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(Circulation. 1999;99:2908-2913.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Heightened Tissue Factor Associated With Tissue Factor Pathway Inhibitor and Prognosis in Patients With Unstable Angina

Hirofumi Soejima, MD; Hisao Ogawa, MD; Hirofumi Yasue, MD; Koichi Kaikita, MD; Koichi Nishiyama, MD; Kenji Misumi, MD; Keiji Takazoe, MD; Yuji Miyao, MD; Michihiro Yoshimura, MD; Kiyotaka Kugiyama, MD; Shin Nakamura, PhD; Ichiro Tsuji, PhD; Kousuke Kumeda, MSc

From the Division of Cardiology, Kumamoto University School of Medicine (H.S., H.O., H.Y., K. Kaikita, K.N., K.M., K.T., Y.M., M.Y., K. Kugiyama); the Department of Molecular and Cellular Biology, Primate Research Institute, Kyoto University (S.N.); and the Chemo-Sero Therapeutic Research Institute (I.T., K. Kumeda), Kumamoto, Japan.

Correspondence to Hisao Ogawa, MD, Division of Cardiology, Kumamoto University, School of Medicine, 1-1-1 Honjo, Kumamoto City 860-8556, Japan. E-mail ogawah{at}gpo.kumamoto-u.ac.jp

	Abstract

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Background—This study was designed to evaluate the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable angina and investigate whether there is a relationship between these levels and unfavorable outcome.

Methods and Results—The plasma TF and free TFPI antigen levels were determined in plasma samples taken from 51 patients with unstable angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The plasma TF and free TFPI antigen levels were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome group. There was a good correlation between TF and TFPI. We established borderline as maximum level in the patients with chest pain syndrome. Seven patients (of the 22 in the high TF group) required revascularization to control their unstable angina during in-hospital stay. On the other hand, only 1 of the 29 patients in the low TF group required myocardial revascularization. Four patients of the 14 patients in the high free TFPI group required myocardial revascularization during in-hospital stay, and 4 of the 37 patients in the low free TFPI group required myocardial revascularization. We compared the TF and free TFPI levels between the cardiac event (+) group and cardiac event (-) group. TF levels were significantly higher in the cardiac event (+) group than in the cardiac event (-) group.

Conclusions—We have demonstrated that not only the plasma TF levels but also the plasma-free TFPI levels are elevated in patients with unstable angina. Patients with unstable angina and heightened TF and free TFPI are at increased risk for unfavorable outcomes. The heightened TF level was a more important predictor in patients with unstable angina.

Key Words: angina • coagulation • plaque

	Introduction

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Tissue factor (TF) is a cell membrane associated glycoprotein that binds and acts as an essential cofactor for factor VIIa.¹ There are some reports demonstrating an association between TF and coronary artery diseases. It was reported that TF protein was expressed in directional atherectomy specimens from patients with unstable coronary syndromes but rarely in those from patients with stable angina.² We have also demonstrated that the expression of TF on macrophages is more frequent in coronary atherosclerotic plaques in patients with unstable angina than those with stable exertional angina.³ We also found that plasma TF levels are elevated in patients with unstable angina and myocardial infarction.^{4 5} Tissue factor pathway inhibitor (TFPI) regulates the initial step of the extrinsic coagulation pathway mediated by TF.⁶ Sandset et al demonstrated that the TFPI level increases in patients with acute coronary disease.⁷ Prothrombin fragment 1+2 (F1+2) is a polypeptide released from the amino terminal end of prothrombin during its conversion to thrombin.⁸ Previous studies showed that F1+2 was a useful marker of thrombin generation and hypercoagulable states.⁹ In this study, we investigated whether there is a relationship among the plasma TF and free TFPI antigen levels and the F1+2 concentrations in patients with unstable angina. Further, we investigated whether there is a relationship between TF, TFPI, and F1+2 levels and unfavorable outcome.

	Methods

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Study Population
We studied 162 patients who underwent diagnostic catheterization (99 men and 63 women, mean age±SD 66±9 years). Unstable angina was defined as chest pain at rest with documented transient ST segment depression or ST segment elevation of 0.1 mV in at least 2 continuous electrocardiographic leads. Fifty-one consecutive patients with unstable angina were included in this study. The last spontaneous attack was required to have occurred within 24 hours before entry into the study. Patients with new Q wave development or an increase in creatine kinase levels of more than twice the normal upper limit were excluded from the study. The stable exertional angina group consisted of 56 patients who had typical exertional chest discomfort associated with horizontal or down-sloping ST segment depression >1.0 mm on an exercise test. We confirmed by coronary arteriography that all patients with unstable angina and stable exertional angina had significant coronary artery stenosis. Patients with valvular heart disease, previous myocardial infarction, atrial fibrillation, malignancy, and age >80 years were also excluded. The chest pain syndrome group consisted of 55 patients who had atypical chest pain not accompanied by electrocardiographic changes and no coronary organic stenosis or no coronary spasm in response to an intracoronary injection of acetylcholine during coronary arteriography. Written informed consent was obtained from each patient. The study was in agreement with the guidelines approved by the ethics committee at our institution.

