© 2000 American Heart Association, Inc.
Thrombosis |
Intravascular Free Tissue Factor Pathway Inhibitor Is Inversely Correlated With HDL Cholesterol and Postheparin Lipoprotein Lipase but Proportional to Apolipoprotein A-II
From the National Cardiovascular Center Research Institute (A.K., A.Y., H.K.) and Hospital (Y.M., T.N., H.N., M.Y., K.M., M.T.) and Chemo-Sera Therapeutics Research Institute (Y.K., K.K.), Osaka, Japan.
Correspondence to Akito Kawaguchi, MD, Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita-shi, Osaka 565-8565, Japan. E-mail akitok{at}ri.ncvc.go.jp
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Abstract |
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Abstract—To elucidate the distribution and clinical implications of tissue factor pathway inhibitor (TFPI) concentrations, we measured TFPI levels consisting of preheparin free, lipoprotein-bound (Lp-bound), and endothelial cell–anchor pools in 156 patients with coronary artery disease (average age, 61.2±9.1 years; range, 32 to 78 years) by heparin infusion (50 IU/kg) and compared them with the preheparin TFPI levels of 229 healthy subjects (average age, 59.6±9.4 years; range, 41 to 80 years). The patients had lower preheparin free TFPI and lower HDL cholesterol (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free TFPI, 15.9±6.5 versus 19.2±8.1 ng/mL). In a partial correlation analysis, the preheparin free TFPI levels were shown to be inversely correlated with the HDL-C concentrations in both the patients (r=-0.454, P<0.001) and the healthy subjects (r=-0.136, P<0.05). As determined by comparison of preheparin and postheparin plasma, the patients generally showed preheparin free TFPI <10%, Lp-bound TFPI at 30%, and endothelial cell–anchor TFPI at 60%. When the patients were divided into 4 categories by their LDL cholesterol (LDL-C, 130 mg/dL) and HDL-C (40 mg/dL) levels to specify their coronary risks, the low–HDL-C groups had significantly increased preheparin and postheparin free TFPI levels and decreased postheparin LPL levels, whereas the high–LDL-C groups showed increased levels of Lp-bound TFPI. In a partial correlation analysis, we found a proportional relation between postheparin free TFPI and apolipoprotein A-II (r=0.5327) and between HDL-C and LPL (r=0.4906), whereas postheparin free TFPI was inversely correlated with HDL-C (r=-0.4280) and postheparin LPL (r=-0.4791). The inverse relationship between TFPI and LPL suggests that increased free TFPI concentrations as a compensatory response of the endothelium to prevent atherothrombotic processes compete with and displace LPL on endothelial surface, resulting in reduced LPL and low HDL-C.
Key Words: TFPI • HDL cholesterol • lipoprotein lipase • apolipoprotein A-II • coronary artery disease
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Introduction |
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Tissue factor pathway inhibitor (TFPI) plays an important role in the antithrombotic properties of vessel walls by inhibiting extrinsic coagulation processes.1 2 Intravascular TFPI consists of free and lipoprotein-bound (Lp-bound) forms.3 The free form includes 2 subfractions except in platelets,4 ie, a circulating free TFPI fraction without carrier in preheparin plasma and a heparin-releasable TFPI fraction from endothelial cells.5 Exogenous administration of recombinant TFPI to experimental animals prevents thrombosis,6 whereas increased TFPI levels have been observed in patients with acute myocardial infarction.7 Although the alteration of serum lipids by cholesterol-lowering therapy influences Lp-bound TFPI profiles,8 9 10 11 little is known about the clinical implications of the TFPI level and its regulation in relation to lipid risk profiles.
