influence the study, 10 patients without coronary heart disease who had received heparin for other reasons were examined for 24 hours on heparin. We found during this time no alterations in TPA (+3.0 ng/mL), PAI (+1.4 arbitrary units [AU]/mL), thrombin–antithrombin III (TAT) complex (+0.2 µg/L), kallikrein activity (+9.0 U/L), factor XII (+0%), high molecular weight kininogen (+4.1%), C1-esterase inhibitor (-2.5%), plasminogen (-1.8%), and D-dimers (+8.1 ng/mL), so significant activation of the contact phase, kallikrein system, and fibrinolysis was not observed under these circumstances.
Blood Sampling and Measurements
Blood sampling was done
initially; 3, 9, and 24 hours after
admission; and 2, 5, and 10 days after admission. During an interval of
at least 2 hours after cardiac catheterization with radiographic
contrast agents, no samples were taken since it is known that the
contrast media cause transient alterations in part of the parameters
measured.14 Apart from initial blood sampling on day 1,
our aim was to obtain the blood samples between 7:00 and 8:00
AM to minimize the effect of diurnal
variation.15 Blood was always taken by separate venous
puncture and was combined with the routine blood tests of the patients.
Venous blood was obtained in citrated 10-mL vials (10% citrate
solution, Sarstedt). The citrated blood was centrifuged for 20 minutes
at 2000g at 20°C, and the plasma was then shock-frozen in
200-µL aliquots in liquid nitrogen. The plasma was stored deep-frozen
until the measurements were performed. For the various determinations,
commercially available kits were used according to previously published
methods14 ; therefore, the tests are described only
briefly. All assays were performed in duplicate.
Plasma kallikrein-like activity was determined using a chromogenic substrate test according to the method described by Gallimore and Friberger16 with the chromogenic substrate S-2302 (Chromogenix). For the validation test, plasma (Chromogenix) was used.
Prekallikrein also was measured using a chromogenic substrate test according to the method of Gallimore and Friberger16 with a commercially available kit using the chromogenic substrate S-2302. Plasma was incubated with plasma prekallikrein activator in buffer, and the extinction was red against a standard curve established with normal plasma (Chromogenix).
For determination of the kallikrein inhibition capacity of the plasma, a chromogenic substrate test was used according to Gallimore and Friberger16 with a commercially available kit (Chromogenix). Plasma was incubated with a defined amount of plasma kallikrein. After incubation and supplement of the chromogenic substrate S-2302, the extinction was red at 405 nm and compared with the plasma of healthy volunteers.
High molecular weight kininogen was determined with a commercially available kit (Behring Werke). Diluted plasma was mixed with high molecular weight kininogen-deficient plasma (Behring Werke). After activation of the coagulation and the addition of calcium, the time for coagulation was measured biomatically and compared with a standard curve obtained from our internal standard plasma pool.
Measurement of factor XII was performed according to the method of Gallimore et al17 with a commercially available chromogenic substrate test kit (Unicorn Ltd) using the chromogenic substrate S-2222 (Unicorn Ltd). A standard curve obtained from our plasma pool was used as reference.
For measurement of the ß–factor XIIa inhibition, a commercially available chromogenic substrate test kit was used (Unicorn Ltd). Plasma was incubated with ß–factor XIIa and the chromogenic substrate, and the extinction was compared with a standard curve obtained with normal plasma (Unicorn Ltd).
C1-esterase inhibitor was determined according to the method of Wiman and Nilsson18 with a commercially available chromogenic substrate test kit (Immuno). Plasma was incubated with chromogenic substrate and C1-esterase. The extinction was compared with a standard curve established using reference standards (Immuno).
Fibrinogen was measured with a commercially available test kit according to the method of Clauss (Baxter).
Plasminogen was determined with a commercially available kit (Chromogenix). Plasma was incubated with streptokinase and the chromogenic substrate S-2251, and the extinction was compared with a standard curve obtained with normal plasma (Chromogenix).
The concentration of TPA was measured according to the method of Kluft19 with a commercially available kit (Coalize-t-PA; Chromogenix). This is an ELISA in sandwich technique; the sensitivity of this test, which is highly specific for single- or double-chain TPA, is 0.5 ng/mL TPA.
PAI-1 was determined with a commercially available chromogenic substrate test (Chromogenix). Plasma was incubated with a defined amount of TPA. Plasminogen was thereafter activated from the residual TPA to plasmin and incubated with the chromogenic substrate S-2403. The activity was given in arbitrary units (AU), which were defined as the amount required to inhibit 1 IU TPA/mL plasma.
