© 1996 American Heart Association, Inc.
Articles |
Factor VII Hyperactivity and Endothelial Cell Damage Are Found in Elderly Hypertensives Only When Concomitant With Microalbuminuria
From the Department of Internal Medicine (K.K.), Awaji-Hokudan Public Clinic, Hokudan, Hyogo; the Department of Internal Medicine (K.K., T. Matsuo) and Central Laboratory (H.K., M.M.), Hyogo Prefectural Awaji Hospital, Sumoto; Clinical Laboratory (T.S.) and Research Institute (T. Miyata), National Cardiovascular Center, Suita, Osaka; and the Department of Cardiology (K.S.), Jichi Medical School, Tochigi, Japan.
Correspondence to Kazuomi Kario, MD, 480-2, Ikuha, Hokudan, Tsuna, Hyogo, 656-16, Japan.
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Abstract |
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Abstract We studied the relationships among albuminuria, factor VII (FVII) hyperactivity, and endothelial cell damage in 61 elderly hypertensive subjects. The plasma levels of activated FVII (FVIIa), FVII coagulant activity, FVII antigen (FVIIag), von Willebrand factor (vWF), and thrombomodulin were measured to assess FVII hyperactivity and endothelial cell damage, and urinary albumin excretion rate (UAE) was calculated using 12-hour nighttime (7 PM to 7 AM) urine collection (mean for 2 consecutive nights). We performed 24-hour ambulatory blood pressure monitoring in all 61 hypertensive patients and classified them into a white-coat hypertension group (n=12) and a sustained hypertension group (n=49). For the levels of FVII, vWF, and thrombomodulin, there were no differences between the white-coat hypertension group and normotensive control subjects (n=25). In the sustained hypertensive group, only the microalbuminuric subgroup (UAE, 15 to 300 µg/min: n=30) showed significant elevation compared with the normotensive group for the level of FVIIa (mean [95% confidence interval]: 4.0 [3.6 to 4.4] versus 3.0 [2.6 to 3.3] ng/mL, P<.001), the FVIIa/FVIIag ratio (an indicator of activation of FVII zymogen to FVIIa) (1.33 [1.19 to 1.50] versus 1.04 [0.92 to 1.19], P<.01), the level of vWF (188 [165 to 214] % versus 144 [129 to 160] %, P<.01), and thrombomodulin (11.7 [10.3 to 13.3] versus 9.3 [8.5 to 10.3] ng/mL, P<.01). In contrast, none of these levels in the normoalbuminuric hypertensive group (UAE <15 µg/min, n=19) differed from that in the normotensive control group. These results suggest that among elderly hypertensives, only those with microalbuminuria show enhancement of FVII activation and endothelial cell damage, while patients with white-coat hypertension and normoalbuminuric hypertensives do not show these accompanying abnormalities. Thus, increased levels of FVII activity and markers of endothelial cell damage might account for the higher risk of cardiovascular events in essential hypertension with microalbuminuria.
