Hemostatic Factors and the Risk of Myocardial Infarction or Sudden Death in Patients with Angina Pectoris
Simon G. Thompson, M.A., Joachim Kienast, M.D., Stephen D.M. Pyke, M.Sc., Frits Haverkate, Ph.D., Jürgen C.W. van de Loo, M.D., for The European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group
Background Increased levels of certain hemostatic factors mayplay a part in the development of acute coronary syndromes andmay be associated with an increased risk of coronary eventsin patients with angina pectoris.
Methods We conducted a prospective multicenter study of 3043patients with angina pectoris who underwent coronary angiographyand were followed for two years. Base-line measurements includedthe concentrations of selected hemostatic factors indicativeof a thrombophilic state or endothelial injury. The resultswere analyzed in relation to the subsequent incidence of myocardialinfarction or sudden coronary death.
Results After adjustment for the extent of coronary artery diseaseand other risk factors, an increased incidence of myocardialinfarction or sudden death was associated with higher base-lineconcentrations of fibrinogen (mean ±SD, 3.28±0.74g per liter in patients who subsequently had coronary events,as compared with 3.00±0.71 g per liter in those who didnot; P = 0.01), von Willebrand factor antigen (138±49percent vs. 125±49 percent, P = 0.05), and tissue plasminogenactivator (t-PA) antigen (11.9±4.7 ng per millilitervs. 10.0±4.2 ng per milliliter, P = 0.02). The concentrationof C-reactive protein was also directly correlated with theincidence of coronary events (P = 0.05), except when we adjustedfor the fibrinogen concentration. In patients with high serumcholesterol levels, the risk of coronary events rose with increasinglevels of fibrinogen and C-reactive protein, but the risk remainedlow even given high serum cholesterol levels in the presenceof low fibrinogen concentrations.
Conclusions In patients with angina pectoris, the levels offibrinogen, von Willebrand factor antigen, and t-PA antigenare independent predictors of subsequent acute coronary syndromes.In addition, low fibrinogen concentrations characterize patientsat low risk for coronary events despite increased serum cholesterollevels. Our data are consistent with a pathogenetic role ofimpaired fibrinolysis, endothelial-cell injury, and inflammatoryactivity in the progression of coronary artery disease.
Coronary thrombosis is now generally recognized as the precipitatingevent in the transition from stable to acute ischemic heartdisease, manifested by unstable angina,1 acute myocardial infarction,2and sudden death from coronary causes.3 Besides local stimulisuch as disruption of plaques, systemic thrombogenic factorsmay contribute to the occurrence, extent, and persistence ofcoronary thrombosis and its clinical sequelae.4 These factorsinclude abnormalities of blood flow,5 platelet hyperreactivity,6,7defective fibrinolysis,8,9 and increased concentrations of hemostaticproteins, specifically fibrinogen and factor VII.10 Thus, withthe use of appropriate laboratory tests, it may be possibleto detect a thrombogenic state and thus identify patients atincreased risk for cardiovascular disease.
Support for this hypothesis comes mainly from prospective studiesof healthy subjects, which have demonstrated a direct and independentassociation between plasma fibrinogen concentrations and therisk of coronary events.5,10,11,12,13,14 However, data on patientswith known coronary artery disease are sparse and come fromsmall cohort studies of patients with angina pectoris15,16 orthose who have had a first myocardial infarction.8,9,17,18,19
In the European Concerted Action on Thrombosis and Disabilities(ECAT) Angina Pectoris Study,20 we recruited more than 3000patients with angina pectoris and used angiography to determinethe extent of coronary artery disease. Our principal objectivewas to investigate the associations between base-line measurementsof hemostatic factors that indicate the existence of a thrombophilicstate or an alteration in the vascular endothelium, on the onehand, and the occurrence of coronary events during a two-yearfollow-up period, on the other.
