Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Stroke Patients
Background and Purpose Abnormal endogenous fibrinolytic activity may be a risk factor for stroke. Since the possible variation of tissue-type plasminogen activator (TPA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen concentrations over time after stroke has been rarely studied, it was examined in plasma from stroke patients in the acute and convalescent phases of the disease and in a control group.
Methods Plasma concentrations of TPA and PAI-1 were determined in 135 stroke patients and in 77 control subjects. All but 4 patients were examined within 7 days after stroke onset, and 32 patients and 18 control subjects were reexamined 2 to 4 years later.
Results In the acute phase, stroke patients had significantly higher TPA (median, 10 μg/L) and PAI-1 (median, 14 μg/L) antigen concentrations, compared with control subjects (median values, 6 μg/L [P=.0001] and 8 μg/L [P<.01], respectively); TPA levels were higher in both the cerebral infarction (n=122) and cerebral hemorrhage (n=12) subgroups, whereas PAI-1 levels were higher in the cerebral infarction subgroup only. Stepwise logistic regression analysis (with correction for age, sex, history of hypertension, diabetes mellitus, and heart disease) showed TPA antigen level to be an independent discriminator between the cerebral infarction subgroup and control subjects (P=.0001), whereas the corresponding difference for PAI-1 antigen levels just failed to reach significance (P=.05). TPA antigen levels were correlated with concentrations of serum cholesterol (Spearman’s ρ=0.15; P<.05), serum triglyceride (ρ=0.33; P=.0001), and plasma homocysteine (ρ=0.19; P<.01). PAI-1 antigen levels were correlated with serum triglyceride levels only (ρ=0.41; P=.0001). At reexamination after 2 to 4 years, neither TPA nor PAI-1 levels had changed significantly from the baseline values.
Conclusions In stroke patients, high TPA antigen concentrations may indicate an activation of the fibrinolytic system or may be due to a delayed clearance of TPA complexed with inhibitors. High PAI-1 antigen concentrations in patients with cerebral infarction represent increased fibrinolytic inhibition. The findings in this longitudinal study suggest that TPA and PAI-1 antigen concentrations both differ little between the acute and convalescent phases after stroke.
The fibrinolytic defense system counteracts thrombus formation caused by fibrin deposits on the vessel endothelium. The proenzyme plasminogen is activated to plasmin by tissue-type plasminogen activator (TPA), which is synthesized by endothelial cells. Plasminogen activator inhibitor-1 (PAI-1), which is also produced by endothelial cells, inhibits the activity of TPA and thereby the fibrinolytic process. A low level of fibrinolytic activity has been shown to be a determinant of ischemic heart disease in younger men,1 and increased concentrations of PAI have been found in patients with myocardial infarction.2 On the contrary, low levels of PAI-1 activity have been reported in a population with an apparent absence of ischemic heart disease.3 These findings are consistent with the hypothesis that decreased intravascular fibrinolytic activity predisposes to ischemic vascular disease. In cerebrovascular disease the situation is unclear. Both normal4 and high5 levels of PAI-1 have been observed in the acute phase of stroke. High levels of releasable TPA have been reported in the convalescent phase after cerebral infarction.6 TPA antigen has been related to cardiovascular events in several studies.7 8 9 In a recent prospective study, high concentrations of TPA antigen were found to be related to increased risk of future stroke.10 Knowledge of the endogenous fibrinolytic activity and fibrinolytic inhibition in patients with acute cerebral infarction may decrease the risk for hemorrhagic complications in thrombolytic therapy.
Here we report the plasma TPA and PAI-1 antigen concentrations in patients in the acute and convalescent phases of stroke caused by cerebral hemorrhage or infarction, compared with findings in a control group.
Subjects and Methods
Patients and Control Subjects
From a consecutive series of 241 patients with stroke,11 defined as an acute focal neurological deficit lasting for more than 24 hours or leading to death from no cause other than cerebrovascular disease, 135 patients (123 with cerebral infarction and 12 with intracerebral hemorrhage) participated in this study. The 106 exclusions were due to heparin treatment or treatment with dicoumarol or warfarin for ≥2 days before blood sampling (n=34), no CT examination having been performed within 15 days after stroke onset or no autopsy performed (n=28), death before blood sampling (n=25), treatment somewhere other than the Department of Neurology or refusal to participate (n=10), and serious general condition including depressed consciousness (n=9).