Measurement of D-dimer was carried out according to Elms et al20 with a commercially available kit (Boehringer). This is a sandwich ELISA followed by a chromogenic substrate test (capture ELISA). All chemicals and standards were obtained from Boehringer.
Determination of TAT was performed according to the method of Pelzer et al21 using a commercially available ELISA (Enzygnost TAT-Micro; Behring Werke). All chemicals used and the control and standard plasma were obtained from Behring Werke.
All data are presented as mean±SEM. The statistical evaluation was performed with the SPSS software package (SPSS Inc). Data for the groups with stable angina or unstable angina and the control group were compared using ANOVA followed by Dunnett's test. The data from the patients with unstable angina pectoris were compared with the control group using the unpaired version of Student's t test (two-tailed) with a Bonferroni correction for multiple comparisons. To detect a possible change of a parameter during the time course of the sampling period, the mean value of the samples from the first 24 hours was compared with the mean of the samples after 2, 5, and 10 days using the paired version of the Student's t test. P<.05 was accepted as the level of significance.
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Results |
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Unstable Angina Pectoris
Coagulation and Kallikrein-Kinin System
Patients with unstable angina pectoris had a significantly (P<.05) increased plasma kallikrein activity up to 46.0±5.3 U/L. Plasma kallikrein-like activity was highest in the first 24 hours but remained slightly elevated until 10 days after admission (Fig 1
). The corresponding levels of the precursor
prekallikrein tended to be lower during this period; however, this
slight reduction was not significant compared with the control group
(Table 1). In patients with unstable angina pectoris,
the level of high molecular weight kininogen, which is the precursor of
bradykinin and consumed if the kinin generation is
increased,22 was reduced to 52% initially. It remained
decreased for the first 24 hours as an index of bradykinin generation.
Thereafter, its level normalized gradually (Fig 2). At
admission, the inhibition capacity of the plasma for kallikrein tended
to be increased compared with control subjects. Over time, it gradually
increased further to 145% on the 10th day after admission
(P<.05; Table 1). A comparable time course was
found for
one of the main inhibitors of kallikrein in the plasma, the
C1-esterase inhibitor. From 106%, it slowly increased to
113% during the observation time in the patients with unstable angina
pectoris (P<.05 tested intraindividually; Table 1).
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The contact phase of the coagulation was considerably activated in
patients with unstable angina pectoris, as indicated by the
significantly reduced factor XII level at admission. There was only
slight recovery to the levels of the control group in the postacute
phase. No significant difference between the initial values and the
values 10 days later was obtained when compared intraindividually
(Table 1
). The ß–factor XIIa inhibition of the plasma
was initially
reduced in patients with unstable angina pectoris; the most marked
reduction was to 114±10% (P<.05) 3 hours after admission
(versus 150±8% in control subjects). From the end of the first day,
the data were not reduced significantly compared with the control
subjects (Table 1).
The TAT levels, a measure of
thrombin generation, were initially nearly
doubled in patients with unstable angina pectoris (7.9±1.7 versus
4.5±0.7 µg/L) and reached a maximum at 2 to 5 days after patient
admission (Table 1).
Fibrinogen and
Fibrinolytic System
In patients with unstable angina pectoris, the
fibrinogen levels
were initially elevated and increased further until the maximum on the
fifth day (508±61 mg/dL; P<.01). The elevated levels
persisted for the entire postacute phase and were still higher compared
with the value for patients with stable angina pectoris at the end of
the observation period (473±46 versus 372±23 mg/dL). The
fibrinogen
levels were significantly correlated to the D-dimer level at admission
(r=.4; y=0.1x+321;
P<.05).
Taking into account data from all time points during the observation
period, the levels of fibrinogen and plasminogen also were
significantly correlated (r=.4;
y=0.1x+87; P<.01).
Initially,
the plasminogen levels of patients with unstable angina
pectoris were not different from those of the control group (120±4%
versus 115±8%), but during the postacute phase a tendency for higher
values to occur was obvious (135±11%; P=NS). An
increase
in the plasminogen was found in 71% of the patients
(P<.01, tested intraindividually; Table 1).