In the present study, we compared TFPI subfractions in preheparin plasmas of normal healthy subjects and patients with coronary artery disease (CAD). Significant negative correlations were observed between the preheparin free TFPI and HDL cholesterol (HDL-C) concentrations in both of these groups. Accordingly, we studied the TFPI distribution further, including endothelial cell–anchor TFPI (EC-TFPI) levels in CAD patients divided according to their different phenotypes of dyslipidemia, especially hypercholesterolemia (raised LDL cholesterol, LDL-C) and low HDL-C to evaluate the patients’ coronary risks. Although Lp-bound TFPI constitutes most of the circulating TFPI before heparin infusion, EC-TFPI released by heparin is still the greater pool in postheparin plasma, which is detected in free form. The free form of TFPI inhibits tissue factor–induced coagulation more effectively than Lp-bound TFPI.12 13 Consequently, EC-TFPI is physiologically the more important pool, mediating the major antithrombotic activity on the endothelial surface. EC-TFPI is believed to bind to heparan sulfate on the cell surface, as does lipoprotein lipase (LPL).14 LPL regulates the LDL and HDL fractions because it contributes to the ultimate formation of LDL particles by hydrolyzing triglyceride (TG)-rich lipoproteins and also mediates the transfer of phospholipids and free cholesterol together with apolipoproteins to HDL particles.15 The endothelial cell surface, therefore, may play an important role in the interactive function between lipid metabolism and antithrombotic properties. We therefore measured the generation of TFPI in patients with CAD and in normal subjects to test the hypothesis that the low–HDL-C state associated with endothelial dysfunction16 17 18 19 20 leads to an increased production of TFPI to reduce the risk of thrombosis on the endothelial surface.
We first documented the inverse relationship between TFPI and LPL on the endothelial cell surface. Our results suggest a close relation between the antithrombotic aspect and lipid metabolism on vascular beds, giving new insight into risk profiles and mechanism of low HDL-C for atherothrombosis in vivo.
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Methods |
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Subjects
Patients with CAD (n=156), 32 to 78 years old, were recruited for the study. These patients were referred to and admitted to the National Cardiovascular Center Hospital (Osaka, Japan) because of stable symptoms or suspected CAD. No patients had hepatic or renal dysfunction, but antianginal drugs, such as nitrates (47.4%), calcium antagonists (46.1%), ß-blockers (28.8%), and aspirin (44.1%), had been administered. When the patients were divided into subgroups (see below), there was no significant difference of the distribution of therapies among the subgroups. The patients who had been given lipid-lowering drugs, those with a TG level >4.5 mmol/L (400 mg/dL), and those with familial hypercholesterolemia or type III hyperlipidemia were excluded from this study. All patients were examined by coronary angiography to evaluate the severity of coronary atherosclerosis. Blood samples were obtained during the diagnostic catheterization procedure in the early morning. Preheparin plasma samples were collected from a femoral artery just after the insertion of the sheath for catheter manipulation. Postheparin plasma samples were obtained 10 minutes after an intravenous injection of unfractionated standard heparin (Novo-Nordisk A/S) with a bolus of 50 IU/kg body wt. The blood samples were drawn into evacuated tubes containing 0.38% trisodium citrate (1:9 vol/vol) and disodium EDTA (0.1%), immediately placed in a refrigerator, and centrifuged at 3000g at 4°C within 1 hour to obtain platelet-poor plasma. Aliquots were stored at -80°C until assay.
As control subjects, 229 normal volunteers 40 to 81 years old were selected from the population-based prospective cohort in the district of Ise (Kisei-cho, Mie Prefecture in Japan). Serum lipids and TFPI were measured without heparin infusion. After the subjects had fasted overnight, blood samples were obtained from an antecubital vein into evacuated tubes. Informed consent was obtained from all patients and healthy subjects for the blood sampling and measurements.
Classification
To evaluate their coronary risk according to their lipid
profiles, the CAD patients were divided into 4 categories according to
their LDL-C and HDL-C levels (Figure 1
):
the normal group (a), low–HDL-C group (b), low–HDL-C and high–LDL-C
group (c), and high–LDL-C group (d). The cutoff value for LDL-C
(3.34 mmol/L [130 mg/dL]) is the point above which drug therapy
is recommended to patients with established atherosclerotic disease
(Adult Treatment Panel II),21 and that for HDL-C
(1.03 mmol/L [40 mg/dL]) is the diagnostic level for
low HDL-C in the guidelines of the Japanese
Atherosclerosis Society.22 HDL-C was
plotted as reciprocal values (1/HDL-C) as a negative risk factor. This
classification according to lipid risk profiles can be used to evaluate
the independent contributions of the 2 confounding variables of
HDL-C and LDL-C. A simple factorial ANOVA (2-way ANOVA) was applied to
determine the separate abilities of HDL-C and LDL-C levels to affect
the dependent variables.