Methods
Patients
Men and women who underwent coronary angiography because ofsuspected coronary artery disease were eligible for the study.Patients who had had a myocardial infarction within the precedingtwo months or who had severe right-heart failure or noncardiacdiseases likely to cause death within one year were excluded.A total of 3043 patients from 18 European centers (listed inthe Appendix) were recruited between October 1984 and June 1987.
Blood Sampling and Measurements of Hemostatic Factors
The conditions of blood sampling and storage and the measurementof hemostatic factors have been described in detail elsewhere.21The technicians were trained at the central laboratory, andan external quality-assessment scheme was used to monitor theirperformance throughout the study.22,23
The following tests were performed. The number and functionof platelets were assessed by means of whole-blood plateletcounts and measurements of -thromboglobulin and platelet factor4. The state of the coagulation system was assessed by measurementsof the activated partial-thromboplastin time, fibrinogen, fibrinopeptideA, von Willebrand factor antigen, factor VIII activity, antithrombinIII antigen and activity, and protein C antigen and activity.The fibrinolytic system was assessed by the measurement of plasminogen,2-antiplasmin activity, histidine-rich glycoprotein, and plasminogen-activatorinhibitor type 1 (PAI-1) antigen and activity. Tissue plasminogenactivator (t-PA) antigen and activity, as well as the euglobulinclot-lysis time, were measured before and after 10 minutes ofvenous occlusion.
The hematocrit, white-cell count, and ABO blood type were determinedaccording to standard local procedures, as were the total cholesteroland triglyceride concentrations. C-reactive protein was measuredby a nephelometric method.
Coronary Angiography
Coronary angiography was performed, usually by the Judkins techniquebut occasionally by the Sones technique.24 For the purpose ofthis study, the angiographic results were expressed as the numberof vessels (0 to 4) with stenosis of at least 50 percent ofthe vessel diameter or occlusion.
Follow-Up and Ascertainment of End Points
Patients were evaluated annually for two years, and informationon deaths, coronary events, hospital admissions, and currentdrug use was obtained at each follow-up contact. Reported clinicalevents were reviewed independently by an end-points committeewhose members were blinded to the results of the hemostatictests. The primary end points of the study were fatal or nonfatalmyocardial infarction, defined according to standard diagnosticcriteria,25 and sudden death from coronary causes, defined asdeath within one hour of the onset of cardiac symptoms. Eventsoccurring within 72 hours of surgery (usually coronary-arterybypass surgery) or angioplasty were considered primarily relatedto the intervention. Patients with such events were excludedfrom the analyses, as were patients with possible but unconfirmedmyocardial infarction or death from other cardiac causes, othercauses, or uncertain causes.
Statistical Analysis
To investigate the association between the concentrations ofhemostatic factors and the incidence of definite coronary events,we used multiple regression analysis, with the hemostatic factoras the dependent variable. Mean differences between the patientswho had events and those who were event-free were calculatedafter adjustment for the medical center; the patient's age,sex, and ABO blood type; and any of the following base-linecharacteristics if they were demonstrated to be significantlyrelated (P<0.01) to the incidence of events: drugs used atthe time of blood sampling; previous myocardial infarction;history of diabetes or hypertension; smoking; history of chestpain, including the type of angina; extent of coronary arterydisease as assessed angiographically; left ventricular ejectionfraction and end-diastolic pressure; body-mass index (the weightin kilograms divided by the square of the height in meters);blood pressure; and total cholesterol and triglyceride concentrations.Hemostatic variables were analyzed on a logarithmic scale whenthis transformation produced a more symmetrical (gaussian) distribution.
A separate analysis was carried out of the association betweenother (nonhemostatic) factors and the risk of coronary events;for this analysis we used multiple logistic-regression techniquesand the same variables listed above.
The P values given here for differences in laboratory-test resultsreflect adjusted data and are two-tailed. The standardized relativerisk was calculated as the relative risk of a coronary eventfor each increase of 1 SD in a given variable.26
Results
Base-Line Characteristics
Of the 3043 patients enrolled in the study, 2960 (97 percent)were followed for two years. During this period 837 patientsunderwent coronary-artery bypass surgery, 223 underwent coronaryangioplasty, and 49 underwent both interventions. A total of106 definite coronary events were reported, 40 of which occurredin patients undergoing bypass surgery or angioplasty eitherjust before or after the clinical event. An additional 154 majorevents did not fulfill the criteria for study end points (Table 1).
