CLINICAL STUDIES
Changes of hemostasis, endogenous fibrinolysis, platelet activation and endothelins after percutaneous transluminal coronary angioplasty in patients with stable angina
Markus Borries, MDa,a,
Michael Heins, MD*,
Yuriko Fischer, MDa,
Hugo Stiegler, MDa,
Ansgar Peters, MDa,
Hans Reinauer, MD*,
Frank C. Schoebel, MD,
Bodo E. Strauer, MD, FACCa and
Matthias Leschke, MDa
a Klinik für Kardiologie, Pneumologie und AngiologieHeinrich-Heine-Universität, Düsseldorf, Germany
* Institut für Klinische Chemie und Laboratoriumsdiagnostik, Heinrich-Heine-Universität, Düsseldorf, Germany
Manuscript received September 14, 1998;
revised manuscript received March 15, 1999,
accepted April 22, 1999.
Reprint requests and correspondence: Dr. Markus Borries, Heinrich-Heine-Universität Düsseldorf, Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstr. 5, 40225 Düsseldorf, Germany
Markus.Borries{at}uni-duesseldorf.de
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Abstract
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OBJECTIVES
This study investigated parameters of endogenous fibrinolysis, activation of coagulation and platelets, and endothelin levels before and after elective percutaneous transluminal coronary angioplasty (PTCA) in patients with stable coronary artery disease (CAD).
BACKGROUND
Abrupt vessel closure is a serious short-term complication after PTCA and is often unforeseeable. Detailed insight into the effect of PTCA on hemostasis, platelets and the release of vasoconstrictive substances, which are among the mainly discussed mechanisms of abrupt vessel closure, is needed to enhance the safety of coronary intervention.
METHODS
Plasma levels of markers of platelet activity, coagulation, endogenous fibrinolysis and endothelins were determined in 20 patients with stable CAD undergoing elective PTCA. The blood specimens were drawn before, immediately after, 1 h after intervention and on the next morning.
RESULTS
All patients showed an initially uncomplicated PTCA. Regarding the efficacy of anticoagulation after receiving 15.000 IU heparin during PTCA, two groups were compared. In eight patients with ineffective anticoagulation production of thrombin and platelet activation directly after and 1 h after PTCA was significantly higher compared with 12 patients with effective anticoagulation. Despite the strong activation of coagulation, only a low fibrinolytic response could be observed. Endothelins rose significantly after PTCA in both groups but stayed longer on higher levels in patients with distinct thrombin generation. Three of the eight patients without sufficient heparin treatment suffered abrupt vessel closure.
CONCLUSIONS
Initially uncomplicated dilation of coronary arteries leads to systemically measurable activation of coagulation and platelets in patients with ineffective doses of heparin and release of endothelins in all patients. Therefore, individual adjustment of anticoagulation and platelet inhibition in combination with effective antivasospastic substances are needed in every patient before, during and after initially uncomplicated PTCA to prevent this serious complication.
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Abbreviations and Acronyms
| | APTT | = activated partial thromboplastin time | | AT | = antithrombin | | beta-TG | = beta-thromboglobulin | | CAD | = coronary artery disease | | F1+2 | = prothrombin fragment 1+2 | | PAI | = plasminogen activator inhibitor | | PAP | = plasmin- 2-antiplasmin complex | | PTCA | = percutaneous transluminal coronary angioplasty | | TAT | = thrombin-antithrombin complex | | t-PA | = tissue plasminogen activator |
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Although the initial success rate (90% to 95%) of percutaneous transluminal coronary angioplasty (PTCA) is high (1), abrupt vessel closure remains a serious complication in about 2% to 8% of the cases (2). Coronary thrombosis, which occurs in up to 90% of cases within 1 h after uncomplicated PTCA (3), is considered to be the major cause in abrupt vessel closure (4,5). Dilation of coronary plaques leads to more or less dissection of the artery with exposure of subendothelial vessel wall components and consecutive activation of the coagulation system, platelets and release of vasoconstrictive substances (4,6,7). Some risk factors for ischemic complications, such as unstable angina and left ventricular function, are known, but abrupt vessel closure is often unforeseeable. In the case of good angiographic results of PTCA without flow limiting dissection or thrombus generation, many patients receive standard doses of heparin and aspirin only before and during intervention without information about activation of coagulation and platelets after PTCA.
