Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:628-633
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:628-633.)
© 1997 American Heart Association, Inc.
The Relationship of Soluble Fibrin and Cross-linked Fibrin Degradation Products to the Clinical Course of Myocardial Infarction
L. Veronica Lee;
Gregory A. Ewald;
Clark R. McKenzie;
;
Paul R. Eisenberg
From the Washington University School of Medicine, Cardiovascular
Division, St. Louis, Mo.
Correspondence to Paul R. Eisenberg, MD, MPH, Washington University School of Medicine, Cardiovascular Division, Box 8086, 660 S Euclid Ave, St. Louis, MO 63110. E-mail eisenber{at}visar.wustl.edu
 |
Abstract
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Abstract Recently, increases in the plasma concentration of
soluble
fibrin (SF) have been suggested to be sensitive and specific
for
myocardial infarction (MI). However, the relationship between
elevations
in the SF concentration and the onset of symptoms and
clinical
course of MI is unknown. In addition, there are no data
regarding
the relationship between SF concentrations and concentrations
of
other markers of procoagulant (fibrinopeptide A
[FPA]) and fibrinolytic
(cross-linked fibrin degradation products
[XL-FDPs]) activity
in patients with MI. In this study,
concentrations of SF were
measured with a novel antigen-based assay for
93 MI patients
and 29 control subjects, and the relationship between SF
concentrations
and those of XL-FDPs and FPA was determined. Increases
in SF,
FPA, and XL-FDP concentrations were documented in 55.9%,
45.2%,
and 73.9%, respectively, of patients with MI, but there was
no
relationship between the concentrations of these markers.
Increases in
the concentration of SF or XL-FDPs did not show
a relationship to
increases in the concentration of FPA. Concentrations
of XL-FDPs but
not of SF were elevated to a greater extent in
patients with MI
complications (defined as death, ventricular
arrhythmia,
severe congestive heart failure, or mural
thrombus). Increases
in SF and XL-FDPs were not sensitive enough for
the diagnosis
of MI, but increased concentrations of XL-FDPs appear to
predict
those patients who are at higher risk for MI-related
complications.
Key Words: myocardial infarction soluble fibrin fibrinopeptide A cross-linked fibrin degradation products
 |
Introduction
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Plasma concentrations
of fibrin and fibrinogen moieties specific
for the enzymatic activity
of thrombin and plasmin, such as
FPA, XL-FDPs, and SF, are useful in
characterizing procoagulant
fibrinolytic activity in patients with
MI.
1 2 3 4 Increases
in the concentration of FPA, a marker of
fibrin formation, reflect
thrombin activity in these patients, and
concentrations are
very high in samples obtained early after the onset
of symptoms.
2 Even in patients who are not given
anticoagulants, FPA levels
decrease rapidly after admission, presumably
because thrombin
activity is transient and the half-life of FPA short
(

3 to 5
minutes).
5 Persistent increases in FPA levels
may indicate
an increased risk for MI-related complications, but
because
obtaining blood samples in which accurate measurement can be
made
is difficult, assessment of FPA has been of limited value in
clinical
practice. Plasma concentrations of XL-FDPs, which reflect
plasmin
turnover of cross-linked fibrin, are also increased in patients
with
MI,
1 3 6 7 pulmonary
embolism,
8 9 10 11 12 and peripheral
vascular
disease.
13 14 15 16 17 However, the XL-FDP concentration
is a more
sensitive marker of thrombosis than is the FPA level,
partially because
of the longer half-life of the former (3 to
6 hours).
18 We
have shown that marked increases in the concentration
of XL-FDPs are
indicative of thrombotic complications in patients
with MI,
particularly in those who present more than 8 hours
after the onset
of symptoms, and that these increases likely
reflect enhanced
physiological fibrinolysis as a
result of ongoing
thrombosis or a more pronounced fibrinolytic response
to coronary
thrombosis and infarction.