Table 1. Study Population and Events during Fol low-up.
The base-line characteristics of the 106 patients who had definitecoronary events and the 2700 patients in the event-free groupare summarized in Table 2. After adjustment for medical center,sex, and age, when appropriate, the patients who had coronaryevents were older, tended to have more severe angina, and weremore likely to have a history of myocardial infarction thanthose without such events. They also had more extensive coronaryartery disease and were more likely to have been treated withdiuretic agents or digitalis. These differences, along withother base-line factors, were accounted for in the multipleregression analysis of the associations between the concentrationsof hemostatic factors and the incidence of coronary events.A detailed analysis of base-line clinical and laboratory datawas published earlier.20
Table 2. Base-Line Characteristics of the Patients with and without Coronary Events.
Concentrations of Hemostatic Factors and Other Test Results in Relation to Outcome
Among the various hemostatic variables measured, only the levelsof fibrinogen, von Willebrand factor antigen, and t-PA antigenwere significantly and directly related to the incidence ofcoronary events, after adjustment for other confounding factors(Table 3).
Table 3. Laboratory-Test Results According to Outcome.
Regression analyses indicated significant positive correlationsbetween the fibrinogen level and age (P<0.001), the body-massindex (P<0.001), the extent of coronary artery disease atenrollment (P<0.001), and smoking status (P = 0.003). Inaddition, the mean fibrinogen concentrations were 7.6 percent,5.8 percent, and 4.3 percent higher in patients receiving heparin,diuretics, and oral anticoagulants, respectively (P<0.002for all comparisons). After adjustment for these confoundingfactors, fibrinogen concentrations in the group with coronaryevents were on average 6.5 percent higher than those in theevent-free group (P = 0.01).
Concentrations of von Willebrand factor antigen increased withage (P<0.001) and were significantly higher in the patientsreceiving diuretics, digitalis, heparin, or oral anticoagulantsthan in those not receiving these agents (P<0.01 for allcomparisons). Patients with blood type O had substantially lowermean concentrations of von Willebrand factor antigen (107 percent)than patients in blood group A (140 percent), B (150 percent),or AB (146 percent) (P<0.001 for all comparisons). Afteradjustment for these variables, the concentration of von Willebrandfactor antigen was on average 8.5 percent higher in the patientswho subsequently had coronary events than in those who did not(P = 0.05).
Among the fibrinolytic factors, the level of t-PA antigen, measuredbefore venous occlusion, was significantly higher in the patientswho subsequently had coronary events; the mean difference betweenthe groups was 10.2 percent (P = 0.02) after adjustment forthe confounding influence of age, sex, medications (heparinand diuretics), smoking status, body-mass index, triglycerideconcentrations, extent of coronary artery disease, and ejectionfraction. Concentrations of t-PA antigen were directly correlatedwith both PAI-1 activity and PAI-1 antigen (r = 0.40 and r =0.47, respectively; P<0.001 for both comparisons). However,neither PAI-1 antigen and activity nor the ratio of PAI-1 antigento t-PA antigen differed significantly between the group withcoronary events and the event-free group when all confoundingfactors were adjusted for (P>0.2 for all comparisons).
The concentrations of C-reactive protein were on average 20.2percent higher in the patients who had coronary events thanin those without such events (P = 0.05), after adjustment forsmoking status, body-mass index, ejection fraction, extent ofcoronary artery disease, triglyceride concentrations, and useof diuretics, digitalis, and heparin. The base-line measurementsof C-reactive protein and fibrinogen, both of which are knownto be hepatic acute-phase proteins,27,28,29 were strongly correlated(r = 0.49; P<0.001). The association of fibrinogen concentrationswith the risk of coronary events remained statistically significant(P = 0.013) after adjustment for the C-reactive protein concentration,whereas the relation of the concentration of C-reactive proteinto the risk of coronary events was no longer significant afteradjustment for the fibrinogen concentration (P = 0.48).