Concentration of TPA antigen was higher (P<.05) in the
patients with stable angina pectoris (10.4±1.0 ng/mL) than in the
control subjects (5.1±0.4 ng/mL). In patients with unstable angina
pectoris, the even higher levels of TPA antigen (15.9±1.9 ng/mL) were
significantly (P<.01) different from those of the control
subjects at admission and increased slightly further during the 10-day
follow-up (Table 1).
PAI-1 showed a strong trend toward
higher levels (P=.12,
two-tailed) in patients with unstable angina pectoris compared with the
control subjects (9.9±2.6 versus 4.6±1.6 AU/mL). Even higher
PAI-1
levels were measured during the following 10 days (13.3±6.1 AU/mL on
the 10th day; Fig 3). An increase during follow-up was
observed in 51% of the patients.
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In the group with unstable angina
pectoris, there was a strong trend
toward elevated levels of D-dimer, indicating increased fibrinolysis
(474±81 versus 272±71 ng/mL; P=.08, two-tailed).
This
difference, which did not reach statistical significance at the single
time points, was found persistently during the entire first 10 days
after admission (Fig 4).
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Stable Angina Pectoris
There were no significant measurable
differences between patients
with stable angina pectoris and the control subjects in the
kallikrein-kinin system, with the exception of the slightly higher
kallikrein inhibition (Table 2). The level of the plasma
kallikrein activity was comparable; there also was no difference in the
high molecular weight kininogen levels (Table 2). Prekallikrein
was
slightly lower in the patients with stable angina pectoris. Factor XII
was not significantly lower in the patients with stable angina
pectoris; the ß–factor XIIa inhibition was 22% lower than the
inhibition capacity of the control group (Table 2).
C1-esterase inhibitor and TAT were not different from
control values. Patients with coronary heart disease and stable
exertional angina pectoris had higher fibrinogen levels (372±23 versus
300±12 mg/dL) compared with the control subjects, whereas for
plasminogen only a trend but no significant difference—with higher
values in the group with stable angina pectoris—was found (Table
2).
The mean PAI in the patients with stable angina pectoris was 141% of
the level of the control subjects (P=NS). The TPA antigen
was significantly higher (10.4±1.0 versus 5.1±0.4 ng/mL) in
patients with exertional angina pectoris. D-dimer levels in patients
with coronary heart disease and stable symptoms were 31% higher, but
this difference from that of the control subjects was not significant.
The data for these groups are listed in Table 2.
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Discussion |
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The results of the present study provide evidence that in patients with unstable angina pectoris, the contact phase of the coagulation is activated with stimulation of the plasma kallikrein system and an enhanced bradykinin generation. Furthermore, disturbances of the fibrinolytic system and a hypercoagulative state also persist in the postacute phase after successful clinical stabilization of the patients.
Contact Phase of the Coagulation and Kallikrein-Kinin Systems
In contrast to the results in patients with stable angina
pectoris, who had a normal kallikrein activity and normal factor XII
levels, a significant activation of the contact phase indicated by
decreased factor XII and increased plasma kallikrein activity was
observed in the acute phase in patients with unstable angina pectoris.
Factor XII and kallikrein activity are connected via a positive
feedback loop.23 There is very little information on these
compounds in acute coronary syndromes; all prior studies were done in
acute myocardial infarction and used unspecific global tests to assess
kallikrein activity.24 25 Both studies observed an
elevated activity in the kallikrein system. Torstila25
described a consumption of the precursor prekallikrein in correlation
to the infarct size. This is in accordance with findings in a smaller
number of patients, with non–Q-wave infarction or unstable angina
pectoris, in which a moderate reduction in prekallikrein was
observed.12 The slight initial reduction in the
prekallikrein level in the present study, which did not reach
statistical significance, indicates that in the absence of myocardial
necrosis, the kallikrein activation is not so marked and sustained to
reduce the precursor level. Also in accordance, the inhibitor levels
were not significantly decreased. The C1-esterase
inhibitor, which is the main inhibitor of both factor XII and plasma
kallikrein26 and the main plasma inhibitor of the
plasminogen activator,27 was not reduced initially but
increased slightly after normalization of the kallikrein activity. A
consumption of the C1-esterase inhibitor might be due to an
increased release of plasminogen activator. The measurement of TPA
antigen as used in the present study included plasminogen activator
bound to its inhibitors as C1-esterase but could not
quantify its relative amount.