Key Words: factor VII • endothelial cell damage • hypertension • microalbuminuria • elderly
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Recently, hemostatic abnormalities have been recognized as a risk factor for cardiovascular disease.1 However, there have been only a few studies on hemostatic abnormalities in hypertension, and their results were not all consistent. Some authors have reported that plasma levels of fibrinogen, FVII, and plasminogen activator inhibitor-1 are increased in hypertension,2 3 while others have noted contradictory findings.4 Microalbuminuria, defined as increased UAE, is often present in patients with essential hypertension and is associated with an increased risk of cardiovascular mortality and morbidity in nondiabetic individuals.5 6 7 However, the mechanisms and implications of microalbuminuria in relation to essential hypertension have not been as clearly elucidated as they have in relation to diabetes mellitus. Lipid abnormalities, cardiac hypertrophy, hyperinsulinemia, and endothelial cell damage are reported as factors confounding the influence of microalbuminuria on cardiovascular events in hypertension.4 8 9 Concerning the role of hemostatic abnormalities in hypertension, in only one of the previous studies4 were hemostatic abnormalities assessed along with the UAE, and in none was the 24-hour ambulatory BP monitored to exclude patients with white-coat hypertension, whose BP is persistently elevated when measured in the physician's office or clinic but normal at other times, in whom target organ damage is not necessarily related to the office BP.7 10 11 12
FVII plays an important role in initiation of the tissue factor–induced coagulation pathway.13 An increase of FVIIc has been proposed as an independent cardiovascular risk factor and has been observed in various atherosclerotic diseases.1 14 15 16 17 18 19 At sites of vascular injury, tissue factor (an integral membrane protein) comes into contact with circulating FVII and forms a bimolecular complex. Formation of this complex is widely believed to be the initial event in the tissue factor–induced coagulation pathway. A direct assay for plasma FVIIa that is not affected by interference from the zymogen form of FVII has recently been developed using soluble tissue factor.20 21 22 Normal individuals have trace levels of circulating FVIIa (0.5% to 1% of the total FVII antigen level),20 21 22 and these trace amounts of circulating FVIIa may initially activate FVII complexed with cell-surface tissue factor. Thus, an increase of plasma FVIIa levels may indicate hypercoagulability related to the early phase of tissue factor–induced coagulation (FVII hyperactivity). Our recent cross-sectional studies have disclosed that FVIIa levels are more closely related than are FVIIc levels to cardiovascular disease and microalbuminuria in diabetic patients.22 23 24
vWF is a glycoprotein stored in endothelial cells and secreted into the circulation,25 while thrombomodulin is a membrane glycoprotein expressed on the surface of endothelial cells, where it is an important cofactor in the thrombin-catalyzed activation of protein C. Soluble thrombomodulin is also present in human plasma, probably owing to proteolysis.26 Although their release mechanisms from endothelial cells are different, vWF and thrombomodulin have been reported to show increase paralleling the degree of endothelial cell damage both in vitro and in vivo.4 27 28 29 30 Thus, the plasma levels of vWF and thrombomodulin are widely used as indicators of endothelial cell damage,4 27 28 29 and these levels were reported to be increased in diabetic patients with microalbuminuria.27 29
The purpose of the present study using 24-hour ambulatory BP monitoring in elderly outpatients with essential hypertension was to clarify the status of FVII hyperactivity, assessed by the plasma FVIIa level, and of endothelial cell damage, as reflected by increased vWF and/or thrombomodulin levels, and their relationship with microalbuminuria.
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Methods |
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Subjects
We studied 61 hypertensive outpatients aged >60 years, in whom office SBP>160 mm Hg and/or office DBP>95 mm Hg had been recorded after measurement on three or more occasions. The office BP was measured in the sitting position using an automated sphygmomanometer (BP103N-II, Nippon Colin Co, Ltd) after the patient had rested for at least 5 minutes. The patients previously treated with antihypertensive medication were 4 (33%) of the 12 with white-coat hypertension, 6 (32%) of the 19 with normoalbuminuric hypertension, and 9 (30%) of the 30 with microalbuminuric hypertension, and there were no significant differences of the prevalence in each group. None of the patients had received any antihypertensive medications for at least 1 month before this study. All of the subjects were ambulant and had a normal appetite. The results of physical examination and laboratory studies (blood and urine tests, chest x-ray, and resting electrocardiography) were normal or consistent with World Health Organization hypertensive stages I and II. Patients with renal failure and hepatic damage (serum creatinine >1.5 mg/dL, blood urea nitrogen >30 mg/dL, or aspartate aminotransferase or alanine aminotransferase >40 IU/L), as well as obvious present or previous coronary artery disease, stroke, congestive heart failure, or malignancy, were excluded from this study. Patients who possibly had diabetes mellitus (fasting glucose >100 mg/dL or hemoglobin A1c >6.2%) were also excluded. Neither the studied subjects nor their family members had any history of venous thrombosis or pulmonary embolism. Twenty-five normotensive healthy individuals without microalbuminuria (matched for age and sex) were also studied, as controls. Smokers and nonsmokers were defined by their current smoking status. The body mass index was calculated as the weight (kg)/height squared (m)2.