Prediction of the Risk of Coronary Events
Table 4 shows the relative risk of definite coronary eventsin five equal subgroups of the patient population defined accordingto the distributions of laboratory variables that were independentlyrelated to the incidence of coronary events. Whereas fibrinogenwas associated with a threefold increase in risk from the lowestto the highest quintile group, a 1.5- to 2-fold increase inrisk was observed with increasing levels of each of three factors:von Willebrand factor antigen, t-PA antigen, and C-reactiveprotein.
Table 4. Relative Risk of Coronary Events According to the Concentrations of Hemostatic Factors.
A history of myocardial infarction was associated with a 1.6-foldincrease in the risk of coronary events (P = 0.04) but did notsignificantly influence the relation of the variables mentionedabove to the incidence of coronary events. Furthermore, thestandardized relative risks shown in Table 4 did not differsignificantly among patients with stable angina on exertion,those with unstable angina, and those who had angina withouttypical chest pain (for example, acute left abdominal pain,anxiety, or dyspnea).
Higher left ventricular end-diastolic pressures measured atbase line were associated with a 20 percent increase in therisk of coronary events for each additional 5 mm Hg of pressure(P = 0.02). In addition, patients who were receiving diureticswhen they entered the study had a 2.5-fold risk of subsequentcoronary events (P<0.001), an increase that probably reflectsthe poor prognosis of patients with heart failure. Finally,patients in blood groups A and B had 1.6 times the risk of coronaryevents of patients with blood type O (P = 0.05). Significantassociations with these base-line characteristics were takeninto account in our analysis of the relation of hemostatic factorsand other laboratory measurements to the risk of coronary events.
As expected, the extent of coronary artery disease was the singlemost powerful predictor of coronary events (Table 5). However,despite the correlation between the concentrations of fibrinogen,t-PA antigen, and C-reactive protein and the extent of coronarydisease,20 these variables remained independently predictiveof subsequent coronary events and were valuable in identifyingpatients at low and at high risk of such events regardless ofthe severity of coronary disease.
Table 5. Relative Risk of Coronary Events According to Angiographic Status at Base Line.
Serum total cholesterol concentrations were not independentlyrelated to the risk of coronary events in this group of patients;the mean serum cholesterol concentration was 257 mg per deciliter(6.66 mmol per liter) in patients who subsequently had coronaryevents, as compared with 246 mg per deciliter (6.37 mmol perliter) in the event-free group after adjustment for other coronaryrisk factors (P = 0.33). However, when we analyzed the combinedinfluence of fibrinogen, C-reactive protein, and total cholesterolon the risk of coronary events, it was clear that high fibrinogenconcentrations, and particularly the combination of high fibrinogenconcentrations with high concentrations of C-reactive protein,added markedly to the association of increased risk with hightotal cholesterol concentrations (Figure 1A and Figure 1B).Conversely, patients with low concentrations of both fibrinogenand C-reactive protein had a low risk of coronary events evenin the presence of high total cholesterol concentrations.
Figure 1. Incidence of Coronary Events during Two Years of Follow-up, According to Concentrations of Fibrinogen, C-Reactive Protein, and Total Cholesterol.
Panel A shows the risk of coronary events according to fibrinogen and total cholesterol concentrations. Panel B shows the risk according to fibrinogen and C-reactive protein concentrations combined, as compared with total cholesterol concentrations. The concentrations of these variables are divided into three categories (lower, middle, and higher), each containing a third of the sample, according to their respective distributions. In panel B, "intermediate" refers to all combinations of fibrinogen and C-reactive protein concentrations other than lower–lower or higher–higher. The values used to divide the sample into thirds were 2.71 and 3.31 g per liter for fibrinogen, 5.79 and 6.80 mmol per liter (224 and 263 mg per deciliter) for cholesterol, and 0.88 and 2.17 mg per liter for C-reactive protein. The number of coronary events and the number of patients at risk are shown for each group. Only patients for whom data on both fibrinogen and total cholesterol concentrations were available are included in the analysis.