Blood Sampling
Blood samples for measuring the lipid concentrations and those for the free TFPI and TF antigen and F1+2 concentration assays were drawn. The samples were centrifuged immediately (4°C, 3000 rpm, 15 minutes) and stored at -80°C until analyzed. Venous blood samples from the patients with unstable angina were obtained on admission before the start of heparin administration and additional drugs because TFPI is rapidly released as free TFPI from the endothelial surface into the plasma by the administration of heparin.¹⁰ Repeated samplings were performed in all patients with unstable angina >1 week after the cessation of the heparin administration. Venous blood samples from patients with stable exertional angina were obtained on the morning following admission and about 2 weeks later, and those from the patients with chest pain syndrome were obtained on the morning following admission.

Plasma TF Antigen, Free TFPI Antigen, and F1+2 Assay
The plasma TF antigen levels were measured by ELISA kit (Sanko Junyaku Co.).¹¹ Sample buffer for this TF-ELISA contains Triton X-100 and EDTA to dissociate any TF from complex with VIIa, VIIa/Xa, or VIIa/Xa/TFPI, and hence current TF-ELISA is able to measure both types of TF, free and associated form. The plasma-free TFPI antigen levels were also measured by ELISA kit.¹² An enzyme immunoassay kit was used for measuring plasma F1+2 concentrations (Enzygnost F1+2, Behringwerke).¹³

Outcome Events
The outcome event was the occurrence of cardiac death, myocardial infarction, and the need for myocardial revascularization to control unstable angina during the in-hospital stay. The patients were also followed up for the occurrence of cardiac death, myocardial infarction, and unstable angina, which required re-admission after the discharge (17.0±6.5; range, 6 to 26 months).

Statistical Analyses
All data are expressed as mean±SD. Changes in the levels of plasma-free TFPI, TF antigen levels, and F1+2 concentrations on admission and after treatment were compared by paired t test. The comparisons of continuous data among the 3 patient groups were performed with 1-way ANOVA followed by Scheffé's F test. The frequency data were compared by the ² test. A linear regression analysis was used to determine the correlations between pairs of variables in the unstable angina group. P<0.05 was considered significant.

	Results

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Patient Characteristics
The clinical characteristics of each patient group are shown in Table 1. The unstable angina and stable exertional angina groups were matched for medications and extent of coronary artery disease. TF and TFPI can be influenced by age, sex, hyperlipidemia, diabetes mellitus, hypertension, smoking, and obesity. However, there were no significant differences in these variables among the 3 study groups.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics in the 3 Study Groups (Means±SD)

Assessment of Plasma TF, Free TFPI, F1+2 Levels
The plasma TF antigen levels were higher in the unstable angina group (238±54 pg/mL) than in the stable exertional angina (189±30 pg/mL) and chest pain syndrome groups (180±30 pg/mL, Figure 1). The plasma-free TFPI antigen levels and plasma F1+2 concentrations were also higher in the unstable angina group (39.2±11.2 ng/mL, 2.67±0.99 nmol/L, respectively) than in the stable exertional angina (27.7±6.0 ng/mL, 1.66±0.59 nmol/L, respectively) and chest pain syndrome groups (24.3±7.9 ng/mL, 1.40±0.46 nmol/L, respectively; Figure 1). The plasma TF, free TFPI, and F1+2 levels in the patients with unstable angina were decreased from admission to after treatment (213±51 pg/mL, 26.8±9.6 ng/mL, 1.69±0.67 nmol/L, respectively; Figure 2). In contrast, there were no significant changes by treatment in those levels of 52 of the patients with stable exertional angina (Figure 2). Repeated blood sampling was not performed from the 4 patients because they had chest pain attacks the day before the repeated sampling.

View larger version (25K): [in this window] [in a new window]   Figure 1. Left, Plasma tissue factor (TF) antigen levels in the 3 study groups. Middle, Plasma-free tissue factor pathway inhibitor (TFPI) antigen levels in the 3 study groups. Right, Plasma prothrombin fragment 1+2 (F1+2) concentrations in the 3 study groups.

View larger version (51K): [in this window] [in a new window]   Figure 2. Top left, Plasma TF antigen levels in unstable angina group on admission and after treatment; bottom left, plasma TF antigen levels in stable exertional angina group on admission and after treatment. Top middle, Plasma-free TFPI antigen levels in unstable angina group on admission and after treatment; bottom middle, plasma-free TFPI antigen levels in stable exertional angina group on admission and after treatment. Top right, Plasma F1+2 concentrations in unstable angina group on admission and after treatment. Bottom right, plasma F1+2 concentrations in stable exertional angina group on admission and after treatment. Abbreviations as in Figure 1.