ECG-LVH in the hypertensive patients was graded into two classes31 : It was defined as abnormally high QRS voltages (R in V5 plus S in V1 >3.5 mV) associated either with flat T waves (<10% of R) or with ST segment depression (>0.1 mV) and diphasic T waves. None of the subjects showed the more severe grade of ECG-LVH characterized by a prolonged ventricular activation time, depressed downsloping ST segments, and asymmetrically inverted T waves in the left precordial leads. The patients with normal ECG findings and those with high-voltage QRS complexes alone were in each instance defined as not having ECG-LVH.
24-Hour BP Monitoring
Noninvasive ambulatory BP monitoring
was carried out on a
weekday using an automatic ambulatory BP monitor with gas-powered
cuff inflation (ABPM-630, Nippon Colin Co), which recorded the BP
and heart rate every 30 minutes for 24 hours. The accuracy of this
device has previously been validated.32 The ambulatory BP
data used in the present study were obtained with the oscillometric
mode of this device.11 32 Subjects recorded a daily
action profile from which information about the precise times of
sleeping and waking was obtained. The onset of sleep was identified as
the time that the subject went to bed. The mean (95% confidence
interval) duration of sleep was 8.0 (7.6 to 8.3) hours. In three
hypertensive patients and one control subject, the initial BP data were
rejected because of artifacts in more than 10% of the total
measurements, but the examination was repeated and the second set of BP
data was included in the analysis. Individuals with disturbed
sleep (frequent nocturnal awakening) were not included in this
study.
Patient Classification by 24-Hour Ambulatory BP Monitoring
and UAE
The ambulatory BP criteria were set somewhat arbitrarily, as
there are no well-defined standards. On the basis of previously
reported ambulatory BP data for normal subjects,33 the 61
hypertensive patients were classified into 12 with white-coat
hypertension (mean 24-hour SBP and 24-hour DBP<135/80 mm Hg) and 49
with sustained hypertension (mean 24-hour SBP and 24-hour DBP
135/80
mm Hg).
To control for the influence of daily physical activity and to facilitate uniformity of urine collection, we asked the patients to collect urine on 2 consecutive days between 7 PM and 7 AM for urinary albumin measurement. The 49 hypertensive patients were divided into the following two groups on the basis of the UAE: 19 patients in the normoalbuminuric group, with UAE<15 µg/min, and 30 in the microalbuminuric group, with UAE of 15 to 300 µg/min.
Laboratory Tests
After a minimum 12-hour fasting period,
blood samples for
hemostatic determinations were collected into disposable siliconized
vacuum glass tubes containing 0.1 vol of 3.8% trisodium citrate, and
blood from the second tube was used for the coagulation assay. Samples
were centrifuged at 3000g for 15 minutes at room
temperature within 1 hour of collection to separate plasma, which was
stored in plastic tubes at -80°C until laboratory
determinations were performed.
FVIIa levels were measured by a fluorogenic assay employing a fluorogenic peptide substrate for thrombin (N-tert-butoxycarbonyl-Val-Pro-Arg-4-methylcoumaryl-7-amide), congenital human FVII-deficient plasma (George King Bio-Medical), and recombinant soluble human tissue factor (residues 1 to 217), as described previously.22 Human plasma FVIIa for use as the standard was kindly provided by the Chemo-Sero-Therapeutic Research Institute. Soluble human tissue factor was expressed in yeast and purified according to the previously reported method.34 FVIIc was measured with a chromogenic assay autoanalyzer (Behring Chromotimer, Behringwerke AG), using a human placental calcified thromboplastin reagent (Chromoquick, Behringwerke AG) and immunoadsorbed FVII-deficient plasma (Behringwerke AG). FVIIag was determined with an enzyme-linked immunosorbent assay (ELISA) kit (Diagnostica Stago). Fibrinogen levels were determined with a one-stage clotting assay kit, Data-Fi. The plasma levels of vWF and thrombomodulin were determined with ELISA kits (Diagnostica Stago and Teijin Co Ltd, respectively). For FVIIc, FVIIag, and vWF assay, the value for commercially available pooled plasma (CTS Standard Plasma, Behringwerke AG) was taken as 100%. The FVIIa/FVIIag ratio was calculated as an indicator of the extent of activation of FVII zymogen to FVIIa by taking the mean plasma FVIIa level in young Japanese control subjects (2.1 ng FVIIa per milliliter) as 100%.22
Concerning lipid profiles, we measured the five lipid parameters of total cholesterol and its major apolipoprotein (apolipoprotein B), HDL cholesterol and its major apolipoprotein (apolipoprotein A-I), and lipoprotein(a), which are proposed as cardiovascular risk factors. Serum total cholesterol and triglyceride levels were determined using commercial enzyme assay kits (Wako). Serum HDL cholesterol was determined by an enzymatic procedure after precipitation with phosphotungstic acid (Wako). Apolipoprotein A-I and apolipoprotein B were measured by turbidimetric immunoassays (Apo-auto, Daiichi Kagaku Yakuhin). Lipoprotein(a) was measured with an ELISA (Biopool). Serum glucose was determined by the glucose oxidase method with a commercial enzyme assay kit (Kanto Chemicals), and serum creatinine was also measured with a routine enzyme assay kit.