The control group comprised 77 nonhospitalized subjects without stroke or transient ischemic attack, randomly selected from the local population register as described earlier.12 The study design was approved by the Ethics Committee of the University of Lund. Informed consent to participate was given by all subjects (or relatives if the patients were unable to communicate).
Cerebral hemorrhage or infarction was diagnosed with CT or autopsy. Clinical subtyping of cerebral infarction was based on the Oxfordshire Community Stroke Project (OCSP) classification13 as described earlier11 : (1) total anterior circulation infarcts—both cortical and subcortical symptoms from anterior and middle cerebral artery territories; (2) partial anterior circulation infarcts—more restricted and predominantly cortical symptoms from the same arterial territories; (3) lacunar infarcts—lacunar syndromes in anterior, middle, or posterior cerebral or vertebrobasilar artery territories, including sensorimotor lacunar syndrome; and (4) posterior circulation infarcts—vertebrobasilar or posterior cerebral artery symptoms. Cortical involvement of the cerebral lesion was considered to be present if the patient manifested total or partial anterior circulation infarct syndrome.
Hypertension, diabetes mellitus, and heart disease were considered to be present if the patient was receiving medical treatment for these diseases at the time of investigation. In addition, a history of heart disease was considered to be present if the patient had previously received medical or surgical treatment for heart disease.
Brain Imaging, Carotid Artery, and Heart Examinations
Of the 135 patients, 133 were examined with CT of the brain within 15 days after stroke onset, and 2 were examined with autopsy only. All control subjects were examined with CT or MRI of the brain.12 Of the 123 patients with cerebral infarction, 118 underwent sonography of the carotid arteries and 109 echocardiography of the heart.14
Because the levels of both TPA antigen and PAI-1 activity are characterized by a diurnal variation,15 16 fasting blood samples were taken between 7:30 and 9:30 am. Blood samples were drawn from patients within 7 days (median, 2 days) after acute stroke onset in 131 patients. The remaining 4 patients (3 with cerebral infarct and 1 with cerebral hemorrhage) had blood samples taken 7 to 18 days after stroke onset. Blood was drawn after at least 10 minutes of rest in the recumbent position. The first 5 mL of blood was discarded and the next 9 mL collected in Diatube H tubes (Diagnostica Stago) that contained 0.109 mmol of sodium citrate and inhibitors of platelet aggregation (theophylline, adenosine, and dipyridamole). The samples were immediately centrifuged at 2000g for 20 minutes, and the recovered plasma was frozen at −70°C until analyzed. Plasma concentrations of TPA antigen were measured with an enzyme-linked immunosorbent assay (Imulyse t-PA, Biopool), which also detects TPA in complex with specific inhibitors (eg, PAI-1); intra-assay variation was ±8%, and interassay variation was ±10%. Plasma concentrations of PAI-1 antigen were also measured with an enzyme-linked immunosorbent assay (Imulyse PAI-1, Biopool), which detects both active and latent forms of PAI-1, although complexes (eg, with TPA) are poorly detected; intra-assay variation was ±5%, and interassay variation was ±11%.
Plasma homocysteine levels were determined as described previously.17 Serum cholesterol and triglyceride concentrations were measured with standard laboratory methods. Survival status was determined 3 to 4 years after stroke onset, and baseline TPA and PAI-1 antigen levels were compared for deceased patients and survivors.
Of the 135 patients originally examined, 32 were also reexamined and TPA and PAI-1 antigen levels determined 3 to 4 years after stroke onset. Reexamination was not performed in 103 patients for the following reasons: death (n=65), not answering when telephoned (n=13), severe general condition or transportation problems (n=9), receiving anticoagulation treatment (n=7), technical problems in laboratory analysis (n=6), and refusal to participate (n=3). To allow comparison, 18 control subjects were also reexamined 2 to 4 years after the original examination.
Because TPA and PAI-1 antigen concentrations were not uniformly distributed, median values and the Mann-Whitney U test were used for comparison of patient and control groups. Differences between patients and control subjects for nominal scale variables were assessed with the χ2 test. Spearman’s ρ was applied to test for correlation between continuous variables. Kruskal-Wallis one-way ANOVA was used for comparison of cerebral infarction subtypes and continuous variables without normal distribution (eg, TPA and PAI-1). The Wilcoxon signed-rank test was used for comparison of baseline and follow-up results. P<.05 was considered significant. Patients with cerebral infarction manifesting cortical symptoms (ie, total or partial anterior circulation infarcts) were compared with those with lacunar infarcts. The possibility of correlation between the occurrence of carotid artery or heart disease and either TPA or PAI-1 antigen concentrations was investigated. Stepwise logistic regression analysis (with SPSS software, SPSS Inc) was used to study the influence of TPA or PAI-1 antigen concentrations in patients and control subjects after correction for age, sex, current smoking, history of hypertension, heart disease, and diabetes mellitus.