3
Because it may also be a more sensitive indicator of ongoing thrombosis
than is FPA, has a longer half-life (several hours), and is less
susceptible to sampling artifact, SF has recently been investigated as
a marker of thrombin activity. Previous studies have shown that SF is
increased in patients with MI,1 19 20 but the relationship
of SF concentration to the onset of symptoms, the clinical course of
MI, and other measures of procoagulant or fibrinolytic activity is
unclear. Furthermore, previous studies in which SF was measured in
plasma used assays that were not specific for fibrin moieties. We
therefore undertook a study using a novel monoclonal antibodybased
assay for SF. The present study was designed to characterize the
relationship of SF concentrations to those of FPA and XL-FDPs and to
determine the extent to which increases in the concentrations of SF are
a useful marker of MI and its complications.
 |
Methods
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Patients who were admitted to the Barnes Hospital Cardiac Care
Unit
with suspected MI were considered eligible for enrollment if
they
did not have any of the following: another condition requiring
treatment
with anticoagulants; a previously diagnosed active
malignancy,
hemostatic disorder, or chronic renal failure; or limited
venous
access. In some instances, patients admitted to the Cardiac
Care
Unit with the diagnosis of MI had been treated with
thrombolytic
and/or anticoagulant therapy before
admission. A diagnosis of
MI was made when symptoms of ischemia
were prolonged (>30
minutes) and there was electrocardiographic
evidence of ischemia
and an elevation of CK-MB to >6 mg/mL
(CK-MB, Stratus Assay).
The study was approved by Washington
University's Human Studies
Committee. Blood samples were drawn at the
time of admission
to the hospital for measurement of SF, XL-FDP, and
FPA concentrations.
Patients were followed up throughout their
hospitalization for
complications of MI, which were defined a priori as
severe CHF
(confirmed by chest radiograph), sustained
ventricular tachycardia,
mural thrombus, or
death, since these complications are easily
defined clinically and were
previously found to be associated
with increased thrombin generation
and fibrinolytic activity.
3 Control blood samples were
also obtained from 33 normal, healthy
volunteers who gave their
informed consent.
The investigator who performed the data collection and entry of
clinical demographics was blinded to all assay results. Clinical end
points and complications were reviewed and evaluated by two members of
the research team who were blinded to the SF, FPA, and XL-FDP assay
results.
Blood Sampling Procedure
Specially trained technicians obtained all of the blood samples
by nontraumatic venipuncture, and stringent quality-control
procedures were followed as previously described.2
Samples were collected into precooled tubes containing 5 mmol/L
EDTA, 20 mmol/L PPACK, and 1000 KIU/mL aprotinin; immediately
cooled to 4°C; and centrifuged. Platelet-poor plasma was
separated and frozen at -20°C for
24 hours and then frozen at
-70°C until batch testing was performed.
Assay for SF
SF was measured with a recently developed assay based on an
ELISA that incorporates a monoclonal capture antibody specific for a
neoepitope on the
-chain of fibrin that is formed after FPA cleavage
(Ortho Diagnostics Systems)18 and a "tag"
monoclonal antibody specific for the D region of fibrin in
fibrinogen21 (4D2, AGEN) conjugated to horseradish
peroxidase. In initial studies to define the normal range of
measurements with this assay, stored plasma samples from 93 normal
blood bank donors were analyzed and found to have a mean SF
concentration of 0.69 µg/mL, with a normal upper limit of 1.45
µg/mL.22 In our study, the mean SF level in freshly
collected blood samples from healthy volunteers was 1.73±1.38 µg/mL,
with a normal upper limit of 4.5 µg/mL.
Assay for XL-FDPs
To measure XL-FDPs, we used a newly developed assay based on an
ELISA that incorporates a monoclonal antibody specific for the
cross-linked D region of fibrin as the capture
antibody21 23 (3B6, AGEN) and a fibrin-specific tag
antibody (ID2, D-Dimer GoldAGEN) conjugated to horseradish
peroxidase.24 The use of the fibrin-specific tag antibody
obviates the measurement of any noncross-linked fibrin(ogen)
degradation products complexed with XL-FDPs.6 This
assay appears to be more specific for higher-molecular-weight XL-FDPs.
Measured concentrations of XL-FDPs with this assay were 45 ng/mL in 60
healthy volunteers and 70 ng/mL in 60 hospitalized patients without a
thrombotic condition.25
Assay for FPA
FPA was measured by radioimmunoassay after bentonite adsorption
of the plasma (Byck-Sangtek Diagnostica) as previously
described.2 26 The normal upper limit for FPA level is 2.0
ng/mL in our laboratory.
Fibrin Formation In Vitro
To characterize fibrin formation in vitro, pooled, citrated
plasma was recalcified with 25 mmol/L CaCl2 and
incubated with 0.1 nmol/L thrombin at 37°C. Fibrin formation was
measured in serial aliquots of the reaction mixture by use of the
assays for FPA and SF.