Discussion
We designed this study to assess the prognostic value of theextent of coronary artery disease and of selected hemostaticvariables in patients with angina pectoris who were undergoingcoronary angiography. Three hemostatic variables — namely,the concentrations of fibrinogen, von Willebrand factor antigen,and t-PA antigen — proved to be directly and independentlycorrelated with the risk of subsequent coronary events. We alsofound an association between the risk of coronary events andthe concentration of acute-phase reactant C-reactive protein.
Not surprisingly, the extent of coronary artery disease assessedby angiography at study entry was the single most importantindicator of outcome. It was positively related to the plasmaconcentrations of fibrinogen, t-PA antigen, and C-reactive protein,but even after adjustment for the extent of coronary arterydisease, these variables remained independently associated withthe risk of coronary events, and they were valuable in identifyingpatients at low and at high risk within each category of diseaseseverity. Moreover, the predictive value of these factors didnot seem to depend on the type of angina at the base-line examination.Indeed, in this study,20 although not in others,30,31,32,33the type of angina was unrelated to the results of hemostatictests and measurements of C-reactive protein. Hence, these variablesappear to be independent markers of coronary atherosclerosisthat is likely to progress to atherothrombotic vessel occlusionin patients with symptomatic angina pectoris.
A strong association with the risk of subsequent coronary eventswas observed for the fibrinogen concentration; the risk tripledfrom that for the patients in the bottom fifth of the samplein terms of fibrinogen levels to that for those in the top fifth.The strength of this association in our patients with anginapectoris is similar in magnitude to that in healthy subjects.10,11,12,13,14Thus, on the basis of the available evidence, an increased fibrinogenconcentration — even within the normal range — canbe regarded as a strong and independent predictor of cardiovascularrisk not only in apparently healthy people, but also in patientswith manifest coronary artery disease.
Our findings regarding the prognostic value of the concentrationsof von Willebrand factor antigen extend recent observationsin smaller cohorts of patients with stable angina or those whohad had myocardial infarctions.15,18 Increased plasma concentrationsof von Willebrand factor derived from endothelial cells havebeen reported in various vascular disorders.34 Thus, increasesin the concentration of this factor in patients at high riskfor coronary thrombotic occlusion may reflect endothelial perturbation.
The association we found between the concentration of t-PA antigenand the risk of coronary events accords with the results ofrecent prospective studies in patients with severe angina pectoris16and in healthy men35; these studies also identified t-PA antigenas a marker of cardiovascular risk. The significant positivecorrelations between t-PA antigen and plasma PAI-1 antigen andactivity in our study and that of others36 suggest that increasedconcentrations of t-PA antigen in large part reflect circulatingt-PA–PAI-1 complex and thus indicate reduced rather thanenhanced fibrinolytic activity. Irrespective of these considerations,increased synthesis of t-PA antigen by endothelial cells mayindicate dysfunction of these cells.
Increased concentrations of C-reactive protein have been reportedin patients with acute coronary syndromes33,37,38 and predictpoor outcomes in patients with severe unstable angina.39 Theirrelevance in patients with other types of angina and their long-termprognostic value with respect to cardiovascular risk have beenunclear, however. The positive association of increasing concentrationsof C-reactive protein with increases in the risk of coronaryevents in our study suggests a possible role of inflammationin the progression of coronary artery disease. This processmay account, in part, for the association of risk with the concentrationof fibrinogen, which is also known to act as a hepatic acute-phaseprotein.29
An interesting new aspect of our results is the effect of fibrinogenconcentrations, either alone or in combination with those ofC-reactive protein, on the risk of coronary events even withinsubgroups of patients defined by serum cholesterol level. Highconcentrations of fibrinogen and C-reactive protein could beused to identify patients with hypercholesterolemia who areat particularly high risk for coronary events. In contrast,low fibrinogen concentrations were associated with a low riskof new coronary events even in patients with high serum cholesterollevels. Similarly, healthy subjects with high serum levels oflow-density lipoprotein cholesterol and low fibrinogen concentrationshave a lower risk of coronary events than similar subjects withhigh fibrinogen concentrations.14 These findings have implicationsfor risk-factor control and should be considered in the designof future interventional trials.