Although the elevated kallikrein activity was mainly present in the acute phase, the activation of the factor XII system persisted in many patients during the postacute phase. This prolonged activation, which was not reported until now, was not due to consumption of inhibitors or to a lack of inhibition capacity as described during thrombolytic therapy28 and was not so marked as to reduce the level of C1-esterase inhibitor with possible effects on the TPA. The activation of the plasma kallikrein was associated with markedly increased bradykinin generation, as indicated by the highly significant consumption of its precursor, high molecular weight kininogen, in the acute phase of unstable angina pectoris. An increased kinin generation was reported for acute myocardial infarction22 24 29 30 or experimental ischemia,31 but comprehensive data on the kallikrein-kinin system for a larger number of patients with unstable angina pectoris have not been available until now. The time course of the enhanced bradykinin generation is similar to the peak of the plasma kallikrein activation, and it is known that the bradykinin generation is stimulated by kallikrein.23 The elevated kinin generation appears to be of special importance, as an increasing number of patients after a prior myocardial infarction will undergo treatment with angiotensin-converting enzyme inhibitors, which also enhance the bradykinin levels by inhibiting its degradation via the kininase II.32 Thus, bradykinin effects, such as hypotensive reactions and edema formation, a stimulation of thrombolysis,23 33 34 or a potentially beneficial effect on myocardial ischemia,35 might be amplified.
Thrombin Generation
To assess the coagulant activity,
thrombin generation, measured as
TAT complexes, was determined. In prior studies, an elevation of the
thrombin generation was described in the acute phase in patients with
unstable angina pectoris.36 37 Our data indicate that
this
known elevation of the thrombin generation persists for a prolonged
period (several days) after clinical stabilization. A comparable
finding was reported by Szczeklik et al38 for patients
with acute myocardial infarction. Because heparin therapy influences
the thrombin generation,38 it can be assumed that during
the first 2 days during intravenous heparinization, the thrombin
generation without this therapy would have been even higher in our
patients. The increased procoagulant activity documented by the
elevated levels of TAT was also detectable during the postacute phase,
indicating that the activation via the kallikrein is not the sole
underlying mechanism; however, the contact phase (factor XII) also was
activated for a prolonged period.
Fibrinogen and Fibrinolysis
Elevated levels of fibrinogen and
of plasminogen, as observed in
the patients with unstable angina pectoris, have been reported to a
lesser extent, even in patients with stable angina
pectoris.39 Marked elevation in fibrinogen was found in
patients with acute myocardial
infarction.10 40 41 Its
elevation was attributed to both increased levels in patients with
stable angina pectoris and coronary heart disease and the "acute
phase" reaction. In patients with unstable angina pectoris, the
latter was also evident in the increase of the C-reactive
protein,42 which was described as increasing similar to
fibrinogen in patients with acute coronary syndromes.43
Other groups did not observe a significant increase in fibrinogen or a
decrease of the factor XII levels in patients with unstable angina
pectoris compared with the significant changes found in patients with
acute myocardial infarction.10 Differing findings in the
behavior of fibrinogen in several studies might result from the use of
different populations, varying severity of the ischemic burden, and
variations in the time of blood sampling.
We found a strong trend for elevated D-dimers in patients with unstable angina pectoris compared with a control group and compared with patients with stable angina pectoris. An elevated D-dimer level is not specific for coronary thrombosis or thrombolysis, especially in the coronary system,44 but it indicates an enhanced level of fibrin degradation. Increased fibrinopeptide A levels45 46 and elevated D-dimer levels were also reported for patients with unstable angina pectoris by Kruskal et al8 and demonstrate an increased level of fibrinogen degradation due to thrombus formation or a hypercoagulative state.44 In contrast, other investigators9 47 observed no elevation in D-dimer levels in peripheral blood or in coronary sinus blood samples in such patients. These differences among the studies might be due to technical differences in the test systems used (radioimmunoassays, ELISAs), specificity of the antibodies used, or, in part, the small numbers of patients or the inclusion of patients with different degrees of unstable angina pectoris. This could also explain the statistically nonsignificant strong trend of an elevation in our study group, in which we observed persistently higher D-dimer levels for several days even after cessation of the episodes of angina pectoris. It cannot be excluded that D-dimers detected by the test used in the present study stem in part from soluble fibrin.44 However, this is no argument against a hypercoagulative state in our patients. In support of our findings, fibrinopeptide A was found to be elevated in patients with unstable angina pectoris, whereas platelet factor levels were normal.46
In patients with unstable angina pectoris, a disturbance of the fibrinolytic system is present, as indicated by the elevated levels of TPA antigen and PAI-1. This constellation, which is similar to the findings of Munkvad et al7 in patients at risk of developing a myocardial infarction and associated, according to these authors, with a decreased TPA activity, is found not only in the beginning but also for a prolonged period in patients with unstable angina pectoris. Zalewski and coworkers3 also found elevated PAI-1 levels in patients with unstable angina pectoris, but they reported normal TPA activity. The endothelial release capacity of TPA was also found to be reduced in patients with coronary artery disease.48 The elevation of PAI-1, which has a considerable diurnal variation, was shown to be related to recurrent coronary events7 49 50 and was still observed months and years after myocardial infarction.50 51 In the present study, the elevation in the PAI-1 level persisted during the first days and was not normalized by 10 days after admission to the hospital. Also, patients with stable angina pectoris had higher PAI-1 levels compared with the control group. Similar results were obtained for the TPA antigen, which includes TPA combined with PAI or C1-esterase inhibitor. The levels were approximately threefold higher than normal at admission and persisted at this level. The patients with stable angina pectoris had approximately twofold the level of those of the control groups. These results are in accordance with the data from patients with stable angina pectoris in the ECAT study39 indicating a persistent disturbance of fibrinolysis in coronary heart disease with special aggravation in patients with acute coronary syndromes.