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) and 156
patients with CAD (
). All subjects were divided according to their
LDL and HDL cholesterol levels into 4 categories: (a)
normal lipid profile, (b) low-HDL cholesterolemia, (c)
low-HDL cholesterolemia and high-LDL
cholesterolemia, and (d) high-LDL
cholesterolemia. The cutoff levels (dotted lines) of
LDL cholesterol and HDL cholesterol were 130
mg/dL (3.34 mmol/L) and 40 mg/dL (1.03 mmol/L),
respectively.
Measurements of Lipids and Risk
The serum total cholesterol and TG levels of
preheparin and postheparin plasma samples were determined
by enzymatic methods23 24 with reagents commercially
supplied by Daiichi Kagaku for cholesterol and by Nihon
Shoji for TG and with an autoanalyzer (COBAS MIRA plus, Nihon
Roche). HDL-C was determined in the supernatant after heparin-manganese
precipitation of the apolipoprotein (apo) B–containing
lipoproteins.25 Apo A-1, A-II, B, C-II, C-III, and E were
measured immunoturbidimetrically with kits (Daiichi
Kagaku).26 LDL-C was calculated by Friedewald’s
formula.27 In the patients, blood pressure and body mass
index (BMI: body weight divided by height in square meters) were
measured, and alcohol and smoking habits were also documented on the
basis of a standard questionnaire.
TFPI and LPL Antigen Determination
Both the total and free TFPI concentrations were measured by a
1-step sandwich ELISA method using "total" and "free" TFPI
reagent kits (Kaketsuken) in both preheparin and
postheparin plasma.28 Monoclonal anti-TFPI
antibodies for the Kunitz 3 domain (K9) and for the tertiary structure
of the first and second Kunitz domains (K270) were prepared to detect
the free and total TFPI levels, respectively. Because
heparin-releasable TFPI from the EC-TFPI pool is detected as free after
a heparin infusion, EC-TFPI was calculated by subtracting the total
TFPI concentration in the preheparin plasma from total TFPI
concentration in the postheparin plasma. The amounts of
preheparin and postheparin Lp-bound TFPI were calculated by
subtracting the free TFPI concentration from the total TFPI
concentration in both preheparin and postheparin plasmas,
respectively. Preheparin Lp-bound TFPI is different from
postheparin Lp-bound TFPI, because a part of the
heparin-releasable TFPI from endothelium newly binds to
lipoprotein, as described in the Results. The plasma LPL mass was
measured by a sandwich ELISA with commercial reagent kits
(Daiichi Kagaku).29 The EC-LPL level was calculated by
subtraction of the preheparin LPL concentration from the
postheparin LPL concentration.
Statistical Analysis
Statistical analysis was performed with SPSS software
(SPSS Inc). A 2-tailed Student’s t test was applied for the
differences between the control subjects and CAD patients, except for
the sex distribution (
2 test). Comparisons of
the dyslipidemic categories were made by a simple factorial
ANOVA (2-way ANOVA) to determine the differences in clinical
parameters, where HDL and LDL cholesterol were
the 2 independent factors. Significant differences of the main effect
of each factor were examined after that of their interaction. Partial
correlation coefficients were also calculated for the preheparin and
postheparin TFPI, LPL, lipid, and apolipoprotein levels.
The TG concentrations were logarithmically transformed because of their
skewed distribution. Values of P<0.05 were considered
significant.
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Results |
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Comparison of Serum Lipid, Apolipoprotein, and TFPI Levels in Control Subjects and Patients
Figure 1
shows a scattergram of the LDL-C and HDL-C levels
of the healthy subjects and CAD patients. The HDL-C levels of the
patients were clearly shifted to the lower range, characterizing lipid
profiles of patients at risk for atherosclerosis; 80
patients (51%) had HDL-C levels <1.03 mmol/L (40 mg/dL). The CAD
patients had significantly lower serum lipid and apolipoprotein levels
than the control subjects, with the exception of apo C-II levels (Table 1). However, the apo A-II level
divided by HDL-C was higher in the patient group than in the healthy
subjects, indicating a relative abundance of apo A-II–rich HDL
particles in the CAD patients.
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Both the preheparin free and total TFPI concentrations were
significantly lower in the patients than in the control subjects. The
Lp-bound TFPI concentrations were not significantly different between
the patients and control subjects. The preheparin free TFPI/total TFPI
ratios and Lp-bound TFPI/total TFPI ratios showed that the TFPI in the
control group was 
25% in the free form and 75% in the Lp-bound
form. The TFPI of the patients was 20% in the free form and 80% in
the Lp-bound form. In the healthy group, male subjects had
significantly higher Lp-bound TFPI (67.9±19.1 ng/mL versus 59.5±18.7
ng/mL; P<0.005) and lower HDL-C (1.37±0.30 mmol/L
versus 1.48±0.33 mmol/L; P<0.05) levels than female
subjects, but no sex difference was found in the patient group.