Statistical Methods
All results are reported as mean and SE. The normal upper limits
for SF and XL-FDPs were calculated based on the sum of two times the SD
and the mean concentration in plasma from normal volunteers. Further
group testing was done with
2 tests and ANOVA. SF,
XL-FDP, and FPA data were logarithmically transformed before
analysis. Sensitivity, specificity, and positive and negative
values were calculated by standard formulas. Patients who developed >1
MI-related complication were counted only once in the data
analysis.
 |
Results
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Characteristics of Patients With MI
Samples were obtained from 93 patients who were admitted to
the
Barnes Hospital Cardiac Care Unit with the probable diagnosis
of MI,
which was subsequently confirmed by a measured increase
in CK-MB
levels. Clinical characteristics of the patients are
listed in Table 1

. Study patients suffered the following complications
associated
with MI during their hospitalization: 11 patients (11.8%)
had
severe CHF, 10 patients (10.8%) had sustained
ventricular tachycardia,
3 patients (3.2%) had
mural thrombus, and 8 patients (8.6%)
died. Patients who suffered >1
MI-related complication were
counted only once with their most severe
outcome (death>CHF>ventricular
tachycardia>mural thrombus), for
an overall event rate of
29.0%, a death rate of 8.6%, a CHF rate of
9.7%, a sustained
ventricular tachycardia rate
of 8.6%, and mural thrombus rate
of 9.2%. More than three fourths
(79.1%) of patients had none
of the above MI-related complications
(Fig 1

). Of note, no patient
developed a reinfarction
during hospitalization.

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Figure 1. Presence of MI-related complications, defined
a priori as severe CHF, ventricular (vent.)
tachycardia, mural thrombus, or death. If a patient had >1
complication, the most severe outcome
(death>CHF>ventricular tachycardia>mural
thrombus) was used to classify the event and the patient was counted
only once. The overall event rate was 29.0%: death, 8.6%; CHF, 9.7%;
sustained ventricular tachycardia, 8.6%; and
mural thrombus, 2.1%. More than three fourths (79.1%) of patients had
none of the above MI-related complications.
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Time From Onset of Ischemic Symptoms to Arrival at the
Hospital
The majority of patients (73%) arrived at the hospital >10 hours
after the onset of ischemic symptoms. There was no relationship
between the concentrations of the markers for thrombotic or
fibrinolytic activity and the interval between the onset of
ischemic symptoms and blood sampling (FPA: r=.06,
P=.48; XL-FDPs: r=.16, P=.21; SF:
r=.12, P=.24). MI complications were more common
in patients who presented >10 hours after the onset of
ischemic symptoms (P=.01).
Relationship of Physiological
Fibrinolysis and Thrombotic Activity
Concentrations of SF and XL-FDPs were markedly elevated in
patients with MI (32.4±5.3 µg/mL and 234.5±40.4 ng/mL,
respectively) compared with those in normal volunteers (1.7±0.26
µg/mL, and 22.6±2.9ng/mL, respectively), and concentrations of
FPA (12.7±1.5 ng/mL) were elevated compared with the normal upper
limit for our laboratory of 2.0 ng/mL. Although changes in the
concentrations of FPA and SF were similar when soluble fibrin was
produced in vitro (Fig 2
), the correlation of FPA with
SF levels in patients was poor (r=.08). SF was increased in
56% of the patients; 46% of the patients also had increases in
XL-FDPs and 22% had increases in fibrin generation and fibrinolytic
activity (P<.0001). There was no relationship between
increases in the concentration of XL-FDPs and SF (r=.12) or
of XL-FDPs and FPA (r=.20; Fig 3
).

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Figure 2. Relationship of physiological
fibrinolysis and thrombotic activity in vitro. Pooled,
recalcified, citrated plasma was incubated with 0.1 nmol/L thrombin at
physiological temperature. Fibrin formation was
measured in serial aliquots to determine the concentrations of FPA
(ng/mL) and SF (µg/mL).
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Figure 3. Lack of correlation between SF and XL-FDPs in MI
patients. The log of the concentrations for SF and XL-FDP are plotted,
and the normal upper limits for each assay (4.5 µg/mL and 60 ng/mL,
respectively) are demarcated by the horizontal (SF) and vertical
(XL-FDP) line. Slanted line represents the line of regression
(r=.12).
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Sixteen patients had received thrombolytic therapy
before they were admitted to the hospital; all had elevations of
XL-FDPs (524.4±618.9 ng/mL) that were higher than those of patients
not treated before admission (169.7±284.9 ng/mL; P=.002).
These data are consistent with the proteolysis of cross-linked
fibrin in patients treated with thrombolytic agents.
