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(Stroke. 1996;27:1296-1300.)
© 1996 American Heart Association, Inc.

Articles

Hemostatic Markers in Acute Ischemic Stroke

Association With Stroke Type, Severity, and Outcome

William M. Feinberg, MD; Laurie P. Erickson, MD; Denise Bruck, AAS John Kittelson, MS

the Department of Neurology (W.M.F., L.P.E., D.B.) and the Division of Biostatistics, Arizona Cancer Center (J.K.), University of Arizona Health Sciences Center, Tucson.

Correspondence to William M. Feinberg, MD, Department of Neurology, Arizona Health Sciences Center, Tucson, AZ 85724. E-mail feinberg@u.arizona.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality.

Methods We measured fibrinopeptide A, cross-linked D-dimer, and ß-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model.

Results The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and ß-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality.

Conclusions Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Key Words: cerebral infarction • fibrin fibrinogen degradation products • thrombosis • platelet activation • prognosis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke is a thrombotic process in at least 80% of cases.^{1 2 3} Studies from our laboratory and others in which hemostatic markers were used have shown brisk activation of fibrin formation and platelet activation in the acute phase after stroke.^{4 5 6 7 8 9 10} Several studies have found that the level of elevation of hemostatic markers is associated with mortality after stroke.^{4 5} However, recent studies have also shown that activation of hemostatic markers differs among stroke types,^{11 12 13 14} which might explain an association. We reviewed the acute stroke cases studied in our laboratory to further assess the association of these markers with stroke type and severity and to assess whether these markers provided additional information about prognosis.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Between 1987 and 1991, we obtained blood samples for hemostatic markers on 72 patients (mean age, 69±13 years; range, 25 to 91 years) within the first week of acute ischemic stroke. Five patients were younger than 50 years. The study was approved by our institutional Human Subjects Committee. Informed consent was obtained from all patients or their legal representative.

We collected blood by flawless venipuncture using a 21-gauge butterfly needle. We added 6.3 mL of blood to a plastic tube containing 0.7 mL anticoagulant solution consisting of heparin 1000 U/mL, aprotinin 900 KIU/mL, and EDTA 40 mmol/L. After it was chilled in ice for 20 to 30 minutes, the sample was centrifuged at 3000 rpm (1500g) for 20 minutes at room temperature. Plasma aliquots were stored at -40°C until assayed for D-dimer and FpA.

Four milliliters of blood was collected into a prechilled freshly prepared 5 mL syringe containing 1 mL acid-citrate-dextrose buffer, 0.75 mL of 1.0 mol/L acetylsalicylic acid, and 1 µg prostaglandin E₁. After it was chilled in ice for 20 to 30 minutes, the sample was centrifuged at 8500 rpm (8600g) for 25 minutes at 4°C. Plasma aliquots were stored at -40°C until assayed for BTG.

We measured D-dimer, FpA, and BTG using ELISA methodology.^{15 16 17 18 19 20} We used commercial ELISA kits (D-dimer, American Diagnostica; FpA and BTG, American Bioproducts). All aliquots were assayed within 3 months of collection. Assays were performed according to the insert instructions, with all samples assayed in duplicate. Elevated results were verified by repeated analysis. D-dimer and FpA results were expressed as nanograms per milliliter and BTG results as international units per milliliter. Our laboratory normal values (mean±SD) are 77±42 for D-dimer, 4.6±5.9 for FpA, and 22±11 for BTG.

Strokes were classified as atherothrombotic, cardioembolic, small-vessel occlusive (lacunar), or unknown cause as previously described based on standard criteria.^{1 6 21} Initial stroke severity was assessed with the Toronto Stroke Scale.²²

Follow-up data on stroke patients were obtained through chart review and contact with the patient or the patient's family or physician if necessary. We were able to obtain current information on 70 of 72 patients. The mean age was 69±14 years, and there were 34 men and 36 women. Median follow-up time (median of the censoring distribution) was 1.22 years (range, 22 days to 3.3 years). We obtained death certificates on all patients who had died.

Survival curves were constructed according to the method of Kaplan and Meier²³ with variance estimates given by Greenwood's formula.²⁴ The hemostatic markers were dichotomized to provide approximately equal numbers of deaths in each group. Survival associations were analyzed with the Cox proportional hazards method, with all reported probability values computed from the score statistic.²⁵

Univariate analysis was used to examine correlations between each of these markers and survival after stroke. The data for hemostatic markers were analyzed in a logarithmic scale to reduce the skew in the data and avoid statistical problems resulting from a few overly influential data points. Univariate analysis was also used to assess the association between survival and clinical characteristics (age, sex, hypertension, diabetes, coronary artery disease, smoking, alcohol use, and antithrombotic therapy at time of stroke), stroke type, and stroke severity (Toronto Stroke Scale). Multivariate Cox proportional hazards models were used to assess confounding between hemostatic markers and other clinical variables.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient characteristics and mean levels of hemostatic markers are summarized in Table 1. Initial marker values grouped according to stroke type are shown in Table 2. Nineteen patients had cardioembolic stroke, 22 atherothrombotic stroke, 14 small-vessel occlusive stroke, and in 15 patients the diagnosis was "other/uncertain." Patients with cardioembolic stroke had significantly higher log(D-dimer) values than those with noncardioembolic stroke (P=.033, two-tailed t test). There were trends for elevated levels of log(BTG) and log(FpA) values in cardioembolic patients compared with noncardioembolic patients (P=.08 and P=.15, respectively).