The urinary albumin concentration was assayed by a nephelometric method, and UAE was expressed as micrograms per minute. Urinary creatinine was measured by a method based on the Jaffé reaction, and the creatinine clearance rate, expressed as milligrams per minute, was calculated by the following formula: 12-hour urine volumexurinary creatinine/(serum creatininex720).
As measured in our laboratory, the coefficient of variation was 4.2% for the FVIIa assay, 2.8% for the FVIIc assay, 4.4% for the FVIIag assay, 2.5% for the fibrinogen assay, 3.8% for the vWF assay, 4.7% for the thrombomodulin assay, and 5.2% for the UAE.
Statistical Analysis
Data are shown as the mean and 95%
confidence interval. The
distributions of the levels of vWF, thrombomodulin, FVIIa, FVIIc,
FVIIag, FVIIa/FVIIag ratio, lipoprotein(a), triglycerides,
and UAE were examined and log10 transformed to reduce
skewness and kurtosis of the distributions before statistical
analysis. The geometric means of these parameters
were determined. After one-way ANOVA, the unpaired t
test was used for the comparison between mean values in two groups. In
addition, Pearson's correlation coefficients were calculated for the
different variables. A value of P<.05 was considered to
indicate a significant difference.
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Results |
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White-Coat and Sustained Hypertension
Table 1
shows the characteristics of the 61
hypertensive patients (12 with white-coat hypertension and 49 with
sustained hypertension) and the 25 age- and sex-matched
normotensive controls. The office SBP and DBP were significantly higher
in the white-coat hypertension group than in the normotensive
control group, but the mean 24-hour SBP (24-hour SBP), mean 24-hour DBP
(24-hour DBP), the lipid profiles (data not shown), and levels of FVII,
vWF, and thrombomodulin did not differ in these two groups. The plasma
levels of FVIIa and vWF were significantly higher in the sustained
hypertensive group than in the normotensive control subjects or
white-coat hypertensive group.
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Microalbuminuria, BP Levels, and
Cardiovascular Risk Factors
Table 2 shows the clinical
and
metabolic characteristics of the 49 elderly sustained
hypertensive patients and the 25 normotensive control subjects. In the
former patients, none of the BP parameters listed in the
microalbuminuric subgroup differed significantly from the
corresponding value in the normoalbuminuric subgroup. The
serum creatinine levels were higher in the
microalbuminuric subgroup than in the normotensive control
group. There were no significant differences among the
normoalbuminuric hypertensive, microalbuminuric
hypertensive, and control groups for creatinine clearance,
lipid profiles, or fasting serum glucose levels.
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Microalbuminuria and FVII, vWF, and
Thrombomodulin Levels
Table 3 shows the plasma levels
of coagulation
factors (FVII and fibrinogen) and endothelial
cell–derived molecular markers (vWF and thrombomodulin) in the
sustained hypertensive patients and normotensive control subjects.