Correlations Between Pairs of Variables
The correlation coefficients among the free TFPI and TF antigen levels and F1+2 antigen levels were calculated on admission in the all patients. There were good correlations between the plasma TF and free TFPI antigen levels, between the plasma TF antigen levels and F1+2 concentrations, and between the plasma F1+2 concentrations and free TFPI antigen levels (Figure 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. Left, Correlation between plasma TF antigen levels and free TFPI antigen levels. Middle, Correlation between plasma TF antigen levels and F1+2 concentrations. Right, Correlation between plasma F1+2 concentrations and free TFPI antigen levels.

Clinical Course During the Follow-Up Period
We followed up the 51 patients with unstable angina for the occurrence of outcome events during the follow-up period for 17.0±6.5 months. There were no cardiac events in patients with stable exertional angina and chest pain syndrome during the follow-up period. (We established borderline as maximum level in the patients with chest pain syndrome in each variable.) The patients with unstable angina were divided between high TF group (TF levels 250 pg/mL) and low TF group (TF levels <250 pg/mL). There were 7 patients who required myocardial revascularization in the high TF group to control their unstable angina during the in-hospital stay. Two patients had unstable angina requiring re-admission, 2 had acute myocardial infarction, 1 died after myocardial infarction, and 1 died after bypass surgery in the high TF group after the discharge. Thirteen of the 22 patients in the high TF group had coronary events during the follow-up period. On the other hand, only 3 of the 29 patients in the low TF group experienced coronary events during the follow-up period (Table 2).

View this table: [in this window] [in a new window]   Table 2. Comparison of High TF Group and Low TF Group in Patients With Unstable Angina (Mean±SD)

The patients with unstable angina were divided between high free TFPI group (free TFPI levels 45.0 ng/mL) and low free TFPI group (free TFPI levels <45.0 ng/mL). Nine of the 14 patients in the high free TFPI group had coronary events during the follow-up period. On the other hand, seven of the 37 patients in the low free TFPI group had coronary events (Table 3).

View this table: [in this window] [in a new window]   Table 3. Comparison of High Free TFPI Group and Low Free TFPI Group in Patients With Unstable Angina (Mean±SD)

The patients with unstable angina were divided between high F1+2 group (F1+2 levels 2.50 nmol/L) and low F1+2 group (F1+2 levels <2.50 nmol/L). Twelve of 25 patients in the high F1+2 group had coronary events during the follow-up period. On the other hand, 4 of 26 patients in the low F1+2 group had coronary events (Table 4).

View this table: [in this window] [in a new window]   Table 4. Comparison of High F1+2 Group and Low F1+2 Group in Patients With Unstable Angina (Mean±SD)

Sixteen patients had cardiac events during the in-hospital stay and after the discharge. We divided the patients with unstable angina between cardiac event (+) group and cardiac event (-) group. We compared the TF, free TFPI, and F1+2 levels between the cardiac event (+) group and cardiac event (-) group. There was a significant difference in TF level between cardiac event (+) group and cardiac event (-) group (Table 5). Each high variable and low variable group were matched for age, sex, coronary risk factors, length of follow-up period, and medications. The cardiac event (+) group and cardiac event (-) group were also matched for those characteristics.

View this table: [in this window] [in a new window]   Table 5. Comparison between Cardiac Event (+) Group and Cardiac Event (-) Group in Patients With Unstable Angina (Mean±SD)

	Discussion

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Recently, it has been reported that presence of TFPI in human atherosclerotic plaques is associated with reduced TF activity.¹⁴ This study showed that not only the plasma TF levels but also the free TFPI levels were increased in patients with unstable angina compared with those with stable exertional angina and chest pain syndrome. There was also a good correlation between the elevated TF and TFPI levels. Recently, Falciani et al also reported that unstable angina patients showed higher amounts of plasma TF and TFPI levels than patients with effort angina; a positive correlation was observed between plasma TF and TFPI levels.¹⁵ Ardissino et al found that plaques from patients with unstable angina or myocardial infarction had significantly greater concentrations of tissue factor antigen and activity than those from patients with stable angina, and that there was a close correlation between the amount of tissue factor antigen and tissue factor activity.¹⁶ We have previously demonstrated that the expression of TF was more frequent in the coronary atherosclerotic plaques of patients with unstable angina than those with stable exertional angina.³ In plasma, there are 2 types of TF: one is a membrane-bound form with potent procoagulant activity and the other is in soluble form with a faint procoagulant activity.¹¹ The circulating form of several receptors having transmembrane–domain-like TF was well known, although their generation mechanism into blood circulation was only partly deduced. The membrane form of TF is probably shed as a small vesicle that is generated from the cell surface of TF-expressing live cells.¹⁷ Other cases will be cellular fragmentation occurred during apoptosis or necrosis of dying TF-expressing cells. We reported that there is a good correlation between procoagulant activity and plasma membrane-bound TF levels in patients without renal dysfunction.¹¹ Furthermore, we observed a highly positive correlation between plasma TF levels and membrane-bound TF levels in other studies on unstable angina without renal dysfunction (S. Nakamura, PhD, unpublished observations, 1998). Therefore, it is suggested that the elevation of plasma TF level reflects the heightened TF activity (ie, heightened procoagulant activity) and the increase of membrane-bound TF from atherosclerotic lesions of unstable angina.

