© 1995 American Heart Association, Inc.
Articles |
Evaluation of Factor XIa–
1-Antitrypsin in Plasma, a Contact Phase–Activated Coagulation Factor–Inhibitor Complex, in Patients With Coronary Artery Disease
From the Departments of Clinical Sciences and Laboratory Medicine (T.M., Y.K., M.M., H.T.) and Second Internal Medicine (M.K., T.I.), Kansai Medical University, Osaka, Japan.
Correspondence to Takashi Murakami, MD, Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570, Japan.
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Abstract |
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Abstract Excess activated factor XI (FXIa) in plasma indicates increased activation during the contact phase of blood coagulation. To investigate the relationship between such elevations and coronary atherosclerosis, we examined FXIa values in patients with coronary artery disease (CAD) by an enzyme-linked immunorsorbent assay method that we developed that detects FXIa in plasma samples as an FXIa–
1-antitrypsin
complex (FXIa-1AT). The presence and extent of CAD were
documented by coronary angiography and assessed by a recently
developed scoring system for semiquantitative estimation of
coronary atherosclerosis. Plasma
FXIa-1AT levels were significantly increased in patients
with angiographically proven CAD (13.9±3.0 µg/L, n=42) compared with
age-matched, healthy control subjects (11.9±1.7 µg/L, n=20) as well
as patients with angiographically normal coronary arteries
(12.0±2.3 µg/L, n=25). Moreover, in the total patient population,
the FXIa-1AT level was related to the number of
significant coronary artery stenoses as well as to the
total coronary score. FXIa-1AT showed a positive
correlation with thrombin–antithrombin III complex, fibrinogen, and
Lp(a) and an inverse correlation with apo A-I, as determined by
multivariate analysis. Our studies provide
evidence that increased activation of the contact pathway occurs in
patients with CAD and is related to the severity of the disease.
Although it is unknown whether this abnormality is the cause or the
result of the vascular lesion, it may be important for progression of
the underlying atherosclerosis or for propagation of
the atherosclerotic process itself.
Key Words: factor XI • activated coagulation factor–inhibitor complex • hypercoagulability • coronary artery disease
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Introduction |
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Excess FXIa in plasma, which indicates increased activation during the contact phase of blood coagulation, is detectable by ELISA as an activated coagulation factor–inhibitor complex, namely, FXIa-
1AT.1 2 Measurement of the
FXIa-1AT level allows detection of the early stages of
hypercoagulability in patients with disseminated intravascular
coagulation.2 3 Furthermore, we have demonstrated
age-related fluctuations in FXIa-1AT levels in a healthy
population3 and elevated FXIa-1AT levels in
patients with non–insulin-dependent diabetes mellitus.4
On the basis of these observations, we have suggested another possible
application of FXIa-1AT determination, ie, for
evaluation of disease-associated atherosclerosis. Many investigators have reported that various abnormalities of the hemostatic system occur in patients with CAD. Among these, a high plasma fibrinogen level, which is found most frequently in prospective studies, is a dependent risk factor for cardiovascular events and therefore seems to be a strong predictor of coronary atherosclerosis.5 6 7 8 9 In addition, increased levels of coagulation factors, eg, factor VII, factor VIII, and von Willebrand factor, have also been reported in such patients as a sign of "hypercoagulability."7 10 11 12 13 However, these studies have simply shown that high levels of such coagulation factors are epidemiologically linked to the incidence of CAD, because the presence of large amounts of such factors per se does not constitute direct evidence of the hypercoagulable state.
In this regard, many recent quantitative immunoassays for "markers" that result from activation of various steps of the coagulation cascade have been developed; specific ELISAs or radioimmunoassays have been designed that apply released activating peptides, such as fibrinopeptide A14 and prothrombin fragment 1+2,15 to monitor the activity of thrombin and factor Xa, respectively, and the activated coagulation factor–inhibitor complex TAT.16 By using these methods, attempts have been made to clarify the relationship between hypercoagulability and the prevalence or incidence of atherosclerotic vascular disease such as CAD.17 18 19 20
However, the role of contact-phase activation has received less
attention in studies of blood coagulation in patients with CAD. In this
study, we investigated whether the FXIa-1AT level
reflected the presence or absence of CAD in patients diagnosed by
coronary angiography and whether determination of the
FXIa-1AT level could be valuable in assessing the
severity of coronary atherosclerosis. In
addition, to compare FXIa-1AT levels in these patients,
we also examined the levels of TAT, which is an indicator of the later
products of the coagulation system.