Stroke Patients Versus Control Subjects
Median age was 76 years (mean, 75.2 years; range, 38 to 98) in the patient group (n=135) and 66 years (mean, 64.5 years; range, 36 to 95) in the control group (n=77) (P=.0001, Mann-Whitney U test). We found no statistically significant difference between patients and control subjects regarding sex distribution, hypertension, or current smoking. Demographic data for patients and control subjects are shown in Table 1⇓.
The median TPA antigen concentration was 10 μg/L for the patient group and 6 μg/L for the control group (P=.0001). The upper 90th percentile for TPA in the control group was 11 μg/L. Fifty-three of the patients (40%) had TPA antigen concentrations above this level (P=.0001, χ2 test, compared with control subjects). The median PAI-1 antigen concentration was 14 μg/L for the patient group and 8 μg/L for the control group (P<.01). The upper 90th percentile for PAI-1 in the control group was 24.6 μg/L. Thirty-three of the patients (24%) had PAI-1 antigen concentrations above this level (P<.05, χ2 test, compared with control subjects). TPA and PAI-1 antigen levels were correlated (Spearman’s ρ=.47; P=.0001). The distributions of TPA and PAI-1 antigen levels in patients and control subjects are shown in Figs 1⇓ and 2⇓.
Patients with cerebral infarction and control subjects were divided into three age groups: <55 years, 55 to 74 years, and ≥75 years. TPA antigen levels were significantly higher among patients with cerebral infarction than among control subjects in all three age groups, whereas PAI-1 antigen levels differed only in the ≥75-year age group.
To ascertain whether patients with cerebral infarction differed from control subjects regarding vascular risk factors, stepwise logistic regression analysis of the data was performed. Compared with controls, this patient group was characterized by higher age (P=.0001), higher prevalences of diabetes mellitus (P<.001) and heart disease (P<.05), and higher TPA antigen levels (P=.0001). Thus, even after controlling for age, TPA antigen concentrations differed significantly between patients with cerebral infarction and control subjects. If TPA was exchanged for PAI-1 in the statistical model, the patients were older (P=.0001) and there were higher prevalences of diabetes mellitus (P=.0001) and heart disease by history (P<.01), but the difference in PAI-1 antigen concentrations just failed to reach significance (P=.05).
Cerebral Infarction Versus Intracerebral Hemorrhage
The cerebral infarction subgroup (n=123) did not differ from the intracerebral hemorrhage subgroup (n=12) in median TPA antigen concentrations (10 versus 10 μg/L) or PAI-1 antigen concentrations (14 versus 11.5 μg/L). Compared with control subjects, TPA antigen levels were higher in both the cerebral infarction (n=122) and cerebral hemorrhage (n=12) subgroups, whereas PAI-1 antigen levels were higher in the cerebral infarction subgroup only (n=123, Table 2⇓).
Cerebral Infarction Subgroups
The clinical subgroups of cerebral infarction, according to the OCSP classification,13 did not differ significantly from each other in TPA or PAI-1 antigen concentrations (Table 3⇓). Patients with cerebral infarction manifesting cortical symptoms did not differ from those with lacunar infarcts regarding TPA and PAI-1 antigen concentrations.
Levels of TPA and PAI-1 in Relation to Other Vascular Disease Risk Factors
TPA antigen concentrations correlated with age in control subjects (Spearman’s ρ=.25; P<.05) but not in patients. When patients and control subjects were taken together, TPA antigen levels were higher in individuals with diabetes mellitus (n=24; median, 10.5 μg/L) than in those without diabetes mellitus (n=187; median, 8 μg/L; P<.05). Individuals with a history of heart disease (n=72) also had higher TPA antigen levels (median, 10 μg/L) than those without heart disease (n=139; median, 8 μg/L; P<.01). TPA antigen levels were correlated with concentrations of serum cholesterol (Spearman’s ρ=.15; P<.05), serum triglyceride (ρ=.33; P=.0001), and plasma homocysteine (ρ=.19; P<.01). There was no correlation between TPA antigen levels and sex, current smoking, or history of hypertension. When homocysteine, cholesterol, and triglyceride levels were entered into the stepwise logistic regression model, TPA antigen was still an independent discriminator between stroke patients and control subjects.