Partial Correlation Coefficients in Control Subjects and
Patients
The preheparin free TFPI levels were inversely correlated
with the HDL-C levels (Table 2) in both
the healthy subjects (r=-0.1358; P<0.05) and
the CAD patients (r=-0.4540; P<0.001; Figure 2). In the control subjects, HDL-C was
correlated with apo A-I (r=0.7895; P<0.001) and
apo A-II (r=0.3054; P<0.001), whereas in the
patients, HDL-C was weakly correlated with apo A-I
(r=0.1898; P=0.026) and not at all with the apo
A-II level (r=-0.0638). Despite the negative correlation of
preheparin free TFPI with HDL-C, the preheparin free TFPI concentration
was positively correlated with the apo A-II level in both groups, more
so in the patients. Although the preheparin free TFPI was related to
apo A-II rather than apo A-I in both the patients and the control
subjects, the patients who had low HDL-C levels had a stronger
correlation between preheparin free TFPI and apo A lipoproteins (apo
A-I and apo A-II). Only in the control group was preheparin free TFPI
correlated with the TG level (r=0.254; P<0.001)
and LDL-C level (r=0.1669; P<0.01).
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Lp-bound TFPI was found in the LDL fraction as the major constituent in the control subjects (r=0.4587; P<0.001) and in the patients (r=0.4623; P<0.001). In the control group, the HDL fraction (r=0.3152; P<0.001) also contributed significantly to the level of Lp-bound TFPI. In the patients, by contrast, a linkage between Lp-bound TFPI and HDL was not observed.
Different Forms of TFPI Associated With Dyslipidemic
Profiles
The patients were divided by their LDL-C and HDL-C levels into 4
categories (Table 3). The low–HDL-C
groups (b and c) had higher BMI and lower alcohol consumption
values than the patients with normal HDL-C (a and d). There was no
significant difference in smoking status and drug administration among
the groups. LDL-C and HDL-C contributed to the significant differences
of total cholesterol, apo A-I, and apo B between the
patients with low HDL-C (b and c) and high LDL-C (c and d) without any
secondary interaction. Although the apo A-II levels were lower in the
high–LDL-C groups, the apo A-II/HDL-C ratio was significantly elevated
in the low–HDL-C groups. Apo C-II levels were also higher in the
low–HDL-C patients than in the patients with normal HDL-C.
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The heparin infusion (50 IU/kg) caused marked increases in the free
TFPI levels, from 7.7- to 11.1-fold, and in LPL concentrations, from
12- to 16-fold, compared with preheparin plasma (Table 4). The low–HDL-C groups were
characterized by significantly higher preheparin and
postheparin free TFPI and reduced LPL levels compared with
the normal HDL-C groups. Accordingly, the calculated EC-TFPI values
were also increased in the low–HDL-C groups compared with the
normal–HDL-C groups, whereas the EC-LPL levels were significantly
lower in the low–HDL-C groups (P<0.005) and higher in the
high–LDL-C groups (P<0.01) than in the other groups.
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As expected, the Lp-bound TFPI levels in both the preheparin and
postheparin plasma were increased in the groups with high
LDL-C. However, the total TFPI level in postheparin plasma
was higher in the low–HDL-C groups than in the high–LDL-C groups,
because more EC-TFPI was released by heparin infusion in the low–HDL-C
groups. Interestingly, the Lp-bound form in the postheparin
plasma was increased by 10 to 20 ng/mL compared with that in the
preheparin plasma in all groups. Newly detected Lp-bound TFPI
represented by 
-Lp-TFPI was significantly more abundant
in the high–LDL-C groups (P<0.005). As determined by
comparison of preheparin and postheparin plasmas, the
patients generally showed <10% preheparin free TFPI, 30% Lp-bound
TFPI, and 60% EC-TFPI, regardless of the dyslipidemia. The
preheparin free TFPI level was 10% to 14% the EC-TFPI level.