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Methods |
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Patient Population
Between April and June 1994, 186 patients were hospitalized at the Division of Cardiology at our institute for cardiac catheterization for evaluation of CAD or treatment with PTCA. To prevent possible confounding due to pre-existing CAD, 119 patients were excluded for the following reasons: previous coronary artery bypass surgery or PTCA (n=100), significant valvular stenosis and regurgitation (n=9), cardiomyopathic (n=5) or inflammatory (n=3) disease, and myocardial infarction during the previous 3 months (n=2). The remaining 67 patients were enrolled in this study population. No patient had clinically significant renal, hepatic, infectious, or malignant diseases, and none were taking anticoagulant agents such as warfarin. Informed consent was obtained from all patients, and the trial was approved by the hospital Ethics Committee.
To compare FXIa-1AT levels with those in a normal
population, 63 healthy volunteers were randomly recruited from the
hospital staff. Because age is slightly correlated with
FXIa-1AT level,3 20 subjects (12 men and 8
women) who were matched by age to the patients were selected as control
subjects. None of the control subjects had any evidence of
ischemic heart disease, diabetes mellitus, or vascular
accident, and none were taking any medication. Although the control
subjects did not undergo coronary angiography for ethical
reasons, blood sampling and analyses similar to those conducted
for the patient group were performed.
Coronary Angiograms
Coronary angiography was performed using a
percutaneous standard femoral approach by the Judkins
technique.21 Angiograms were assessed by two cardiologists
(Drs Karakawa and Iwasaka) who were unaware of the patient's clinical
characteristics and laboratory profile. The presence and extent of CAD
were determined in 15 proximal coronary arterial
segments according to the Ad Hoc Committee on Grading of
Coronary Artery Disease of the American Heart
Association.22 The patient group was subdivided into two
groups: of the 67 initially enrolled in the study, the 25 who had no
significant coronary artery stenosis (reduction of
luminal area <50% in any of the major coronary arteries on
selective arteriograms) were defined as patients with
"angiographically normal" coronary arteries (group 1),
and the remaining 42 had one or more significant stenoses
(group 2). The patients in group 2 were further subdivided into those
with one-, two-, or three-vessel disease; patients in group 1 were
classified as those having no vessel disease.
Furthermore, to evaluate the severity of CAD by another approach, we used a scoring system based on a modification of the method of Reardon et al,23 which provides a numerical value for lesion severity. Normal arteries or those with lesions that reduce the luminal diameter by less than 25% are scored as "0"; those with luminal diameters reduced by 25% to 49%, "1"; those with luminal diameters reduced by 50% to 74%, "2"; those with luminal diameters reduced by 75% to 99%, "3"; and totally occluded arteries, "4." The scores for each lesion in the 15 proximal coronary artery segments were summed, and a final score was obtained. By linear regression analysis, patients with angiographically normal coronary arteries were also included in the study population, because even these patients had total scores greater than 0 on the basis of this scoring system. When the total coronary scores in the patients with no, one-, two-, and three-vessel disease were calculated, their mean±SD values were 0.5±0.9, 4.6±2.1, 10.6±4.0, and 15.6±4.1, respectively.
Blood Sampling and Processing
After admission, fasting blood samples were obtained in the
early morning 24 hours prior to cardiac
catheterization. Samples were carefully drawn by
specially trained staff from an antecubital vein into a plastic syringe
containing 10% (vol/vol) 0.13 mol/L trisodium citrate for plasma
determination and were immediately centrifuged for 15 minutes
at 1500g at 4°C. For assay of coagulation
parameters, a suitable anticoagulant mixture was added to
the supernatant plasma (for FXIa-1AT, benzamidine HCl
[1 mol/L, 1% vol/vol] was selected), and aliquots were stored at
-80°C until testing. A previously described2 3 4 ELISA
was used for FXIa-1AT determination. TAT level was
assayed by ELISA with a commercially available kit
(Behringwerke).16 All samples for FXIa-1AT
and TAT determinations were analyzed in one batch in
duplicate.
Plasma fibrinogen, HbA1c, serum cholesterol,
and triglyceride levels were assessed as described
previously.4 HDL and LDL cholesterol levels
were measured by standard enzymatic methods.24 Apo A-I and
apo B levels in serum were obtained by an immunoturbidimetric method
(Daiichi Pure Chemicals). The Lp(a) level in serum was determined by a
latex-enhanced turbidimetric immunoassay method.25 All
samples except those for FXIa-1AT and TAT determination
were analyzed on the day of venipuncture.