PAI-1 antigen levels were correlated with serum triglyceride levels (ρ=0.41; P=.0001) but not to any of the other potential stroke risk factors mentioned above. In patients with cerebral infarction, there were no relationships between TPA or PAI-1 antigen concentration and carotid artery stenosis ≥50% or ≥80%, atrial fibrillation, or major potential cardiac embolic sources on echocardiography.
Survival status 3 to 4 years after stroke onset did not correlate with baseline levels of TPA or PAI-1 antigen, median baseline TPA antigen levels of 10.5 μg/L in the stroke survivor group (n=68) and 9 μg/L in the deceased patient group (n=65), or their respective median PAI-1 antigen levels of 14.5 and 12 μg/L.
There was no correlation between the time (ie, number of days after stroke onset) of blood sampling in the acute phase of stroke and the TPA or PAI-1 antigen concentrations (Spearman’s ρ).
Reexamination of Patients and Control Subjects
At reexamination, neither TPA nor PAI-1 antigen levels had changed significantly (Wilcoxon signed-rank test) from baseline values in patient or control groups (Table 4⇓), although there were individual variations in both groups. The concentrations of TPA antigen differed significantly between patients and control subjects at follow-up, but concentrations of PAI-1 antigen did not.
The TPA antigen assay used in our study detects both TPA and TPA in complex with PAI-1. The PAI-1 antigen assay detects both active and latent forms of PAI-1 but not PAI-1 in complex with TPA.
Our finding that TPA antigen and PAI-1 antigen levels are high in patients in the acute phase of ischemic stroke is in agreement with findings in some5 but not all4 previous studies. We found no significant changes over time in the subset of patients reexamined for TPA and PAI-1 antigen concentrations, nor did we find any differences between clinical subgroups of cerebral infarction. We are not aware of any earlier studies in which TPA antigen concentrations were measured in the same individuals in both the acute and convalescent phases after stroke.
The clinical importance of altered fibrinolytic activity in acute stroke is unclear. The reported finding that fibrin formation may greatly exceed endogenous fibrinolysis during the acute phase of ischemic stroke18 may indicate that the acute stroke phase is an acute hypercoagulable state. Two main possibilities need to be considered: Altered fibrinolytic activity may be (1) an acute-phase reaction, either specific, reflecting certain types of acute vascular events, or unspecific due to general stress, or (2) a cerebrovascular risk factor already present before stroke onset.
(1) Acute-Phase Reaction
Both TPA and PAI-1 antigens have been suggested to be acute-phase reactants. The acute-phase behavior of PAI-1 has been proposed to be due in part to increased synthesis by the liver19 ; levels of the acute-phase proteins fibrinogen and C-reactive protein, which are synthesized in the liver, have been found to correlate with those of TPA antigen and total PAI-1 antigen in patients with angina pectoris.20 A relationship has also been reported between orosomucoid levels and TPA and PAI-1 levels in patients with autoimmune thrombocytopenia or hemolytic anemia; the conclusion was drawn that hemostatic factors of the vessel wall may be involved in a wide spectrum of diseases.21
However, it is possible that the acute-phase increases of TPA and PAI-1 are very short. Thus, in one study TPA and PAI-1 levels increased immediately after intracranial surgery but returned to baseline values within 24 hours.22 A similar rapid increase followed by a decrease of TPA and PAI-1 antigen levels has been reported after aortic graft surgery, in which both TPA and PAI-1 antigen levels increased immediately after surgery but on postoperative day 1 did not differ significantly from preoperative levels.23 In our study the early rapid increases of TPA and PAI-1 antigen were probably undetected because most of the blood samples were collected 1 to 3 days after stroke onset. Because stroke is also an acute event followed by a convalescent phase, the findings of these surgical studies may have an implication for the interpretation of our findings. Therefore, it is possible that the increased TPA and PAI-1 antigen levels found by us were not due to an acute-phase response.