TFPI can be separated into free TFPI, lipoprotein-associated TFPI, and endothelial cell–associated TFPI. Total TFPI consists of free TFPI and lipoprotein-associated TFPI. TFPI is a protease inhibitor with K1, K2, and K3 domain, but K3 domain is masked in lipoprotein associated TFPI.¹² Therefore, it is thought that the anticoagulant activity of lipoprotein-associated TFPI is markedly lower than that of free TFPI.¹⁸ It has been shown that free TFPI antigen level is positively correlated with free TFPI activity, but the correlation of total TFPI antigen level with total TFPI activity is poor; free TFPI generally reflected the changes in endothelial cell–associated TFPI.¹⁹ Thus, we measured not total TFPI but the free TFPI antigen levels in the present study. We found that the plasma-free TFPI levels were elevated on admission and decreased after treatment in the patients with unstable angina. These changes may reflect the increase in endothelial cell–associated TFPI level in patients with unstable angina.

The plasma F1+2 concentrations were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome groups. A previous study also reported that the plasma F1+2 concentrations were higher in patients with angiographically verified coronary artery disease than in the subjects with normal coronaries.²⁰ In addition, the plasma F1+2 concentrations in the patients with unstable angina were improved after treatment. Our data show that there is an activation of the coagulation system in the acute phase of unstable angina. Lupu et al recently found that the exposure of endothelial cells to thrombin resulted in the release of TFPI.²¹ In the present study, the plasma F1+2 concentrations were closely correlated with the plasma-free TFPI levels. One mechanism of the elevation of plasma TFPI in patients with unstable angina may be associated with thrombin generation. There was also a good correlation between the plasma TF levels and plasma F1+2 concentrations in patients with unstable angina. This result is consistent with a pathological study which showed that fibrin deposition was associated with the infiltration of the TF-positive macrophages in patients with unstable angina.³ The increased plasma TF, TFPI, and F1+2 levels decreased in the patients with unstable angina after treatment but did not change in patients with stable exertional angina. There were no differences in medications and time intervals of 2 sampling points between the 2 patient groups, except for heparin administration. Because samplings on admission and after treatment were performed before the start of heparin administration and >1 week after the cessation of heparin, we think that there were no effects of heparin on the plasma TF, TFPI, and F1+2 levels in this study.

Previous studies have reported the prognostic importance of the increased levels of markers of thrombin generation in patients with unstable angina.²² Our study indicates that elevated levels of TF, free TFPI, and F1+2 are predictors of subsequent fatal and nonfatal cardiovascular events in patients with unstable angina. Merlini et al demonstrated that increased F1+2 levels in patients with acute coronary syndrome were associated with occurrence of outcome events.²² In our data, the patients with increased levels of F1+2 are at increased risk for unfavorable outcomes. The patients with unstable angina and increased levels of TF and free TFPI are also at increased risk for unfavorable outcomes. Sixteen patients had cardiac events during the in-hospital stay and follow-up period after discharge. We compared the levels of TF, free TFPI, and F1+2 between the cardiac event (+) group and cardiac event (-) group. The only heightened TF level was associated with poor prognosis in patients with unstable angina.

In conclusion, we have demonstrated that not only the plasma TF levels but also the plasma-free TFPI levels are elevated in patients with unstable angina when compared with patients with stable exertional angina and chest pain syndrome. The heightened TF and free TFPI levels probably reflects the increase of TF and TFPI activity in patients with unstable angina, respectively. Patients with unstable angina and heightened TF, free TFPI, and F1+2 levels are at increased risk for unfavorable outcomes. The heightened TF level among 3 factors was the most important predictor in patients with unstable angina.

	Acknowledgments

 
This study was supported in part by a Research Grant from Suzuken Memorial Foundation, Nagoya, Japan; a Research Grant from the Smoking Foundation; and a Research Grant for Cardiovascular Diseases (9A-3 and 10C-5) from the Ministry of Health and Welfare, Tokyo, Japan.

Received November 19, 1998; revision received March 9, 1999; accepted March 23, 1999.

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