Statistical Analysis
Data are shown as mean±SD unless stated otherwise. Statistical
significance for differences in the clinical characteristics and
laboratory variables between the patient and control subject groups
was determined by ANOVA; differences between pairs of means were
examined by Scheffe's F test. Pearson's 
2
analysis was used for categorical data between the patient and
control subject groups. Coefficients of skewness and kurtosis were used
to test for deviations from a normal distribution, and a logarithmic
transformation was performed on individual values of
triglyceride and Lp(a) level before statistical testing
because of their original nonnormal distribution. Coronary
score was also logarithmically distributed; thus, for linear regression
analysis to compare FXIa-1AT and TAT levels, a
point of 1 was added to each individual score. Linear regression
analysis was used to compare the relation between the
FXIa-1AT level and other laboratory data.
Multivariate analysis using multiple stepwise
regression methods was performed to examine the effect of potential
interactions among risk factors on FXIa-1AT level.
Values of P<.05 were considered statistically
significant.
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Results |
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Clinical Characteristics of the Study Population
We investigated 67 patients, of whom 25 had angiographically normal coronary arteries (group 1) and the remaining 42 had at least one major coronary artery with significant stenosis (group 2), and 20 age-matched control subjects. Table 1
shows clinical characteristics of the control subjects
and each patient group. There were no significant differences in age
among the three groups. When compared with the control subjects by
ANOVA and Scheffe's F test, both group 1 and group 2 patients had
significantly higher values for body mass index, but no significant
differences were observed for systolic or diastolic blood
pressure. This finding was expected, as hypertensive patients had
received appropriate antihypertensive therapy. There were fewer current
smokers among the control subjects, but there were no differences in
smoking habit between group 1 and group 2 patients. ("Current
smokers" were defined as those who smoked at least one cigarette per
day; "nonsmokers" as those who had never smoked; and all others
as "ex-smokers.") Compared with group 1, group 2 had a
significantly higher incidence of a previous (>3 months prior to entry
into the study) myocardial infarction. The other risk factors did not
differ significantly between patient groups.
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Laboratory Data for the Study Population
Table 2 shows lipid, lipoprotein, apolipoprotein,
and hemostatic variables for the control subjects and both patient
groups. No significant difference in total cholesterol
level was found between the control subjects and the patient groups.
Group 2 had significantly lower levels of HDL cholesterol
and apo A-I compared with both the control subjects and group 1 and
significantly higher levels of LDL cholesterol and apo B
compared with the control subjects by ANOVA and the Scheffe F test. As
expected, the ratio of LDL cholesterol to HDL
cholesterol, which is widely accepted as an atherogenic
index, was progressively higher in group 1 and group 2 than in the
control group. Group 2 also had higher triglyceride levels
compared with the control subjects. A slight elevation in median Lp(a)
level was observed in group 2, but the difference was not significant.
Group 2 had significantly higher levels of fibrinogen compared with the
control subjects and group 1 and higher levels of HbA1c
compared with the control subjects. No significant difference was found
in TAT level between the control subjects and patient groups. There was
no significant difference in the FXIa-1AT level between
the control subjects and group 1 subjects. However,
FXIa-1AT levels in group 2 were significantly increased
compared with those in both the control subjects and group 1. Although
all patients were being treated pharmacologically for CAD, the drug
regimens were not identical in groups 1 and 2: 81 mg/d
maintenance dose of oral acetylsalicylic
acid (39% and 70%, respectively; P<.05), ß-blockers
(29% and 53%, P<.05), calcium antagonists
(54% and 47%, P=NS), and nitrates (50% and 88%,
P<.01). Although the use of ß-blockers has been known to
affect serum lipoprotein levels, we did not observe any such effect,
nor was the FXIa-1AT level influenced by any drug
used.
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Relationships Between FXIa-1AT Level and the
Severity of CAD
To investigate the relationship between FXIa-1AT
level and the severity of CAD in more detail, we analyzed
FXIa-1AT levels in both patient groups and in the
control subjects by ANOVA and Scheffe's F test (Fig 1).
The patients with no vessel (12.0±2.3 µg/L, n=25) and one-vessel
(13.0±2.6 µg/L, n=21) disease had no significant differences in
FXIa-1AT levels compared with the control subjects
(11.9±1.7 µg/L, n=20). However, patients with two-vessel (14.5±3.5
µg/L, n=11) and three-vessel (15.2±2.5 µg/L, n=10) disease had
significantly higher FXIa-1AT levels compared not only
with the control subjects and the patients with no vessel disease but
also with those with one-vessel disease. Furthermore, the
FXIa-1AT level was significantly correlated with the
total coronary score in the total patient population
(containing groups 1 and 2; Fig 2). Because the total
coronary score had a skewed distribution, a logarithmic scale
was used to plot coronary score (+1) versus
FXIa-1AT level. In addition, although coronary
score had a weak but significant positive correlation with age
(r=.26, P<.05) and fibrinogen level
(r=.26, P<.05), multiple regression
analysis still showed a significant correlation between
FXIa-1AT level and the adjusted-age coronary
score and fibrinogen level.