Study Limitations
The definition of unstable angina pectoris,
even if made according
to the criteria of Braunwald,1 includes patients with
varying degrees of duration and frequency of ischemia, of varying
amounts of myocardial mass undergoing ischemia, and of differing
extents of coronary heart disease. Microinfarctions, which do not
significantly increase CK levels or cause persistent ECG changes,
cannot be excluded in these patients. Furthermore, the beginning of the
"instability" often cannot be exactly defined. Thus, the
admission to the hospital as the first time point is somewhat
arbitrary. Furthermore, the dynamics of the disease and the duration of
the period of unstability vary in the patients. We tried to minimize
these effects by investigating for a time period of 10 days only those
patients who responded to drug treatment and needed no interventional
procedure. Nevertheless, the clinical variability in this disease
causes some data scatter.
Due to the severity of their symptoms, all patients were treated in the intensive care unit with several regimens including intravenous heparinization as a standard therapy. Eighty-nine percent of the patients had heparin when they entered the study because many of them were referred from smaller hospitals. Therefore, we cannot report on the alterations of the investigated systems during the natural history of the disease. To cope with possible artifacts caused by the heparinization,52 we measured the heparin levels. With the heparin regimen used in the present study, no significant changes (as test artifacts, for example) in chromogenic substrate measurements are to be expected and an influence of the heparinization on other investigated systems, like the contact phase, appears to be very unlikely.13 53 Coagulometric tests like the high molecular weight kininogen measurement might be influenced by high heparin levels. Even if the low heparin levels in our study cause a 10% to 20% reduction in the measured high molecular weight kininogen levels, this would not alter the parallelism to the activation of the closely linked plasma-kallikrein system. Also, the possible in vivo effect of heparin on the thrombin levels38 appears to be limited in the present study because no increase occurred after cessation of heparin. Nevertheless, thrombin generation during the first day might be even higher in patients without heparin.
Contrast agents also might have an effect on the coagulation. Therefore, we always waited 2 hours after a coronary angiography to avoid any artifactual alteration (which is very unlikely to persist after this time period).14 54 In addition, we investigated a group of control subjects in the intensive care unit but found no activation of the kallikrein system.
Furthermore, a diurnal variation of PAI-1 activity is known,15 and therefore the blood sampling time was standardized. However, the first measurements were timed in relation to the admission of the patients and thus may include a larger data scatter.
Conclusions
The results of the present study demonstrate a
prolonged
activation of coagulation not only during the acute but also during the
postacute phase in patients with unstable angina pectoris. Molecular
markers of thrombin generation such as TAT and of fibrin degradation
were elevated for a prolonged time after clinical stabilization of the
patients, indicating a persistent hypercoagulative state with a
possible risk for recurrent coronary events. This alteration is
associated with a prolonged activation of the contact phase of the
coagulation, whereas the marked activation of the kallikrein-kinin
system is mainly present during the acute phase. Along with these
changes, disturbances of the fibrinolytic system with even higher PAI-1
levels than in patients with stable angina pectoris are detectable.
Prospective studies must clarify whether determination of these
alterations is of prognostic value for recurrent coronary events and
whether these measures can be used for therapeutic stratification.
Received October 31, 1994; accepted December 13, 1994.
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