Our follow-up examination of stroke patients 3 to 4 years after stroke indicates that TPA and PAI-1 levels measured in the acute phase may be similar to those seen later on. Our results are in accord with earlier findings in the chronic phase after stroke.24 A recent study showed the level of PAI-1 activity to be increased in 45 survivors of myocardial infarction, whereas C-reactive protein and fibrinogen levels were lower than those in 54 acute-phase patients with noncardiac disease.25 It was concluded that the increased PAI-1 activity in the patients with earlier myocardial infarction was not due to a prolonged acute-phase reaction.25 One limitation of our study is that only 32 of the 135 patients were reexamined, mainly because almost half of the original study population had died during the 3 to 4 years of follow-up. Selection factors may have been important in this process. Our finding of increased TPA antigen concentrations also in the chronic phase after stroke therefore needs to be confirmed by other studies.
(2) Altered Fibrinolytic Activity as a Vascular Risk Factor
Increased fibrinolytic activity reduces the risk of thrombus formation, and the level of PAI-1 activity has been reported to be low in a population with an apparent absence of stroke and ischemic heart disease.3 A low level of endogenous fibrinolytic activity may be a risk factor for vascular disease. The Northwick Park Heart Study of 1382 men aged 40 to 64 years found the level of fibrinolytic activity (measured as dilute blood clot lysis time) to be low in a subset of 179 individuals with subsequent ischemic heart disease.1
In patients with cerebral infarction, increased levels of TPA antigen (which may be considered a marker of high PAI-1 concentration26 ) and PAI-1 antigen may represent a low level of endogenous fibrinolytic capacity with a consequent predisposition to thrombus formation. The prospective US Physicians Health study of men aged 40 to 84 years showed the mean baseline TPA antigen level to be higher in 88 individuals (11.14 ng/mL) who later developed stroke compared with 471 age-matched control subjects who remained free of cardiovascular disease (9.59 ng/mL; P=.03).10 These results did not change substantially after controlling for hypertension, diabetes mellitus, smoking, and body mass index and were considered to suggest that TPA antigen is an independent marker of stroke risk.
The present study showed high TPA antigen levels in patients in both the acute and convalescent phases of ischemic stroke. Our findings are in accord with those of earlier studies5 24 and also show that high TPA antigen levels can be found in the same group of individuals examined in either the acute or convalescent phase after stroke. The observed correlation between TPA antigen and cholesterol, triglyceride, and homocysteine concentrations may suggest that TPA is only a marker for other possible cerebrovascular risk factors. However, even after correction for these possible risk factors as well as for age, current smoking, history of hypertension, diabetes mellitus, and heart disease, in a stepwise logistic regression model, TPA antigen levels still differed significantly between stroke patients and control subjects. Thus, in all likelihood TPA antigen is an independent marker of increased risk of stroke.
Measurements of Fibrinolytic Activity
Several different methods have been used to measure fibrinolytic activity. Clot lysis time and d-dimer levels—one of the fibrin degradation products (which can also be measured collectively)—may be used to assess the degree of fibrin breakdown. Other suggested measurements of the fibrinolytic system in stroke include α2-plasmin inhibitor/plasmin complex (considered to be an indicator of plasmin generation27 ), plasminogen (with no consistent changes after stroke5 ), protein C28 (which may neutralize circulating PAI but has an uncertain role in acute cerebrovascular disease5 ), and releasable TPA (which is released after venous stasis6 ).
The level of TPA activity, which represents the fibrinolytic activity caused by TPA, can be measured directly, whereas TPA antigen mainly reflects TPA in complex with PAI-1. Therefore, increased TPA antigen levels may indicate reduced (and not increased) endogenous fibrinolytic activity,26 29 and TPA antigen levels may be a marker for vascular disease in general. An alternative explanation may be that TPA antigen levels are high in individuals predisposed to cerebrovascular disease, because the endothelial cells respond to an ongoing pathological process in the vessel wall.30
PAI-1 antigen levels may represent total PAI-1 antigen levels including PAI-1 in complex with TPA or, as in our study, only PAI-1 that is not complex bound. Increases in both PAI-1 activity and PAI-1 antigen are considered to indicate decreased fibrinolytic activity.
TPA antigen has less circadian variation and lower day-to-day variability31 than measurements of TPA and PAI-1 activity. Because simple, easily usable assays for TPA antigen and PAI-1 antigen are available and a relation of TPA antigen to risk of future stroke has been reported,10 the measurements of TPA and PAI-1 antigen in stroke patients are considered appropriate.