Partial Correlation Coefficients Among TFPI, LPL, and Lipids in the
Patient Group
On the basis of the partial correlation analysis
among the patients (Table 5), the
preheparin free TFPI levels were shown to be significantly related to
the postheparin free TFPI concentration
(r=0.6748; P<0.001), whereas preheparin LPL
showed a weak association with postheparin LPL levels
(r=0.3473; P<0.001). Like the results shown by
the dyslipidemic classification, the HDL-C concentration
was inversely correlated with the preheparin and
postheparin free TFPI levels and positively correlated with
preheparin and postheparin LPL. Although the apo A-I and
apo A-II levels were well correlated with each other
(r=0.6458; P<0.001), only apo A-I was associated
with the HDL-C level (r=0.2009; P<0.01). These 2
types of apolipoproteins were positively correlated with preheparin and
postheparin free TFPI levels and were negatively correlated
with postheparin LPL levels, whereas apo A-II was much more
strongly correlated than was apo A-I in both cases.
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Significant correlations were observed between postheparin
free TFPI and apo A-II (r=0.5327; P<0.001)
(Figure 3A) and between
postheparin LPL and HDL-C (r=0.4906;
P<0.001), whereas significant inverse correlations were
documented between intravascular free TFPI and
postheparin LPL (r=-0.4791;
P<0.001) (Figure 3B), between intravascular free
TFPI and HDL cholesterol (r=-0.4280; P<0.001),
and between postheparin LPL and apo A-II
(r=-0.3678; P<0.001).
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Discussion |
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To elucidate the intravascular TFPI distribution in the present study, it was necessary to differentiate the free form from the Lp-bound form of TFPI because of their different anticoagulant properties.12 13 The heparin infusion allowed us to measure the total intravascular TFPI levels, including the EC-TFPI concentration, which was 7.7 to 11.2 times greater than the preheparin free TFPI level, as previously reported.5 As determined by comparison of preheparin and postheparin plasmas, the distribution of intravascular TFPI in the CAD patients studied consisted of <10% as the circulating preheparin free fraction (6% to 9%), 30% as the Lp-bound form (27% to 32%), and 60% as the EC-TFPI fraction (60% to 64%) regardless of the patients’ dyslipidemic profiles. The postheparin free TFPI was strongly correlated with preheparin free TFPI (r=0.6748), indicating a certain physiological equilibrium of free TFPI between the EC-TFPI pool and the preheparin circulating pool. In contrast, the preheparin LPL concentration was not a good predictor of the postheparin LPL levels (r=0.3709).
In our study, the patients with CAD had serum lipid levels that were
lower than those in the healthy subjects. Dietary control during
hospitalization might have affected the lipid profiles of the patients.
However, a critical difference between the healthy subjects and
patients was present in the HDL-C level, which may be a better
indicator for CAD risk rather than
hypercholesterolemia, in the Japanese
population. We observed the inverse correlation between preheparin free
TFPI and HDL cholesterol (r=-0.1358) in the
healthy subjects and in the preheparin (r=-0.4547; Figure 2) and postheparin (r=-0.4280) plasmas
of the CAD patients. In the dyslipidemic classification,
the preheparin free TFPI and EC-TFPI levels were significantly
increased in the patients with low HDL-C concentration compared with
the other groups (Table 4). Hansen et al10
reported that preheparin plasma TFPI activity in 14 patients with
familial hypercholesterolemia was not
correlated with HDL-C or apo A-I, although they did not discriminate
between TFPI activity and antigen, and their small group was highly
heterogeneous. Cella et al30 reported a
positive relationship between HDL-C and total TFPI antigen in
postheparin plasma (20 IU/kg of heparin), analyzing a small
number of heterogeneous subjects (12 hospitalized patients
with marked obesity [mean BMI, 41.4] and 14 normal subjects). The
reason for the difference in findings between that study and ours is
unclear. We demonstrated that symptomatic CAD patients had
lower preheparin free TFPI levels than did normal healthy subjects.
This result indicates a reduction of intravascular (preheparin and
postheparin) free TFPI in the atherogenic vascular milieu,
except for the Lp-bound form, which is dependent on
cholesterol levels. However, the fact that the (preheparin
and postheparin) free TFPI concentrations rose most in
those with low HDL-C suggests a compensatory augmentation of TFPI
levels produced by endothelial cells against the
atherogenic vascular milieu. Increased TFPI levels in patients with
acute myocardial infarction7 may also be evidence of such
an endothelial compensation, although the inflammatory
response after myocardial infarction complicates interpretation.