There were no significant differences for these factors between the
normoalbuminuric hypertensive patients and the normotensive
control group. The microalbuminuric hypertensive group had
significantly higher FVIIa levels, FVIIa/FVIIag ratios, vWF levels, and
thrombomodulin levels than the normotensive control group, while there
were no differences among these three groups for the FVIIc and FVIIag
levels. The FVIIa level and the FVIIa/FVIIag ratio in the
microalbuminuric group were significantly higher than those
in the normoalbuminuric group.
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Correlations of Various Parameters
Table 4
shows the correlation coefficients for
various pairs of FVII, vWF, thrombomodulin, UAE, BP, and lipids in the
sustained hypertensive patients. The FVIIa level and FVIIa/FVIIag ratio
had significant positive correlations with the thrombomodulin level and
UAE. The FVIIa/FVIIag ratio also had significant correlations with
24-hour SBP and DBP.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In this study, the 61 hypertensive patients were classified into 12 with white-coat hypertension and 49 with sustained hypertension by using 24-hour ambulatory BP monitoring, and the sustained hypertensive patients were further subclassified into those with normoalbuminuric and microalbuminuric hypertension. The relationships among coagulation factors, molecular markers of endothelial cell damage, and UAE in hypertensive patients were then studied. The white-coat hypertensive patients did not show any differences from the normotensive control subjects in terms of the plasma levels of FVII, fibrinogen, vWF, or thrombomodulin (Table 1
). These findings
are
consistent with the results of a recent prospective study
revealing that the clinical prognosis in white-coat hypertension is
almost the same as that in normotensive subjects.35
Furthermore, our findings are compatible with the previous reports that
white-coat hypertensive patients are usually free from even silent
target organ damage such as cardiac
hypertrophy,10 silent cerebrovascular disease
detected by magnetic resonance imaging,11 and
microalbuminuria.7
In the patients with sustained hypertension, we found
significantly higher levels of FVIIa and vWF compared with the
normotensive control subjects (Table 1), indicating the
presence of
hypercoagulability and endothelial cell dysfunction.
After further classification of the sustained hypertensive patients
into the normoalbuminuric (UAE<15 µg/min) and
microalbuminuric (UAE=15 to 300 µg/min) groups, we found
that the levels of FVIIa, FVIIa/FVIIag ratio, vWF, and thrombomodulin
were significantly increased compared with normotensive control
subjects only in the microalbuminuric hypertensive group
(Table 3). In contrast, in our recent study on diabetic
patients, we
found that normoalbuminuric diabetic patients showed
increased FVIIa levels compared with the healthy control
subjects.23 24 In vitro activation of FVII is caused
by
various coagulation proteases, including factor Xa, factor IXa, factor
XIIa, thrombin, and FVIIa itself.13 Some of these
coagulation factors might be partly activated in the plasma of
the sustained hypertensive patients with
microalbuminuria, or tissue factor expression on the
vascular cells might take place, although the in vivo mechanism of
FVIIa formation remains unclear.
There were no differences among the normoalbuminuric and
microalbuminuric hypertensive patients and normotensive
control subjects for either the FVIIc level, measured with human
placental thromboplastin, or the FVIIag level (Table 3). Plasma
FVIIc
levels are reported to be increased in various atherosclerotic
diseases, including coronary artery disease, cerebrovascular
disease, and peripheral artery
disease.1 14 15 16 17 18
Previous reports regarding the FVIIc levels in hypertensive patients,
however, have not been consistent. Some authors reported no or
only a slight increase of FVIIc in essential
hypertension,4 whereas others found a marked
increase.2 3 FVIIc assays measure the aggregate of
FVIIa
and FVII zymogen in plasma, and the sensitivity for FVIIa varies widely
depending on the origin of the thromboplastins used.36 We
previously found that FVIIc levels measured using bovine thromboplastin
had a strong positive correlation with FVIIa levels, while FVIIc levels
measured using human or rabbit thromboplastin showed moderate
correlations with FVIIa levels.36 Thus, the differing
results presented in previous reports on FVIIc levels in
hypertensive patients might be attributed to the different types of
thromboplastin used at different laboratories.