The aim of this prospective study was the simultaneous documentation of changes of these three mainly discussed mechanisms of abrupt closure in patients without special risk factors and initially uncomplicated PTCA. Hence, parameters of coagulation (thrombin-antithrombin complex [TAT] antithrombin [AT] activity, prothrombin fragment 1+2 [F1+2], fibrinogen), endogenous fibrinolysis (plasminogen, plasminogen activator inhibitor [PAI] activity, tissue plasminogen activator [t-PA], plasmin-2-antiplasmin complex [PAP], D dimer), platelet activation (beta-thromboglobulin [beta-TG]) and vasoconstrictive factors (endothelin-1, big endothelin-1) were determined in 20 patients with coronary artery disease (CAD) and stable angina pectoris before and after elective and initially uncomplicated PTCA.
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Methods
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Patients.
For this study, 20 consecutive hospitalized male patients with stable angina pectoris and angiographically confirmed coronary artery disease were recruited. All presented with at least one hemodynamic relevant coronary stenosis and underwent elective PTCA. None of the patients had a history of acute myocardial infarction, unstable angina or coronary revascularization within the last six months. Patients had been clinically stable for at least 2 months before entry into the study and none had suffered severe heart failure (New York Heart Association III, IV). Furthermore, patients with chronic or acute systemic or inflammatory diseases, relevant organ dysfunction, neoplastic disorders and other disorders of the heart were excluded. All patients had taken low dose aspirin (100 mg/day) regularly before admission and beta-adrenergic blocking agents, calcium antagonists or angiotensin-converting enzyme inhibitors in different combination and gave their informed consent to this investigation.
Coronary angiography and PTCA.
Selective coronary angiography was performed after the administration of nitroglycerin and at least six standardized projections of the left coronary artery and two projections of the right coronary artery were obtained. Severity of CAD was classified as single-, double- or triple-vessel disease defined by the presence of relevant stenosis (degree >50% of the luminal diameter) of at least one of the three major coronary artery vessels by visual determination. Percutaneous transluminal coronary angioplasty was performed by two experienced investigators according to standard fashion using the Judkin approach following right femoral artery puncture. Before the procedure, patients received 500 mg of aspirin and 10.000 IU heparin plus an extra bolus of 5.000 IU directly after the intervention in the catheter laboratory. The choice of procedural variables such as size of the balloon, number and pressure of inflations etc. was made by the operating interventional cardiologist. To avoid vasospastic reactions after the procedure, patients were kept on continuous intravenous infusion of nitrates for 24 h.
Blood sampling and processing.
Blood specimens were drawn by two trained investigators in the fasting state before PTCA (between 7:30 and 8:30 AM), immediately after PTCA (between 12:00 and 2:00 PM), 1 h after PTCA (between 1:00 and 3:00 PM) and on the following morning (between 7:30 and 8:30 AM). A venipuncture of an antecubital vein was performed with a 19-gauge butterfly set for blood sampling before PTCA and on the next morning according to a standardized protocol without tourniquet. Before venipuncture blood sampling, patients had rested for at least 30 min in a supine position. Immediately after as well as 1 h after PTCA, blood was drawn from the venous catheter sheath. The first 4 ml blood were discarded and the samples were collected immediately in ice chilled Vacutainer tubes (Becton Dickinson, Meylan, Cedex-France). Vacutainer citrate sample tubes and EDTA anticoagulated sample tubes were used for blood collection. Plasma samples were prepared within 30 min in a precooled centrifuge and frozen immediately at –70°C until analysis within 3 months after sampling.
Directly after the procedure activated partial thromboplastin time (APTT) was determined in the routine laboratory after the patients received 15.000 IU heparin. Normal values in our laboratory were <40 s. The highest measurable APTT in our laboratory was 180 s.
Biochemic determinations.
Plasma concentrations of TAT, F1+2, D dimer, PAP, t-PA and beta-TG were determined by enzyme immunoassay (Enzygnost TAT micro, Enzygnost F1+2 micro, Enzygnost D dimer micro, Enzygnost PAP [Behringwerke AG, Marburg, Germany]), Asserachrom beta-TG (Boehringer, Mannheim, Germany), Thrombonostika (t-PA), (Organon Teknika, Eppenheim, Germany). Plasminogen activator inhibitor activity and plasminogen were measured by chromogenic test (Berichrom PAI and Plasminogen, Behringwerke AG, Marburg, Germany), AT activity was measured by using AT reagent and fibrinogen by Multifibren U (both Boehringer, Mannheim, Germany). Endothelin-1 and big endothelin-1 were determined by using a sensitive radioimmunoassay (Biomedica, Wien, Austria).
Correction for hematocrit.
After PTCA the hematocrit showed significant changes (data not shown). The correction for hematocrit was carried out following Keber (8), using the equation:
Statistical analysis.