Lesnik et al31 reported elevated TFPI activity in small,
dense LDL and HDL fractions. Moor et al32 also described
that HDL3b was associated with TFPI in patients
with CAD. A low HDL-C concentration is generally associated with the
presence of small and dense HDL particles, because
HDL2 is transformed to
HDL3.15 Small and dense HDL
particles are enriched in apo A-II. Although apo A-I was positively
correlated with HDL-C in the CAD patients in this study, apo A-II was
inversely correlated with HDL-C among the patients with low HDL-C (80
patients; r=-0.291; P=0.009), indicating that at
lower HDL-C concentrations, HDL-C becomes enriched with apo
A-II. The apo A-II/HDL-C ratio was significantly higher in the
CAD patients than in the healthy subjects (Table 1), and the apo
A-II/HDL-C ratio of the patients with low HDL-C was higher than that of
the patients with normal HDL-C (Table 3). Thus, both the apo
A-II and (preheparin and/or postheparin) free TFPI levels
were inversely correlated with HDL-C levels in both control subjects
and patients, especially in the postheparin plasma of the
patients. The precise relevance of this is uncertain. However, it has
been reported that apo A-II is a discriminator for myocardial
infarction,33 and apo A-II transgenic mice are
atherogenic.34
When the thrombotic process is activated and/or the augmentation of antithrombotic activity is required, endothelial cells may be forced to generate TFPI and compensate for the consumption of free TFPI in response to certain signals, such as thrombin35 or other inflammatory mediators.36 It has been elucidated that HDL improves endothelial function by opposing oxidation16 17 18 and expression of adhesion molecules.19 We postulate that the inverse relationship between HDL-C and preheparin and postheparin free TFPI in the present CAD patients also reflects compensatory augmentation of antithrombotic properties of the vascular wall to maintain normal endothelial function.
The HDL-C concentration is known to be proportional to LPL
levels,37 as in the present study. LPL, like HDL-C,
was negatively correlated with preheparin and postheparin
free TFPI. It is possible that EC-TFPI shares common binding sites of
heparan sulfate proteoglycans and that LPL was replaced by the
increased production of TFPI, resulting in the negative
correlation between the 2 parameters (Figure 3B).
Therefore, some of the reduction of HDL-C may reflect diminished LPL
anchoring, and it is likely to aggravate endothelial
dysfunction and stimulate further TFPI generation.
The present study also revealed the novel finding that 10% (8%
to 15%) of EC-TFPI (10 to 20 ng/mL) was bound to lipoproteins, a level
that was significantly higher in the patients with high LDL-C,
suggesting an instant interaction between TFPI and lipoproteins. TFPI
synthesized in the endothelium is believed to bind to
heparan sulfate proteoglycans on the cell surface, where LPL also
enhances the binding of lipoproteins.38 It is possible
that part of the EC-TFPI is physiologically
bound to lipoproteins mediated by LPL on the cell surface. The
preheparin free TFPI levels were positively correlated with the TG
concentrations only in the control group39 and not in the
patients with CAD, as previously reported.7 This means
that the contribution of TGs to TFPI levels may depend on the
metabolic lipid state in a given population.
Taken together, the present findings indicate that the levels of intravascular free and Lp-bound TFPI are interrelated with lipid metabolism involving HDL-C, LDL-C, LPL, and apo A-II levels. The lower the HDL cholesterol concentration is, the higher the intravascular (preheparin and postheparin) free TFPI level. This may reflect a protective and stabilizing effect on the endothelial surface in the presence of normal HDL concentrations. Subclinical and/or clinical atherothrombotic events may cause increased TFPI as an endothelial compensation in response to atherothrombotic substances. Increased free TFPI may compete with and displace LPL, resulting in reduced LPL and low HDL-C. Thus, endothelial cell surface has the physiological significance to play a crucial role in the risk profiles not only of antithrombotic properties but also the lipoprotein metabolism through heparan sulfate proteoglycans.
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Acknowledgments |
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We would like to thank Dr Paul Nestel (Baker Medical Research Institute, Melbourne, Australia) for his critical reading of the manuscript and constructive discussion. We also thank Akiko Makino and Eiko Saitoh for their expert technical assistance in performing ELISA and using the autoanalyzer.
Received August 20, 1999; accepted August 27, 1999.
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