© 1997 American Heart Association, Inc.
Articles |
The Relationship of Soluble Fibrin and Cross-linked Fibrin Degradation Products to the Clinical Course of Myocardial Infarction
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
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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
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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 antibody–based 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.
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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 non–cross-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.
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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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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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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 agent–induced 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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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%).
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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 activator–mediated 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 non–fibrin-specific tag antibodies may overestimate concentrations of XL-FDPs because in plasma, cross-linked fibrin species may be associated with both cross-linked and non–cross-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.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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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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