Because the dependent variables of coagulation and endogenous fibrinolysis could be influenced by the degree of anticoagulation for statistical analysis, the group was divided into patients with "effective" (APTT  180 s) and "ineffective" (APTT < 70 s) anticoagulation. The Statistical Package for Social Sciences (SPSS 6.0 for Windows; SPSS, Munich, Germany) was used for statistical analysis. For the comparison of two nonparametric variables, the Mann-Whitney U test and for parametric variables the Wilcoxon and Friedman tests were used. A significant difference between groups was assumed at a level of error of <5% and a significant trend at a level of error of <10%.
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Results
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After therapy with 15.000 IU heparin during PTCA, 12 patients (60%) reached APTT 180 s, 8 patients were not effectively treated with heparin (APTT = 34 s, 35 s, 48 s,40 s, 36 s, 62 s, 55 s, 35 s). Because of this distinct difference of efficacy of anticoagulation, in the following these two groups were compared. There was no statistically significant difference between these groups for occurrence of arterial hypertension, hypercholesterolemia, diabetes mellitus, smokers, ex-smokers, family history or prior myocardial infarction. For the clinical and laboratory parameters, see Table 1.
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Table 1 Clinical Characteristics and Laboratory Parameters (Mean ± SD) of the Study Population—Comparison Between Patients With Effective and Ineffective Anticoagulation (AC)
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Coronary angiography and PTCA.
Only one vessel was dilated in every patient without use of stents, and no patient underwent recanalization of an occluded vessel. A reduction of the stenosis by at least 20% luminal diameter or below 50% luminal diameter could be achieved (initially successful PTCA) in every patient. No one had suffered major periprocedural complication like large, flow limiting dissection or reocclusion of the vessel during the time of angiographic control. See Table 2 for the angiographic characteristics and procedural variables.
Effective anticoagulation.
No significant change in F1+2, TAT, AT activity, plasminogen or PAP after PTCA could be documented. Concentrations of D dimer, endothelin-1 and big endothelin-1 rose significantly directly after angioplasty. Endothelins decreased in the following and turned towards baseline levels the next morning, but D dimer concentrations remained increased. For plasma concentrations of fibrinogen, t-PA, PAI activity and beta-TG, a contrary course was documented with a decrease 1 h after PTCA and nearly baseline values on the next morning except for fibrinogen, which showed a slight increase the next day. Tables 3, 4 and 5 give detailed information about the values determined before and after PTCA.
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Table 3 Parameters of Activation of Coagulation and Platelets in Course After PTCA—Comparison Between Patients With Effective (n = 12) and Ineffective (n = 8) Anticoagulation (AC) (Median [Range])
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Table 4 Parameters of Endogenous Fibrinolysis in Course After PTCA—Comparison Between Patients With Effective (n = 12) and Ineffective (n = 8) Anticoagulation (AC) (Median [Range])
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Table 5 Endothelin-1 (ET-1) and Big endothelin-1 (BET-1) in Course After PTCA—Comparison Between Patients With Effective (n = 12) and Ineffective (n = 8) Anticoagulation (AC) (Median [Range])
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Ineffective anticoagulation.
Plasma concentrations of beta-TG, F1+2 and TAT, AT activity, D dimer, plasminogen, PAP, endothelin-1 and big endothelin-1 rose directly after PTCA and stayed on high levels 1 h after intervention. Plasminogen activator inhibitor activity decreased significantly directly after PTCA and was still low 1 h after intervention. No significant changes of concentrations after PTCA were measured for fibrinogen and t-PA. Plasma concentrations of F1+2, TAT and beta-TG were significantly higher immediately and 1 h after intervention, and endothelin-1 showed a strong trend to higher levels 1 h after PTCA in patients with ineffective anticoagulation (Tables 3, 4 and 5).
Abrupt vessel closure.
All 20 patients had an initially successful dilation of the coronary artery, but 3 of the 8 ineffectively anticoagulated patients (APTT = 62 s, 55 s, 35 s) suffered angina pectoris 2–6 h after the angioplasty and a second coronary angiography was performed within 2 h after onset of symptoms. Abrupt vessel closure was documented in all three cases. The patients were successfully redilated and 250.000 IU of urokinase was given for intracoronary lysis. Despite successful redilation, the three patients developed an increase in creatinkinase (CK = 142 U/l, 180 U/l, 220 U/l).
