(Circulation. 1998;98:2527-2533.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Thrombolytic Therapy in Acute Myocardial Infarction
Comparison of Procoagulant Effects of Streptokinase and Alteplase Regimens With Focus on the Kallikrein System and Plasmin
From Medizinische Universitätsklinik, Abt Innere Medizin III, Tübingen, Germany.
Correspondence to Prof Dr Hans Martin Hoffmeister, FACC, FESC, Medizinische Universitätsklinik, Abt Innere Medizin III, Otfried-Müller-Straße 10, 72076 Tübingen, Germany.
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Abstract |
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Background—Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein–contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI.
Methods and Results—Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Moderate thrombin (initial thrombin-antithrombin [TAT] complex 18±5 versus 4±0.3 µg/L, P<0.05) and kallikrein (up to 45±4 versus 30±1 U/L at 3 hours, P<0.01) activation occurs in patients with AMI. D-Dimers are increased (P<0.01), and plasmin is stimulated (P<0.01). Streptokinase and alteplase increase TAT to 50±17 and 51±18 µg/L at 3 hours and to 50±17 and 33±14 µg/L at 6 hours, respectively (P<0.01). Kallikrein activity is elevated (P<0.01) to 76±5 and 71±7 U/L at 3 hours and 64±6 and 47±5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in D-dimers and plasmin-antiplasmin complexes are more marked (P<0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (P<0.01).
Conclusions—The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.
Key Words: streptokinase • alteplase • infarction • thrombolysis • coagulation
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Introduction |
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In acute myocardial infarction (AMI), streptokinase and front-loaded alteplase regimens are commonly used for thrombolysis.1 Unfortunately, reperfusion is not always achieved, and the success of the therapy is limited by reocclusion.2 3 The balance between prothrombotic and thrombolytic processes can be shifted toward thrombolysis by administration of plasminogen activators; however, procoagulant effects of such drugs have been reported.4 5 6 7 8 9 10 11 These side effects are important because of a procoagulant state in acute coronary syndromes.12 13 14 15 16 17 In patients with AMI and thrombolytic therapy, markedly increased thrombin activation was associated with failure to open the occluded coronary artery and with a high reocclusion rate.18
As one pathway of thrombin stimulation of thrombolytics, activation of the contact phase of the coagulation by plasmin has been found in vitro.19 A recent clinical study measuring indirect plasmin markers proved the activation of the kallikrein–contact-phase system after streptokinase in patients with AMI,13 but no direct data on plasmin activation are available. Another pathway of activation of the kallikrein system may be the complement cascade.20 For the more "clot-specific" thrombolytic alteplase, no comparable data on the contact phase are available.
In a prospective, randomized clinical study, we compared the usual regimen with streptokinase and front-loaded alteplase on the kallikrein–contact-phase system and on molecular plasma markers of coagulation and fibrinolysis to examine (1) whether plasmin-mediated activation of the contact phase is related to thrombin generation and (2) whether differences in extent or duration of thrombin and plasmin stimulation exist after administration of these thrombolytic regimens in AMI.
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Methods |
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Patients and Protocol
Sixty-one patients with AMI who were eligible for thrombolytic therapy were included. All patients were referred to the intensive care unit for treatment of AMI. The patients fulfilled standard criteria of diagnosis of AMI: ST-segment elevation >0.1 mV in 2 limb leads or >0.2 mV in 2 chest leads, chest pain for
30 minutes, and start of symptoms within 8 hours before admission.
Diagnosis was confirmed by serial documentation of 12-lead ECG and by
serial creatine kinase level determination.
Thirty percent of the patients were on aspirin, and 3% were on ACE
inhibitors. All patients received aspirin (300 mg) and
systemic heparin to prolong the activated partial
thromboplastin time (aPTT) to double the upper normal value (bolus of
5000 IU followed by 1000 heparin IU/h adjusted according to repeated
aPTT determinations). Patients were randomized for
thrombolytic therapy with streptokinase (Behring; 1.5
million U IV within 1 hour) or with recombinant tissue
plasminogen activator (rtPA; Thomae) with a
front-loaded and weight-adjusted regimen (up to 100 mg over 90
minutes).1 Randomization was done monthly for all
patients admitted to the intensive care unit. Data are listed in Table 1
and indicate the absence of any
significant difference between the 2 groups after randomization.