The control group was younger and had diabetes mellitus and heart disease less frequently than the stroke patients, which is a limitation of our study. We have adjusted for this difference between patients and control subjects by including age, cholesterol level, triglyceride level, prevalence of diabetes mellitus, hypertension, and heart disease in stepwise logistic regression analyses. We also divided patients with cerebral infarction and control subjects into three age groups and compared the TPA and PAI-1 antigen levels within the age groups. Even after these corrections, TPA antigen levels differed between patients and control subjects.
Acute-phase indicators such as C-reactive protein were not analyzed in our study. We therefore cannot make a conclusion about the importance of these indicators in stroke patients. It is recommended that in future studies of acute stroke patients acute-phase indicators be compared with concentrations of TPA and PAI-1 antigen.
The fibrinolytic system is often altered in patients with stroke in both the acute and convalescent phases, which may be of importance for understanding pathogenetic mechanisms of both cerebral hemorrhage and cerebral infarction. Although TPA and PAI-1 antigen levels may be increased as an acute-phase reaction, this increase is often of very short duration, and our follow-up results show that increases in TPA antigen among stroke patients cannot be explained as being due solely to an acute-phase reaction. Accumulated evidence suggests that elevated TPA antigen levels may indicate an increased risk of stroke. However, TPA antigen levels need to be further correlated with the traditional stroke risk factors. Further studies of fibrinolytic activity in different phases after stroke are needed.
This study was supported by the Rut and Erik Hardebo Donation Fund, the Elsa Schmitz Foundation, the 1987 Foundation for Stroke Research, the Medical Faculty of the University in Lund, the Swedish Association for the Neurologically Disabled (Neurologiskt Handikappadcs Riksförbund), the Swedish Medical Research Council (grant No. 04523), and the Swedish Heart and Lung Foundation. Advice on statistics was given by Eva Kelty of Clinical Data Care AB.
Presented in part at the 4th International Symposium on Thrombolytic Therapy in Acute Ischemic Stroke, Copenhagen, Denmark, May 30-June 1, 1996.
- Received October 23, 1995.
- Revision received February 8, 1996.
- Accepted March 5, 1996.
- Copyright © 1996 by American Heart Association
Lindeberg S, Carlsson R, Berntorp E. Haemostatic variables in Trobriand Islanders apparently free from stroke and sudden coronary death—the Kitava study. In: Lindeberg S. Apparent absence of cerebrocardiovascular disease in Melanesians. Lund University, Sweden: Department of Community and Health Sciences; 1994:193-221. Doctoral dissertation.
ECAT Angina Pectoris Study Group. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J. 1993;14:8-17.
Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J. 1991;12:157-161.
Lindgren A, Norrving B, Rudling O, Johansson BB. Comparison of clinical and neuroradiological findings in first-ever stroke: a population-based study. Stroke. 1994;25:1371-1377.
Lindgren A, Roijer A, Rudling O, Norrving B, Larsson E-M, Eskilsson J, Wallin L, Olsson B, Johansson BB. Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke: a population-based study. Stroke. 1994;25:929-934.
Lindgren A, Roijer A, Norrving B, Wallin L, Eskilsson J, Johansson BB. Carotid artery and heart disease in subtypes of cerebral infarction. Stroke. 1994;25:2356-2362.
Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1). Circulation. 1989;79:101-106.
Lindgren A, Brattström L, Norrving B, Hultberg B, Andersson A, Johansson BB. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke. 1995;26:797-800.
Feinberg WM, Bruck DC, Ring ME, Corrigan JJ Jr. Hemostatic markers in acute stroke. Stroke. 1989;20:592-597.
Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serradimigni A, Collen D. Plasma plasminogen activator inhibitor-1 in angina pectoris: influence of plasma insulin and acute-phase response. Arteriosclerosis. 1989;9:362-367.
Tohgi H, Takahashi H, Chiba K, Tamura K. Coagulation-fibrinolysis system in poststroke patients receiving antiplatelet medication. Stroke. 1993;24:801-804.
de Bono D. Significance of raised plasma concentrations of tissue-type plasminogen activator and plasminogen activator inhibitor in patients at risk from ischaemic heart disease. Br Heart J. 1994;71:504-507.
Tohgi H, Kawashima M, Tamura K, Suzuki H. Coagulation-fibrinolysis abnormalities in acute and chronic phases of cerebral thrombosis and embolism. Stroke. 1990;21:1663-1667.
Kluft C. Constitutive synthesis of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1): conditions and therapeutic targets. Fibrinolysis. 1994;8(suppl 2):1-7.