There was a distinct difference before PTCA between patients with and without complication in the subgroup of ineffectively anticoagulated patients in plasma concentrations of t-PA ([median; range] without abrupt vessel closure: 17.22 [12.74 to 20.0] µg/l; with abrupt vessel closure: 11.41 [11.06 to 14.39] µg/l) and PAI activity (without abrupt vessel closure: 5.15 [2.0 to 9.09] U/ml; with abrupt vessel closure: 8.66 [7.81 to 11.93] U/ml). For patients with complications, the highest big endothelin-1 concentrations 1 h after PTCA could be documented compared with ineffectively anticoagulated patients without acute vessel closure ([range] without abrupt vessel closure: 2.46 to 4.92 fmol/ml; with abrupt vessel closure: 5.71–6.38 fmol/ml).
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Discussion
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It is well known that dilation of coronary arteries in most cases is accompanied by a dissection of the vessel (2,9,10,11) and consecutive activation of coagulation, platelets and release of vasoconstrictive substances. Therefore, every patient receives heparin, aspirin and nitrates before and during PTCA to reduce the activation of platelets and systemic coagulation and to minimize vasospastic reactions. Because measurement of activated clotting time as a bedside test was not available in our clinic at the time of the study, effectiveness of anticoagulation was determined by APTT in our routine laboratory with temporary delay.
Coagulation system and platelets.
Eight of the 20 patients (40%) showed an ineffective anticoagulation directly after PTCA with substantial thrombin generation, indicated by significantly increasing plasma concentrations of F1+2 and TAT. In patients with effective anticoagulation, there was no significant change of these parameters during the intervention. Despite an individual response to heparin, for example, by differences in plasma concentrations of heparin-neutralizing proteins or body weight, most patients would show "highly effective" (>180 s) APTT values after receiving the empirical dose of 15.000 IU heparin as intravenous bolus. Hence, ineffective anticoagulation with standard doses of heparin after intervention resulted probably not only from an individual response to heparin, but from a much stronger activation of coagulation during PTCA. Different thrombogenicity of coronary plaques and its dependence on the plaque-components were described before (12,13) and could explain the different level of thrombin generation. In contrast with Marmur et al. (14), who documented thrombin generation in a substantial portion of patients shortly after PTCA locally in the coronary artery despite an activated clotting time over 300 s, in our study, activation of coagulation could be measured systemically but only in the ineffectively treated subgroup. Immediately after PTCA and therapy with 500 mg aspirin, plasma concentrations of beta-TG decreased in patients with effective APTT values, indicating either effective platelet inhibition or no substantial platelet activation. In contrast with this, in patients with distinct thrombin generation beta-TG increased after PTCA with statistical significant difference between both groups. The usefulness of antiplatelet drugs in preventing acute ischemic complications after angioplasty was previous described (15,16). This platelet activation could be due to the high plasma concentration of thrombin, a potent stimulus of platelet activation, and to balloon-mediated injury of the plaque with consecutive contact of the blood with von Willebrand factor, collagen and other platelet activators. A strong platelet activation could lead to reduced heparin effect by release of platelet factor 4, a heparin-neutralizing protein (17). The parallel activation of coagulation and platelets only in a subgroup with low level anticoagulation and missing substantial thrombin generation before PTCA in both groups supports the hypothesis of a high thrombogenic plaque in these patients. The lack of visible angiographic complications like a distinct dissection or thrombus formation directly after PTCA showed the uncertainty of the visible result to indicate changes of hemostasis. Recently published data of Narins (18) and Kunert (19) showed a strong relationship between low anticoagulation determined by the activated clotting time and the risk of abrupt vessel closure after PTCA. In our study, three patients developed an early reocclusion of the vessel. This unexpected complication rate of 15% was quite high in our rather small collective and does not reflect the overall rate of our institution (20). Out of a random coincidence there was no other obvious cause; nevertheless, it was remarkable that all three patients belonged to the group with ineffective heparin therapy respective with strong activation of coagulation and platelets. This supports the findings of Narins (18) and Kunert (19). Ineffective heparin treatment in our study was not caused by low AT activity or different body weight because of normal AT activity and similar body weight in both groups. There was also no difference in fibrinogen plasma levels, one discussed risk factor in cardiovascular disease (21,22,23).
Endogenous fibrinolysis.
The lower levels of t-PA concentrations and PAI activity immediately and 1 h after PTCA in both groups were probably based on circadian variation of these parameters (24). The blood of the first and last measurement was taken early in the morning and the blood after PTCA in the late morning or at noon. The assay system for measuring t-PA concentrations determines complexes of t-PA and PAI. This explains the simultaneous decrease in both parameters after PTCA. Concentrations of PAP showed a significant increase after PTCA in patients with high thrombin generation, and a similar rise of D dimer concentrations in both groups. Despite the strong activation of coagulation, the concentrations of PAP and D dimer showed no difference between the patients with and without thrombin generation. The absence of a strong rise in D dimer and PAP concentrations in the patients with distinct activation of the coagulation system may show their insufficiency to enhance their endogenous fibrinolysis. This lack of effective activation of fibrinolysis despite the significant higher plasminogen levels in this group suggests a disturbance in fibrinolytic response as a cause of a low fibrinolytic potency. These findings also show the importance of the determination and prevention of thrombin generation after PTCA.