Intravenous heparin was continued for 48 hours. With this
protocol, plasma heparin levels were <0.5
U/mL.12 Antianginal drugs were administered on an
individual basis and included nitrates and ß-blockers. ACE
inhibitor therapy was not initiated within the first 24
hours. After systemic heparinization, patients were switched to 7500 IU
heparin SC BID until complete mobilization. In 41% of patients,
coronary angiography was performed during the hospital stay,
and coronary artery disease was proved.
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All patients gave informed consent to the protocol after verbal information. The protocol for the study was approved by the Ethics Committee of the University of Tübingen.
An additional group of 24 consecutive patients with AMI but without
thrombolytic therapy was investigated for comparison.
These patients fulfilled the same diagnostic criteria as
the patients receiving thrombolytic therapy, except the
time from the start of symptoms until admission of some patients was
>8 hours (<24 hours). This group included patients with an
unfavorable benefit/risk assessment for bleeding, delayed-admittance
patients, and patients with direct coronary angioplasty.
Therefore, this group was more inhomogeneous. Demographic
and other data are also listed in Table 1
, proving that this group did
not differ (except the prolonged interval until admission) from the
groups receiving thrombolytic therapy.
As control, 30 volunteers of comparable age (32 to 84 years) without any clinical signs of coronary heart disease were examined. Persons with a history of smoking, diabetes, or arterial hypertension were not included. During a 2-year follow-up of this group, there was no evidence of cardiovascular disease in any of the volunteers.
Blood Sampling and Measurements
Blood sampling was performed at admission and 3 hours, 6 hours,
24 hours, 2 days, 5 days, and 10 days later. The measurements were
performed at all sampling time points if not otherwise indicated. The
initial sampling was performed before administration of the
thrombolytic drug and heparin. Except for initial
samplings, the follow-up samplings were done between 7 and 8
AM to minimize diurnal variation. Details of the processing
are published elsewhere.12
Determination of the thrombin-antithrombin (TAT) complex was done with
a commercially available ELISA (Behring Werke).
Plasmin/
2-antiplasmin (PAP) complex was
measured with a sandwich immunoassay (Behring Werke).
tPA was measured with an ELISA (Chromogenix). For determination of plasminogen activator inhibitor (PAI) activity, a chromogenic substrate test (S-2403) was used (Chromogenix). To avoid interference with residual thrombolytics, PAI was not measured 3 hours after the start of drug infusion. It was also not measured at 24 hours and 10 days. D-Dimers were determined by use of a capture ELISA technique (Boehringer). Plasma kallikreinlike activity and factor XII were determined by use of the chromogenic substrate S-2302 or S-2222 (Chromogenix/Unicorn Ltd). Both tests were performed initially, at 3 and 6 hours, and at 2 and 5 days. Fibrinogen (with the method of Clauss), antithrombin III (ATIII), and aPTT were determined in the routine laboratory for clinical chemistry of our institution.
Statistical Analysis
Data are presented as mean±SE. Data were
analyzed with the statistical software package JMP (SAS
Institute Inc). Data that were not normally distributed were converted
to a logarithmic scale before analysis. Data of patients with
AMI were compared (during the first 2 days) with the control subjects
and among the groups of patients with an ANOVA and Tuckey-Kramer
highest-significant-difference test with additional Bonferroni-Holmes
adjustment for multiple comparisons. For comparison of follow-up data,
a repetitive ANOVA was performed. We regarded P<0.05 as
significant.
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Results |
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Coagulation
Initially, a slight activation of thrombin was observed in patients with AMI compared with control subjects (Figure 1
and Tables 2 and 3).
In most of these patients, this activation soon reached normal levels
and within 2 days showed no more significance (Table 2). A similar time
course of activation was found for kallikrein activity (Figure 2). During the first day, activity rose
to 45.2±3.8 U/L in AMI patients (P<0.01) and returned to
normal during follow-up (Figure 2 and Table 2). Factor XII was already
activated at admission and remained activated during
follow-up (P<0.01; Table 2). D-Dimers were
elevated in patients with AMI at admission (P<0.01; Figure 3) and stayed increased (Table 2).
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P<0.01 vs AMI patients without
thrombolysis (mean±SEM).