Results from these patients were excluded in the analysis of
the relationship between XL-FDPs and MI complications because we
hypothesized that thrombolytic agentinduced increases
in XL-FDPs would occur independent of thrombotic events. Increases in
FPA were also related to prior administration of
thrombolytic therapy (prior
thrombolytic therapy, 18.7±19.5 ng/mL; no prior
thrombolytic therapy, 11.3±13.0 ng/mL;
P=.038), but there was no relationship between the increases
in SF formation and prior thrombolytic therapy
(P=.17).
Correlation of Complications During Hospitalization With Thrombotic
and Fibrinolytic Activity
Concentrations of XL-FDPs were significantly higher in patients
who suffered MI complications (431.1±92.4 ng/mL) than in those who did
not (154.1±38.9 ng/mL; P=.02). However, concentrations of
SF and FPA were not significantly different in patients with
complications (24.5±7.6 µg/mL and 14.6±2.9 ng/mL, respectively) and
in those patients without them (36.0±7.3 µg/mL, P=.21 and
10.1±1.8 ng/mL, P=.41). The exclusion of data from patients
who received thrombolytic therapy before admission did
not affect the predictive value of increased concentrations of XL-FDPs
for complications; levels of XL-FDPs were 324.5±83.3 ng/mL in patients
with complications compared with 110.6±28.9 ng/mL in those without
(P=.0028; Fig 4
).

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Figure 4. Association of concentrations of SF, XL-FDPs, and
FPA with MI-related complications. Each graph illustrates the mean
concentration (with SE) for SF, XL-FDPs, or FPA. Patients who had
MI-related complications are represented by black bars;
patients who did not have any complications are represented
by the striped bars. MI-related complications include death,
ventricular arrhythmia, severe CHF, and mural
thrombus. All MI patients are included in the graphs of SF and FPA
concentrations. Only patients who did not receive
thrombolytics before measurement of XL-FDP
concentration are included in the center graph. Results from these
patients were excluded in the analysis of the relationship
between XL-FDPs and complications because of the hypothesis that
thrombolytic agentinduced increases in XL-FDPs occur
independent of thrombotic events.
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Sensitivity and Specificity of SF and XL-FDPs for MI
Increases in SF (>4.5 µg/mL) were specific for MI (89.7%), but
not sensitive (55.9%; Table 2
). In our patients, the
positive predictive value was 94.5% and the negative predictive value
38.8%. Increases in the concentration of XL-FDPs (>60 ng/mL) were
specific (100%) for MI but not sensitive (45.2%). The positive
predictive value of XL-FDPs for MI was 100%, but the negative
predictive value was poor (36.3%). When a value of 60 ng/mL XL-FDPs
was used to predict MI-related complications, sensitivity was 74.0%
and specificity 65.2%, with a negative predictive value of 86%.
Although increasing the value (to 100 ng/mL) considered to indicate a
likelihood of complications increased the specificity to 97%, it
decreased the sensitivity to 40%. The combined use of both SF and
XL-FDPs as predictive indicators improved the sensitivity to detect the
group at risk for MI-related complications (88.9%) but decreased the
specificity (22.7%).
 |
Discussion
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|---|
Our results confirm the findings of previous studies that
increases
in thrombin and plasmin activity in patients with MI (defined
a
priori as severe CHF, ventricular
tachycardia, mural thrombus,
or death) can be characterized
with plasma markers such as FPA,
SF, and XL-FDPs. In this study, we
found that SF and XL-FDP
concentrations were increased 55.9% and
45.2%, respectively,
in patients with MI but that these assays were
not sensitive
for detecting MI. Although the specificity of these
markers
for diagnosis of MI was high in our study (SF, 89.7%; XL-FDP,
100%),
we had the benefit of data from healthy volunteers for
comparison,
and it is likely that the specificity would be considerably
lower
in a population of hospitalized patients with concomitant
illnesses
that increase concentrations of SF and XL-FDPs.
Our results suggest that although SF and XL-FDPs are not useful in the
diagnosis of MI, these markers may be clinically useful as a means of
monitoring the dynamics of thrombosis and fibrinolysis
in patients with MI. Measurements of SF concentrations are a sensitive
marker of ongoing thrombin activity. In this study, increases in SF
concentrations measured with the specific antibody-based assay were as
sensitive as FPA concentrations for detecting fibrin elaboration in
vitro. Although SF concentrations in vivo did not correlate with FPA
concentrations, they were increased in the majority of patients with
MI. This suggests a potential role for the measurement of SF in
characterizing the response of thrombin to anticoagulant interventions.