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

View this table: [in this window] [in a new window]   Table 2. Mean Initial Values of D-Dimer, FpA, and BTG in Various Patient Groups

Fourteen patients had died and 56 patients were alive at the time of this study. The clinical characteristics, hemostatic marker levels, and cause of death in the 14 people who died are shown in Table 3.

View this table: [in this window] [in a new window]   Table 3. Clinical Characteristics and Initial Levels of Hemostatic Markers in Patients Who Died During Follow-up Period

Univariate survival analysis showed that age, stroke type (cardioembolic versus other), stroke severity (Toronto Stroke Scale score), and the logs of each of the hemostatic markers were significantly associated with patient mortality (Table 4). The effect of elevated marker levels is illustrated in the Figure; in these survival curves the marker levels were dichotomized to provide approximately equal information in the two groups. To further evaluate whether hemostatic markers are simply surrogate markers for other prognostic variables such as stroke severity, we examined survival using multivariate proportional hazards models.²⁵ Each hemostatic marker was examined in a model that included the clinical characteristics found to be significant by univariate analysis (age, stroke type, and initial stroke severity [Toronto Stroke Scale score]). In these multivariate survival models both stroke severity and each of the hemostatic markers were significant predictors of mortality. We note that the multivariate models are based on only 14 deaths and therefore may not be reproducible. However, these results indicate that hemostatic markers provide prognostic significance independent of usual clinical characteristics.

View this table: [in this window] [in a new window]   Table 4. Univariate Analysis of Survival: Association With Patient Characteristics, Stroke Severity, and Hemostatic Marker Levels

View larger version (38K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves of mortality under a dichotomization of hemostatic marker levels. The dichotomization was chosen to provide an equal number of deaths in each group. Top, D-dimer; middle, FpA; and bottom, BTG.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Elevated levels of hemostatic markers measured in the acute phase after ischemic stroke were strongly associated with subsequent mortality. The levels of these markers were also associated with stroke severity and stroke type. However, after we adjusted for age, stroke severity, and stroke type, an association with survival persisted. Thus, these markers appear to provide additional information regarding prognosis after a stroke.

The strongest association was found for D-dimer, which is formed when cross-linked fibrin clot is degraded by plasmin.^{17 18 19 26} D-Dimer is thus an index of both clot formation and fibrinolysis. An association was also found for FpA, a measure of fibrin formation and thrombin activity,^{15 16} and BTG, a measure of platelet activation.^{27 28} The association of all three markers suggests that it is activation of the coagulation system in general that is associated with increased risk of subsequent mortality.

Mortality was spread evenly over the duration of follow-up and not concentrated shortly after the stroke (Table 3, Figure). Thus, these elevated levels of hemostatic markers do not appear to be linked to an immediate process causing death. Previous studies in which other coagulation markers were used have suggested an association with mortality after stroke.^{4 5 29} In the study of Anzola et al,²⁹ low levels of protein C after stroke were associated with increased mortality. The authors suggested that these low levels of protein C did not result from congenital deficiencies but rather reflected "massive activation of coagulation factors." Our findings that increased activation of the coagulation system after stroke is associated with subsequent mortality support this postulate.

Our study confirmed higher levels of these markers, particularly D-dimer, in patients with cardioembolic stroke, as has been described by other investigators.^{8 11 12 13 14} Patients with cardioembolic stroke have a higher mortality rate than those with noncardioembolic stroke.³⁰ Conversely, patients with small deep (lacunar) infarction have a low mortality rate³¹ and in most series have had normal levels of hemostatic markers.^{32 33 34} However, an association between hemostatic markers and mortality persisted in our study after we adjusted for stroke type.

Differences in marker levels among stroke types have been used to suggest differences in pathophysiology in different types of stroke.^{11 12 14} However, previous studies did not adjust for clinical characteristics such as stroke severity. Our data suggest that initial stroke severity is an important determinant of hemostatic marker levels, and this variable should be considered in studies of hemostatic markers in stroke.