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After streptokinase application, a marked and prolonged elevation of
the TAT complexes was found (P<0.01). Thrombin activation 2
days after streptokinase did not differ from that of patients without
thrombolysis (Figure 1). The TAT increase after
alteplase was similar to that after streptokinase, but levels 6 hours
after admission were already lower after alteplase compared with
streptokinase (Figure 1). TAT levels within the initial phase were
correlated with PAP complexes in patients who received
thrombolytic therapy (r=0.41;
P<0.01; y=0.61x+2.84). During
follow-up, TAT levels were moderately elevated (P<0.05 by
repetitive ANOVA) in patients with thrombolysis (Table 2).
ATIII tended to be reduced initially in all groups of patients with AMI
(P=NS) and became further reduced in all groups during
follow-up without any significant difference among the patient groups
(P<0.01; Table 2).
Streptokinase increased kallikrein activity to 76.1±4.8 U/L. The
elevated activity persisted for 1 day (P<0.01 versus
control subjects; Figure 2). Activity was also higher as in AMI
patients without thrombolytic therapy
(P<0.01; Figure 2). After alteplase, kallikrein activity
rose to 71.1±7.0 U/L (P<0.01), but the increase in
activity was not as prolonged as after streptokinase
(P<0.05 by repetitive ANOVA between time courses of both
groups; Figure 2 and Table 2). Six hours after alteplase, the
kallikrein activity was no higher than that of patients without
thrombolysis (47.3±4.9 versus 35.9±2.7 U/L;
P=NS) but was still different from that of control subjects
(29.6±1.3 U/L; P<0.05; Figure 2). After 2 days, no
difference in kallikrein activity between the 3 groups could be found
(Figure 2). Kallikrein activity in patients who received
thrombolysis was correlated to PAP levels (admission
until 3 hours after thrombolysis: r=0.60;
P<0.01; y=2.32x-0.45) and to TAT
levels (r=0.42; P<0.01;
y=0.86x-17.47). These correlations
(r=0.3 to 0.45) were also significant (as well as the
correlation of TAT and PAP) if later time points and patients without
thrombolysis were included.
Factor XII consumption was present during AMI (Table 2); the
reductions after streptokinase (63.3±8.9%) and after alteplase
(68.8±6.7%) were not different (P=NS for differences
between groups by repetitive ANOVA).
After thrombolysis, a significant increase in
D-dimer levels occurred for 2 days with streptokinase
versus control subjects and patients without
thrombolytic therapy (P<0.01; Figure 3 and
Table 2). D-Dimers were markedly higher after alteplase
versus streptokinase after the initial 6 hours (P<0.01).
Alteplase caused a significant increase in D-dimer levels
for 48 hours (Table 2), with peak values below those of the
streptokinase group (P<0.05 by repetitive ANOVA; Figure 3
and Table 2). After 6 hours, the levels did not differ from the
slightly elevated levels observed in patients with AMI without
thrombolytic therapy (Table 2).
Fibrinogen and Fibrinolytic System
In patients with AMI, initial fibrinogen levels were elevated
compared with those of control subjects (P<0.01; Table 2).
After streptokinase application, fibrinogen decreased to 59±9 mg/dL
(P<0.01). Fibrinogen, which recovered after 48 hours, rose
further and was markedly elevated until the 10th
day (Table 2). In patients with AMI and no thrombolytic
therapy, fibrinogen similarly increased to values >600 mg/dL beginning
on the second day (Table 2). After alteplase, fibrinogen decreased to
208±23 mg/dL (P<0.01) at 6 hours after the start of
thrombolysis and thus was not as markedly reduced as
after streptokinase (P<0.05 by repetitive ANOVA).
Fibrinogen recovered after 1 day and increased further (Table 2).
PAI levels at admission did not differ significantly in patients with
AMI and no thrombolytic therapy and in control
subjects. At 6 and 24 hours after admission, an upward trend was
observed (P<0.05 for the whole follow-up by repetitive
ANOVA). After streptokinase therapy, no significant difference from
patients without thrombolytic therapy was detectable.
Slightly higher PAI activity, which was statistically not different
from data of other patients with AMI (Table 2), was already observed at
admission in patients who received alteplase (P<0.01 versus
control subjects).
tPA mass concentration was persistently increased in AMI patients; it
was twice as high as in control subjects (P<0.01; Table 2).