The assay we used to make these measurements offers several advantages
over more routinely used nonimmunologic assays. For example, assays
that measure SF activity by stimulation of tissue-type
plasminogen activatormediated
plasminogen interactions are not specific, because a
variety of fibrinogen degradation products can act as a cofactor
for tissue-type plasminogen
activator.27 Furthermore, such assays cannot
be used on blood from patients treated with fibrinolytic agents. In
this study, SF concentrations were not altered in patients who had been
treated with streptokinase or tissue-type plasminogen
activator. Electrophoretic assays are also not specific and
are therefore not clinically useful.6 19
Our findings confirm the fact that elevated concentrations of XL-FDPs
are a risk factor for development of MI complications (defined as
severe CHF, ventricular tachycardia, mural
thrombus, or death). We previously showed a relationship between levels
of XL-FDPs and MI-related complications in 112 patients with MI by use
of an assay that incorporates a tag antibody that recognizes both
fibrin and fibrinogen degradation products.3 We have
also shown that assays based on nonfibrin-specific tag antibodies may
overestimate concentrations of XL-FDPs because in plasma, cross-linked
fibrin species may be associated with both cross-linked and
noncross-linked fibrinogen molecules.6 This is the
likely explanation for the low upper limit of normal for this assay,
which uses a fibrin-specific tag antibody (<60 ng/mL compared with
<300 ng/mL in the older assay), and the slightly greater sensitivity
of the results for MI that we observed (35.7% and 45.2%,
respectively). These results support the hypothesis that elevations of
XL-FDPs in patients with MI complications reflect enhanced
physiological fibrinolysis that
results from more intense or prolonged thrombosis or from thrombosis of
other vascular beds (eg, deep venous thrombosis). The elevations in the
concentrations of SF and XL-FDPs detected in this study were not the
result of delayed clearance in the setting of impaired cardiac or renal
function, since blood samples were drawn on admission of subjects to
the hospital, which preceded the onset of complications in the majority
of patients. In addition, we have previously shown that increases in
the concentration of XL-FDPs are not related to infarct
size.3
SF and XL-FDPs are unlikely to be of value in the diagnosis of MI
because of their low sensitivity and the availability of assays for
other markers of myocardial injury that are more sensitive and specific
(eg, CK-MB isoforms,28 29 troponin I,30 31 32 33 34
and myoglobin35 36 37 ). However, increased concentrations of
XL-FDPs may be useful in the evaluation of risk in patients with MI.
Ridker et al38 have demonstrated that elevated XL-FDP
concentrations, though not an independent risk factor for MI, are a
marker of increased physiological
fibrinolysis before the development of MI. Fowkes et
al39 have shown that increased XL-FDP concentrations in
patients with peripheral artery disease are indicative of
an increased likelihood of MI. Measurements of XL-FDPs have also been
suggested as a means to monitor the potential for rethrombosis after
angioplasty40 41 and medical therapy (eg,
warfarin).42 The results of this study suggest that
increases in XL-FDPs may be a marker of thrombotic risk and may
identify patients who require more aggressive antithrombotic
intervention.
The availability of rapid whole-blood assays for the measurement of
fibrinolytic and thrombotic activity offers the potential to
characterize this dynamic process in patients with MI. One such assay
for XL-FDPs (SimpliRED D-dimer) has been reported to be sufficiently
sensitive to exclude deep venous thrombosis, pulmonary
embolism, and endotoxemia.43 44 45 46 47 The results of this study
suggest that these markers are useful clinical tools for predicting
complications of MI as well as other thrombotic events. Future studies
will define the role of these assays in monitoring the effects of an
anticoagulant therapy.
 |
Selected Abbreviations and Acronyms
|
|---|
| CHF |
= |
congestive heart failure |
| CK-MB |
= |
MB isoenzyme of creatine kinase |
| ELISA |
= |
enzyme-linked immunosorbent assay |
| FPA |
= |
fibrinopeptide A |
| MI |
= |
myocardial infarction |
| SF |
= |
soluble fibrin |
| XL-FDP(s) |
= |
cross-linked fibrin degradation product(s) |
|
 |
Acknowledgments
|
|---|
This study was supported in part by SCOR in Coronary and
Vascular
Heart Disease (grant HL-17646), National Heart, Lung, and
Blood
Institute, National Institutes of Health, Bethesda, Md (to
P.R.E.).
Received December 29, 1995;
accepted April 30, 1996.
 |
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