Interestingly the three patients with acute vessel closure had higher plasma activity of PAI and distinct lower plasma levels of t-PA before intervention in comparison with the patients without complication in the subgroup of ineffectively treated patients. High PAI activity levels are reported in coronary artery disease and acute myocardial infarction (25,26).
Endothelins.
The strong vasoconstrictor endothelin-1 and its precursor big endothelin-1 are discussed with regard to their role in coronary artery disease and acute ischemic syndromes (27,28,29,30,31). Vasoconstriction may be also an important factor in abrupt vessel closure (7).
The significant increase of both peptides directly after PTCA in both groups may indicate endothelial damage. Shear stress and endothelial injury stimulates endothelin-1 production (27,32,33). Also myocardial ischemia during balloon inflation and stress reaction with release of catecholamines could contribute to endothelin-1 release in both groups (27,33). One hour after intervention, the plasma concentrations of endothelin-1 and big endothelin-1 in the patients with effective anticoagulation decreased while endothelin-1 and big endothelin-1 concentrations remained at higher levels in patients with activated coagulation systems. The cause of the elevated levels of the vasoconstrictors in ineffective anticoagulated patients can be a combination of the increased generation of thrombin, a potent stimulus of endothelin-1 production (34), or angiographically nonvisible extensive vessel injury. Endothelin-1 and big endothelin-1 levels 1 h after PTCA in patients with abrupt closure belonged to the highest values in the subgroup compared with patients without complication. Because of its longer half time and higher circulating plasma levels, big endothelin-1 may be the more conclusive parameter. A higher sensitivity of big endothelin-1 for discrimination of patients with stable, unstable angina pectoris and acute myocardial infarction was documented previously (31). Independent of the mechanisms of endothelin-1 release, elevated levels of the peptide measured in peripheral veins are probably much higher at the place of interest and could contribute to abrupt vessel closure.
There was no difference in endothelin-1 and big endothelin-1 concentrations between the groups with and without early complications before PTCA and directly after the procedure. But a missing decrease or further increase of plasma concentrations in course after intervention may be an indicator of higher risks for complications. Big endothelin-1 as a predictor of a severe course of ischemia in patients with unstable angina and endothelin-1 as a prognostic factor after acute myocardial infarction was shown recently (31,35).
Study limitations.
Interpretation of this study is limited by the small sample size and the accidental high rate of abrupt coronary artery closures. For measurement of effectiveness of anticoagulation with high doses of heparin during PTCA, the determination of activated clotting time would have been more reliable. Kunert et al. (19) reported 150 patients with an APTT >180 s after PTCA and after injection of 20.000 IU heparin but who had a range of activated clotting time between 167 s and 628 s. This means that "highly effective" APTT could be "ineffective," because activated clotting times >300 s during PTCA are currently recommended today to prevent abrupt vessel closure. Even though our data indicate a therapeutic effect on thrombin generation, even more intense anticoagulation guided by activated clotting time measurements may be necessary to suppress elevated concentrations of thrombin in the local environment of the dilated vessel. Therefore, this device should be routinely used during PTCA if possible.
Conclusions and clinical implications.
The elevation of the parameters indicating activation of coagulation system or platelets directly after PTCA agreed with an ineffective anticoagulation or vice versa and clearly showed a strong association with the development of early vessel occlusion after an initially uncomplicated procedure. This supports the findings of other authors about the meaning of effective anticoagulation to avoid abrupt vessel closure after PTCA (18,19). Risk factors for development of abrupt vessel closure in our study seem to be based on a combination of vasoconstriction, activation of the coagulation system and platelets as well as a low fibrinolytic potency. These findings and their agreement with the results of other authors should lead to further studies which investigate the benefit of a prolonged and intensified therapy with heparin or with more specific thrombin inhibitors or platelet inhibitors in this subgroup of patients after initially uncomplicated PTCA. Effective anticoagulation should be determined by activated clotting time, which could be shown to be superior to measurement of APTT. Detailed insights into the mechanism of abrupt closure, especially individual measurement of effective anticoagulation and platelet inhibition as well as development of respective experience with new therapeutic options such as endothelin-1- or endothelin-1 receptor-antagonists, and new platelet inhibitors such as glycoprotein IIb/IIIa receptor antibodies will probably help to prevent this serious complication.
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Abstract
Methods