Streptokinase therapy did not alter these levels; 127.7±32.0 ng/mL was
measured after alteplase infusion (P<0.01 versus all other
groups), and the levels were equal to those of the other patients 3
hours later (Table 2).
In patients with AMI who did not receive thrombolysis
(and who entered the intensive care unit later), a stimulated
fibrinolysis was already present and persisted for
the whole observation period (P<0.01; Table 2).
Streptokinase caused a significant increase in PAP complexes
(P<0.01; Figure 4). PAP
levels remained elevated for the first 24 hours compared with those of
patients without thrombolytic therapy
(P<0.01; Figure 4 and Table 2). After alteplase, PAP
complexes also increased markedly during the first day (Figure 4;
P<0.01 versus patients without thrombolytic
therapy) without statistical difference from the patients with
streptokinase treatment (P=NS by repetitive ANOVA).
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Discussion |
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The present prospective study compared the changes in coagulation and fibrinolysis caused by the currently used regimen with streptokinase or front-loaded alteplase.1 Both drugs have a procoagulant action, which was more pronounced (and longer lasting) with streptokinase. The latter regimen also tended to activate the systemic fibrinolysis more markedly compared with the more clot-specific alteplase.
Comparison of Data on Coagulation and Fibrinolysis
With the Literature
In patients with AMI, a moderate hypercoagulative state is
observed similar to that in unstable angina
pectoris.12 13 15 Levels of PAI, tPA mass
concentration, thrombin activation markers, fibrinogen, and other
markers are changed, indicating
activation14 16 17 because it was also found in
patients without thrombolytic therapy in the
present study. Application of thrombolytics causes
marked effects in addition to the preexisting changes.
Streptokinase infusion increases thrombin activation more than 3-fold. This increase is still detectable 6 hours after the beginning of therapy, as reported by others,10 whereas the later measurements of TAT complexes are at the level of those in patients with AMI but without thrombolytic therapy.13 21 The effect of streptokinase is confirmed by measuring fibrinopeptide A as a marker of thrombin action.11 22 23 Detection of marked activation of thrombin after streptokinase was reported to be associated with failure of thrombolysis or early reocclusion.3 23 Thrombin activation is followed by a slight reduction in ATIII corresponding to that in patients without thrombolysis. A reduction in fibrinogen and increases in the fibrin split product D-dimer are detectable for 2 days. Activation of plasmin judged as PAP complexes was about 20-fold compared with that in patients without thrombolytic therapy.
The use of alteplase reveals similar findings: Levels of TAT complexes, prothrombin fragment 1+2, and fibrinopeptide A3 6 8 10 11 18 are higher, along with a reduction in fibrinogen and an increase in D-dimers. High thrombin activation markers are reported to be associated with failure of lysis18 but not with worse clinical outcome.8 Elevated PAI activity after alteplase was also observed by others.24 Thus, PAI does not seem to be related to thrombin or to platelet activity (ß-thromboglobulin was decreased24 ). In contrast, other authors observed prolonged platelet activation after alteplase.25 Prolonged stimulated fibrinolysis compared with the duration of elevated tPA mass concentration was found for alteplase, which could be explained by enhanced binding of alteplase to fibrin.26 27
Comparison of Both Drugs
Comparison of thrombolytic drugs in vivo may
result in very different findings compared with investigations in vitro
because of dynamic changes in various activators and
inhibitors. Differences in dose and mode of administration
limit direct drug comparison. Only the whole
thrombolytic regimen, including heparinization, can be
compared. No data on the kallikrein system in relation to plasmin and
thrombin activation are available for comparison of the currently used
streptokinase and front-loaded alteplase regimens with identical
intravenous heparin. Prior
studies10 11 do not provide data on the
present front-loaded rtPA regimen, which is regarded as the
reference in many studies.28 29
The extent of activation of coagulation is not significantly different between both regimens, but after streptokinase, the procoagulant effect measured as thrombin activation lasts longer. Similarly, the levels of D-dimers and PAP complexes are elevated for a longer time after streptokinase. Cleavage products of kininogen were detected at higher levels after streptokinase versus alteplase up to 24 hours after thrombolysis.20 Enhanced levels after 24 hours are probably not due to the differences in the plasma half-life of the drugs but rather to paradox activation by split products and to action in bound states.27 The local thrombolytic efficacy cannot be directly derived from systemic data, as, for example, the GUSTO I data1 imply a greater beneficial net effect of the alteplase regimen despite less systemically measurable plasmin activation. It may be speculated that the longer procoagulant action of the streptokinase regimen is of greater importance for coronary reocclusion or failure of reperfusion therapy compared with the less marked systemic activation of the fibrinolysis by the more clot-specific alteplase.