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50% in major
coronary arteries on selective arteriograms were significant.
Numbers of patients represented in each column are
displayed at their bases. Data are mean±SD. 0VD indicates no vessel
disease; 1VD, one-vessel disease; 2VD, two-vessel disease; and 3VD,
three-vessel disease. *Significantly (P<.01) different
compared with control subjects and patients with 0VD.
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Relationships Between FXIa-1AT Level and Risk
Factors or TAT
For the patient population, the relationships between
FXIa-1AT level and cardiovascular risk
factors were performed by multiple stepwise linear regression
analysis. Age, body mass index, systolic and
diastolic blood pressures, and laboratory data were entered
into the regression model. Significant partial correlation coefficients
were obtained between FXIa-1AT level and fibrinogen
(r=.38, P<.01), Lp(a) (r=.33,
P<.01), and apo A-I (r=-.28, P<.05)
levels. Furthermore, TAT was positively correlated with
FXIa-1AT (Fig 3). However, there was no
relationship between either the TAT level and the number of significant
coronary artery stenoses or the total coronary
score (r=.23, P=NS), although TAT levels in these
patients were widely dispersed.
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Discussion |
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In this study, we demonstrated for the first time evidence of an elevated FXIa-
1AT level in patients with
angiographically documented CAD compared with healthy, age-matched
control subjects and patients with angiographically normal
coronary arteries. We also demonstrated that patients with two-
and three-vessel disease ("multivessel disease") had
significantly higher FXIa-1AT levels than those with
single-vessel disease. Of course, this classification based on
the number of significant coronary artery stenoses
obscures the severity of the underlying disease; thus, we attempted to
evaluate the extent of coronary atherosclerosis
by using a semiquantitative scoring system and demonstrated a
substantial correlation between FXIa-1AT level and this
latter score.
Nevertheless, we were disappointed initially that the magnitude of
elevation in FXIa-1AT levels in patients with CAD was
not so high, even when compared with that of the control subjects.
Thus, determination of the FXIa-1AT level may not be a
good discriminator of CAD. However, some studies have shown elevations
in other parameters of thrombotic processes in patients
with acute myocardial infarction or unstable angina, whereas no such
elevations have been observed in patients with stable
CAD.26 27 28 29 Enhanced activation of the blood coagulation
cascade may be related to the ongoing intracoronary
thrombosis rather than to coronary
atherosclerosis. However, the aim of this study was to
document the relationship between increased activation during the
contact phase of blood coagulation and coronary atherosclerotic
processes and not to ongoing intracoronary thrombotic
events. The impact of the latter could be discounted from the results
obtained, because we carefully excluded patients with acute
coronary syndromes, such as acute episodes of unstable angina
or myocardial infarction, which are known to affect hemostatic
mechanisms, and our study population included only outpatients who were
asymptomatic and whose disease was well controlled.
Nevertheless, it is unclear whether patients with angiographically
normal (but not necessarily intact) coronary arteries or those
with only one-vessel disease have considerably less
atherosclerosis outside the coronary
circulation compared with those with multivessel disease; nor is it
clear whether the CAD grading that we used could correctly estimate the
systemic atherosclerotic changes that more extensively activate
the hemostatic system.
It is believed that FXI is activated by factor XIIa in the presence of either plasma prekallikrein or high-molecular-weight kininogen when plasma comes in contact with artificial surfaces, such as glass or kaolin in vitro.30 However, in contrast to patients with only an FXI deficiency (a relatively common disorder among Ashkenazi Jews) and who often experience severe injury-related bleeding, those lacking all three of the aforementioned factors of the intrinsic pathway are asymptomatic.31 In this respect, FXI is an essential component for maintenance of normal hemostasis, but the mechanisms by which FXI is activated or initiated in the intrinsic coagulation pathway under physiological conditions remain unknown. Evidence for thrombin-mediated FXI activation on a negatively charged surface, independent of factor XIIa, has recently been reported.32 33 34 It is likely that the small amount of newly synthesized thrombin, which is activated by (theoretically) possible mechanisms, such as the factor VIIa–tissue factor complex, that are formed as a result of damage to vascular surfaces, trigger the contact phase of activation of the intrinsic coagulation pathway if appropriate surfaces are provided.