The pathophysiological reason for an association between hemostatic markers and prognosis is uncertain. Fibrinogen is a strong independent risk factor for stroke and myocardial infarction.^{35 36 37} Fibrinogen levels increase after stroke,^{35 38} and elevated fibrinogen levels are associated with an increased risk of further cardiovascular events in stroke survivors.^{35 39} An increased fibrinogen level is associated with mortality after myocardial infarction⁴⁰ and in patients with claudication.⁴¹ Elevated fibrinogen levels may affect coagulation not only through thrombin-mediated generation of fibrin but also through the important role of fibrinogen in platelet activation.^{35 42} We did not simultaneously measure fibrinogen levels in our study, but one explanation for our results might be that patients with higher baseline levels of fibrinogen had higher levels of coagulation markers when the hemostatic system was activated. It is likely, however, that the explanation is more complicated.

In this study we did not examine markers of other components of the coagulation system, particularly fibrinolysis. Hemostasis is affected by a variety of fibrinolytic activators and inhibitors that may be implicated in the genesis of cerebral ischemia.^{7 32 43} Increased levels of the hemostatic markers in this study might identify patients with reduced release of tissue plasminogen activator or increased levels of plasminogen activator inhibitors.^{32 44} These patients might be predisposed to intense activation of coagulation in response to a variety of stimuli such as infection or trauma. Rather than reflecting the extent of damage in the brain, these markers may reflect something fundamental about the patient's coagulation system. We speculate that stroke patients in whom the coagulation system reacts most intensely may be at greater risk for subsequent thrombotic events. In this way a stroke may serve as a "stress test" of the reactivity of the coagulation system. It would be hypothetically valuable to have a safe way to stimulate the hemostatic system to identify those whose coagulation systems respond most actively to stimuli. These might be the patients at highest risk for subsequent events, in whom more aggressive antithrombotic therapy might be appropriate.

Hemostatic markers are elevated by underlying conditions other than acute stroke, such as infection, surgery, and cancer. We were careful to exclude from our study patients with any of these conditions or other thrombotic events within 6 months. However, it is possible that some patients had unrecognized conditions that elevated their coagulation marker levels and also increased the risk of death. The three patients with the highest D-dimer levels died within 1 month of their stroke, suggesting the presence of systemic disease (Table 3). In two of these three, however, the attending physician felt that the stroke itself was the proximate cause of death. Of the patients who died after the first month, 5 of 10 with a known cause of death had ischemic heart disease. This is in accord with previous studies of patients with stroke.⁴⁵ Patients who respond to a stroke with marked activation of the coagulation system may be those who are at risk for more intense activation in response to coronary triggering events.

We attempted to assess the relationship between hemostatic markers and long-term disability in stroke survivors. We collected data regarding patient's current functional status and classified survivors according to the Rankin Disability Scale.⁴⁶ We categorized patients as having no or mild disability (Rankin grade 1, 2, or 3) or major disability or death (Rankin grade 4, 5, or dead) and analyzed the data in a manner similar to our mortality analysis. We found significant univariate associations between disability at time of follow-up and patient age, log(Toronto Stroke Scale score), log(D-dimer), and log(BTG) (data not shown). Analysis with multivariate models suggested that most of this association was accounted for by initial stroke severity as measured by the Toronto Stroke Scale score. In these multivariate models, the association with hemostatic markers was no longer significant after we adjusted for stroke severity and age. This analysis of disability is not reported in detail because it is based on a retrospective analysis in which disability was not measured at any fixed time after stroke. These associations could be biased by the way in which we collected follow-up data. A prospective study of hemostatic markers and functional outcome appears warranted.

These data may have clinical utility. Although FpA and BTG measurements require special sample preparation and handling, D-dimer measurement is relatively simple and is minimally affected by artifact or venipuncture technique. D-dimer measurement is now available in many clinical laboratories. It is important to measure quantitative D-dimer by ELISA rather than the semiquantitative latex agglutination assay.⁴⁷ Our data suggest that a D-dimer measurement in acute stroke patients may provide valuable prognostic information regarding risk of death. Furthermore, since the association with mortality appears to be with activation of the hemostatic system in general (rather than any specific marker), there may be other indices of coagulation that are more generally applicable.

In summary, hemostatic markers measured during the first week after acute ischemic stroke are correlated with subsequent mortality, and this correlation persists after adjustment for patient age, stroke severity, and stroke type. Elevated hemostatic markers identify stroke patients at increased risk for death and may provide valuable additional prognostic information.

	Selected Abbreviations and Acronyms

 

BTG = ß-thromboglobulin D-dimer = cross-linked D-dimer ELISA = enzyme-linked immunosorbent assay FpA = fibrinopeptide A

	Acknowledgments

 
This study was supported by grants from the Arizona Affiliate of the American Heart Association and the Arizona Disease Control Research Commission.

Received March 13, 1996; accepted May 15, 1996.

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