Mechanisms of the Procoagulant Action
Exposure of thrombin during thrombin dissolution was discussed as
the source of the procoagulant activity,11 but
quantitatively this hypothesis seems to be very unlikely as derived
from clinical data.26 Recently, an in vitro
investigation by Ewald and Eisenberg19 reported
evidence of plasmin-induced thrombin activation via positive feedback
on the kallikrein–factor XII system. They demonstrated the key role of
plasmin in activation of the kallikrein–factor XII pathway in response
to pharmacological thrombolysis using an in vitro test
with or without a plasmin inhibitor. Their experimental
findings support the present study. Plasmin-mediated bradykinin
release from high-molecular-weight kininogen caused by increased
kallikrein activity was also observed in
vitro.20 30 Increased kallikrein activity,
activated factor XII, consumption of inhibitors
(including the C1-esterase
inhibitor), and generation of bradykinin after
streptokinase were proved in a recent study in
vivo.13 Similarly, cleavage of kininogen and
complement was found to be more marked after
streptokinase.20 The correlations among PAP,
kallikrein activity, and TAT support the meaning of this activation
pathway. However, correlations are not proof of only one causal
relationship, as an in vitro study described a plasmin-independent
activation of thrombin by thrombolytic
agents.31 In a limited number of patients with
AMI, an association between TAT and markers of fibrinolytic activity
independent of the thrombolytic regimen was
described.6 Our data indicate that both
streptokinase and alteplase activate the kallikrein-kinin
system in accordance with the difference in procoagulant action
(thrombin activation) of both regimens. It supports the in vitro
findings with respect to kallikrein stimulation with
plasmin.19 Alteplase may also activate
thrombin mainly by a plasmin-associated
pathway.32 It can be supposed that the
plasmin-mediated activation of the kallikrein-kinin system with
consecutive thrombin activation also occurs after alteplase application
in vivo, as a systemic stimulation of the fibrinolysis
is seen. This pathway, which is activated despite
intravenous heparin therapy, does not seem to be specific
for streptokinase but also is important for other
thrombolytics. Interestingly, a recent
investigation33 reported that staphylokinase,
which does not significantly activate the systemic plasmin, has
no procoagulant effect. This finding supports the present results
and the role of plasmin activation for the paradoxical
procoagulation.
Study Strengths and Limitations
The present study was prospective and randomized but not
double-blinded. Measurements were done by technicians who were not
aware of the clinical data. Both intervention groups agreed very well
in demographic and initial blood test data. Because a control group
with AMI without specific therapy cannot be obtained for ethical
reasons, we included consecutive patients with AMI who did not qualify
for thrombolytic therapy. Most of the changes in
coagulation and fibrinolysis13
are known to persist for a prolonged time12 34
with few exceptions. Therefore, the delayed admission of this kind of
patients may affect only the initial blood test but not the later
data.
The steady-state plasma heparin levels with our regimen were <0.5 U/mL12 and did not affect the measurements.12 35 36 After the first blood sampling, all 3 groups had an identical heparin regimen; therefore, differences among the groups cannot be attributed to heparinization. The extent of thrombin activation without heparin therapy might even be higher.7 8 37
Conclusions
The results of the this study demonstrate in a prospective,
randomized comparison a more marked paradoxical activation of the
coagulation system, including the kallikrein system, after
streptokinase versus front-loaded alteplase
thrombolysis. This effect has to be seen in addition to
the preexisting hypercoagulative state in AMI. Because all patients
already had a systemic heparin therapy, a more effective antithrombotic
supportive therapy should be developed to push the balance between
coagulation and fibrinolysis toward
thrombolysis. More detailed knowledge of the involved
pathways, eg, the plasmin-mediated kallikrein activation, will be a
prerequisite to cope with this task.
Received April 15, 1998; revision received August 10, 1998; accepted August 13, 1998.
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