The microalbuminuric hypertensive patients also had
increased plasma vWF and thrombomodulin levels when compared with the
normotensive control subjects (Table 3). Increased vWF and
thrombomodulin levels have been reported in diabetic patients with
microalbuminuria.27 29 Increased plasma
vWF levels were also previously reported in untreated hypertensive
patients,28 especially those with
microalbuminuria,4 but thrombomodulin
levels have not been studied. We found that thrombomodulin levels were
also elevated in the hypertensive patients with
microalbuminuria (Table 3), and were positively
correlated with UAE (r=.398, P<.005), FVIIa
(r=.396, P<.005), and FVIIa/FVIIag
(r=.437, P<.005) (Table 4). Thus,
the
microalbuminuric hypertensive patients would have both
systemic endothelial dysfunction and FVIIa activation,
which might be related to each other. In contrast, vWF levels in
sustained hypertensive patients were not correlated with UAE, FVIIa, or
FVIIa/FVIIag. The reason for this discrepancy between the two molecular
markers of endothelial cell damage might be
attributable to the differing metabolic sequences for these
markers. VWF is stored in specialized endothelial cell
organelles known as Weibel-Palade bodies and secreted into the
circulation in response to a variety of
physiological stimuli,25 whereas
thrombomodulin is a membrane glycoprotein on the surface of
endothelial cells and soluble thrombomodulin is
released into plasma, probably by proteolysis.26
The markers of endothelial cell damage (vWF and
thrombomodulin) tended to be increased in normoalbuminuric
hypertensive patients compared with normotensive control subjects, and
in microalbuminuric hypertensive patients compared with
normoalbuminuric hypertensive patients, though these
differences did not reach statistical significance (Table 3).
These
results suggest that the existence of a spectrum of
endothelial cell damage is likely in patients with
essential hypertension. Gradual, rather than stepwise, vascular damage,
as well as hypertensive renal damage, might occur in hypertensive
patients. On the other hand, the FVIIa and FVIIa/FVIIag ratios in the
normotensive control subjects were not essentially different from those
in the normoalbuminuric hypertensive patients. Thus,
coagulation abnormalities like FVII hyperactivity might not initially
occur in patients with essential hypertension but may gradually become
overt along with hypertensive target organ damages such as increase of
UAE.
In the present study, patients with clinically overt cardiovascular disease (such as coronary artery disease, cerebrovascular disease, and renal failure) were excluded to clarify the specific hypertension-related abnormalities of coagulation and endothelial cell damage. Recently, we have clarified that increased levels of FVIIa and markers of endothelial cell damage are found in patients with coronary artery disease, cerebrovascular disease, or renal failure.22 37 Thus, one implication of the present study is that the FVII hyperactivity and endothelial cell damage are found in asymptomatic hypertensive patients before these hypertensive cardiovascular complications are clinically overt. If that is the case, the FVII hyperactivity and increased markers of endothelial cell damage would be sensitive risk factors for cardiovascular disease. To confirm whether there is predictive value in the observation of increased levels of FVIIa and markers of endothelial cell damage for cardiovascular episodes in hypertensive patients, further studies are necessary, using the prospective cohort paradigm.
Elderly hypertensive patients are reported to often have multiple cardiovascular risk factors and silent target organ damage. In this study, we rarely found evidence of FVII activation and increased markers of endothelial cell damage in white-coat hypertensive patients or in hypertensive patients without microalbuminuria. Both increases of FVII activation and markers of endothelial cell damage were found only in those with microalbuminuria, and this association might account for the higher risk of cardiovascular events and the poorer clinical outcome in these patients.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants from the Foundation for the Development of the Community (Tochigi, Japan), from the Ministry of Education, Science, and Culture of Japan, and from the Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) of the Science and Technology Agency of Japan. We wish to thank Dr Hisao Kato at the National Cardiovascular Center Research Institute for his encouragement and helpful advice. We also thank Dr Tomohiro Nakagaki at the Chemo-Sero-Therapeutic Research Institute (Kumamoto, Japan) for the gift of purified human plasma FVIIa.
Received July 12, 1995; accepted December 21, 1995.
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