In contrast, evidence has also been reported that FXI is not activated by thrombin in plasma.35 36 Although further studies are needed to clarify this controversial hypothesis, we suspect that exposure of subendothelial components at the site of tissue injury and under physiological conditions can directly activate FXI in the contact system. Such events would parallel those, triggered by tissue factor, that occur in the extrinsic system, as well as those that occur on stimulated platelet surfaces, as reported by Walsh et al.37
In this regard, the significant correlation between
FXIa-1AT and TAT levels observed in this study indicates
that there is a close relationship between contact-phase activation and
a later stage of coagulation. In contrast, however, TAT levels were not
correlated to the severity of CAD, suggesting that TAT is a less
sensitive marker of coagulation activity. However, from the point of
view of the coagulation cascade, it appears likely that increases in
FXIa should lead to or accompany abundant thrombin formation. One might
expect TAT levels to be closely linked to thrombin generation, as
thrombin is rapidly inactivated by antithrombin III in
vivo, resulting in the formation of TAT. However, we interpreted our
results as indicating that only a small amount of the newly generated
thrombin might be detected as TAT in plasma because of competition with
the thrombomodulin–protein C mechanism, fibrin clots, and/or cellular
elements of the blood, such as platelets, which also bind or
utilize thrombin.38 39 40 41
Finally, the question arises whether FXIa-1AT levels in
patients with CAD are influenced by other coronary
risk–related variables. Of the laboratory data obtained for this
study, plasma fibrinogen level showed the strongest association with
FXIa-1AT level. Fibrinogen has been shown to be
independently related to the risk of cardiovascular
disease due to an increase in plasma viscosity and/or platelet
aggregability, ie, thrombogenesis.42 43 Moreover, a
significant correlation between coronary score and fibrinogen
level or age was observed, in agreement with previous
investigations.44 45 We suggest that the factors
associated with the hypercoagulable state contribute to
coronary atherosclerosis. Alternatively, it is
reasonable to assume that contact-phase hypercoagulability, including
increased FXIa-1AT levels, finally lead to fibrin
formation and secondary activation of subsequent
fibrinolysis. Whereas previous studies have shown that
increases in the amount of fibrin degradation products accelerate
newly synthesized fibrinogen production by
hepatocytes,46 47 we propose here that the
activated coagulation system could regulate plasma fibrinogen
levels.
Many studies have revealed that plasma levels of HDL
cholesterol, apo A-I, LDL cholesterol, and apo
B can be used to discriminate patients with and those without CAD as
defined by coronary angiography.48 49 50 51 In the
present study, group 2 patients had lower levels of HDL
cholesterol and apo A-I than those in the control subjects
and in group 1. However, group 2 patients did not have
higher levels of LDL cholesterol or apo B than group 1.
Although we do not know whether data from a larger population would
show a significant association between LDL components and CAD, our
findings partially coincide with those of Maciejko et
al,50 who have suggested that apo A-I is a better index of
CAD than is apo B. It is interesting that among the lipids and
apolipoproteins, FXIa-1AT levels showed significant
correlations with apo A-I and Lp(a) levels. Mitropoulos et
al52 have suggested that the larger lipoprotein particles
provide an increased amount of contact surfaces, which in turn induce
activation of the contact phase of blood coagulation, as well as the
subsequent relationship between factor VII activity and
hyperlipoproteinemia. In our study population,
there were no correlations between FXIa-1AT level and
total cholesterol or triglyceride levels. Thus,
the relationships between increased activation of contact-phase
coagulation and such lipid abnormalities remain to be explained.
In conclusion, our studies have shown that increased activation of the
contact phase of blood coagulation, as detected by elevated
FXIa-1AT levels, occurs in patients with CAD and is also
related to CAD severity. Because it is unknown whether increased
activation of the contact phase of blood coagulation is the cause or
result of the vascular lesion, our findings do not constitute evidence
for a role in CAD pathogenesis. However, our findings may be important
for understanding the progression of the disease and/or propagation of
the atherosclerotic process itself. Further longitudinal and
prospective studies are needed to 1) clarify whether increased
activation of blood coagulation plays an important role in increasing
risk of coronary atherosclerosis and 2)
determine whether FXIa-1AT levels can be used as an
additional index for assessing coronary
atherosclerosis severity, which may be associated with
systemic vascular injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the Japan Foundation for Health Sciences (Dr Murakami), the Japan Research Foundation for Chronic Diseases and Rehabilitation (Dr Komiyama), and the Osaka Gas Health Science Foundation (Dr Takahashi). The authors thank Dr Shuji Matsuura of Wako Pure Chemicals Industries for the production of monoclonal antibody to factor XI/XIa.
Received April 3, 1995; accepted May 30, 1995.
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