Our results highlight the role of the concentrations of fibrinogen,t-PA antigen, and von Willebrand factor antigen as independentpredictors of cardiovascular risk in patients with coronaryartery disease. The association of higher concentrations ofboth fibrinogen and C-reactive protein with increased coronaryrisk suggests that the fibrinogen concentration becomes elevated,at least in part, as a consequence of inflammatory reactionsthat occur in progressive atherosclerosis. The positive associationof the risk of coronary events with the concentrations of t-PAantigen and von Willebrand factor antigen, both of which arereleased by endothelial cells, points to possible endothelialperturbation in patients prone to coronary atherothrombosis.
Supported by a grant from the European Community.
* The investigators and institutions participating in the EuropeanConcerted Action on Thrombosis and Disabilities (ECAT) AnginaPectoris Study are listed in the Appendix.
Source Information
From the Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London (S.G.T., S.D.M.P.); the Department of Internal Medicine, University of Münster, Münster, Germany (J.K., J.C.W.L.); and the Gaubius Laboratory, Leiden, the Netherlands (F.H.).
Address reprint requests to Dr. van de Loo at the Department of Internal Medicine, University of Münster, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany.
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Appendix
The following institutions and investigators participated inthe ECAT study of the Commission of the European Communities.Participating centers are listed in descending order of thenumber of patients enrolled, with the number of patients andthe responsible investigators in parentheses: Bordeaux, France(341) — Hôpital Cardiologique, Clinique MedicaleCardiologique (H. Bricaud) and Laboratoire d'Hémobiologie(M.R. Boisseau); Lyon, France (325) — Hôpital Cardiovasculaireet Pneumologique Louis Pradel (J.B. Delahaye) and Facultéde Medicine Alexis Carrel, Laboratoire d'Hémobiologie(M. Dechavanne); Münster, Germany (319) — UniversityDepartments of Cardiology (U.S. Müller) and Haematology(U. Schmitz-Huebner); Bad Rothenfelde, Germany (288) —Schüchtermann-Klinik, Department of Cardiology (R. Buchwalskyand J. Kienast, Münster); Basel, Switzerland (235) —Kantonsspital, University Department of Cardiology (F. Burkart)and Haemostasis Laboratory (F. Duckert); Vienna, Austria (208)— I. University Department of Medicine (G. Kronik andH. Niessner); Athens, Greece (162) — NIMTS Hospital, Departmentof Cardiology (C.D. Michalopoulos), Alexandra Hospital, Departmentof Clinical Therapeutics (S.D. Moulopoulos), and Laikon GeneralHospital, Blood Transfusion Center (T. Mandalaki); Frankfurt,Germany (156) — University Center for Internal Medicine,Departments of Cardiology (W.D. Bussmann) and Angiology (K.Breddin); Giessen, Germany (144) — University Departmentfor Internal Medicine (B. Wüsten and F.R. Matthias); Paris(132) — Hôpital Broussais, Clinique Cardiologique(L. Guize), and Hôtel-Dieu, Laboratoire Central d'Hématologie(M.M. Samama); Bern, Switzerland (128) — Inselspital,University Department of Medicine (H.P. Gurtner and P.W. Straub);Pisa, Italy (118) — Centro Nazionale di Ricerca Instituteof Clinical Physiology (A. L'Abbate and R. de Catarina); Brussels,Belgium (114) — Clinique Universitaire St. Luc, Departmentof Cardiology (F. Lavenne), and University of Louvain, Laboratoryfor Haemostasis and Thrombosis Research (R. Masure); Leeds,United Kingdom (84) — General Infirmary, Departments ofCardiology (D.R. Smith) and Medicine (C.R.M. Prentice); Nauheim,Germany (82) — Kerckhoff-Clinic (M. Schlepper) and MaxPlanck Gesellschaft Research Group for Blood Coagulation andThrombosis (G. Müller-Berghaus); Mannheim, Germany (80)— I. University Department of Medicine (B. Stegaru andW. Kirschstein); Marseille, France (67) — C.H.U. Timone,Department of Cardiology (A. Serradimigni), and Laboratoired'Hématologie (I. Juhan-Vague); and Eindhoven, the Netherlands(60) — Catharina Hospital, Departments of Cardiology (J.J.R.M.Bonnier and H.R. Michels) and Haematology (J.J.M.L. Hoffmann).
The members of the study committees and the principal investigatorsof the reference laboratories were as follows: ECAT AdvisoryBoard: E.F. Lüscher (chairman), Bern; J.P. Boissel, Lyon;P. Brakman, Leiden, the Netherlands; D.G. Julian, London; C.R.M.Prentice, Leeds; M. Verstraete, Leuven, Belgium; ECAT projectleader: F. Haverkate, Leiden; Protocol Advisory Board: H. Bricaud,Bordeaux; F. Duckert, Basel; P.G. Hugenholtz, Rotterdam, theNetherlands; D. Julian, London; J. Lubsen, Rotterdam; U.S. Müller,Münster; C.R.M. Prentice, Leeds; S.G. Thompson, London;and J. van de Loo, Münster; Statistical Center: S.G. Thompsonand S.D.M. Pyke, London; End Point Committee: G. Breithardt,Münster; M. Brochier, Tours, France; and H. Tunstall-Pedoe,Dundee, United Kingdom; Reference Laboratories: R.M. Bertina,Leiden (protein C); J. Conard, Paris (histidine-rich glycoprotein);F. Duckert, Basel (antithrombin III, factor VIII, von Willebrandfactor, fibrinogen); P.J. Gaffney, London (plasminogen); D.S.Pepper, Edinburgh, United Kingdom (platelet factor 4 and -thromboglobulin);L. Petersen, Hvidovre, Denmark (alpha2-antiplasmin); L. Poller,Manchester, United Kingdom (activated partial-thromboplastintime); F.E. Preston, Sheffield, United Kingdom (euglobulin clot-lysistime); P.W. Straub, Bern (fibrinopeptide A); J. Verheijen, Leiden(t-PA activity); I. Juhan-Vague, Marseille (t-PA antigen); E.Kruithof, Lausanne, Switzerland (PAI-1); Laboratory Assay Committee:F. Duckert, Basel (chairman); J.J. Sixma, Utrecht, the Netherlands;J. Jespersen, Esbjerg, Denmark; R.M. Bertina, Leiden; D.S. Pepper,Edinburgh; L. Poller, Manchester; D.C. Rijken, Leiden; CentralAnalysis: R.M. Bertina, Leiden (protein C activity); J. Jespersen,Esbjerg (PAI-1); I. Juhan-Vague, Marseille (t-PA antigen, C-reactiveprotein); and Executive Committee: F. Duckert, Basel; F. Haverkate,Leiden; J. van de Loo, Münster (chairman); S.G. Thompson,London.
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[Abstract][Full Text]
-thromboglobulin and platelet factor 4. The state of the coagulation system was assessed by measurements of the activated partial-thromboplastin time, fibrinogen, fibrinopeptide A, von Willebrand factor antigen, factor VIII activity, antithrombin III antigen and activity, and protein C antigen and activity. The fibrinolytic system was assessed by the measurement of plasminogen, 
2-antiplasmin activity, histidine-rich glycoprotein, and plasminogen-activator inhibitor type 1 (PAI-1) antigen and activity. Tissue plasminogen activator (t-PA) antigen and activity, as well as the euglobulin clot-lysis time, were measured before and after 10 minutes of venous occlusion. 
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