(Stroke. 2001;32:133.)
© 2001 American Heart Association, Inc.
Original Contributions |
Prognostic Influence of Increased C-Reactive Protein and Fibrinogen Levels in Ischemic Stroke
From the Department of Neurology and Neurorehabilitation, Villa Pini d’Abruzzo Care Center, Chieti, Italy.
Correspondence to Dr Mario Di Napoli, MD, Department of Neurology and Neurorehabilitation, Casa di Cura Villa Pini d’Abruzzo, Via dei Frentani 228, 66100 Chieti, Italy. E-mail mariodinapoli{at}katamail.com
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Abstract |
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Background and Purpose—The prognostic influences of fibrinogen and C-reactive protein (CRP) levels and their relations in ischemic stroke have not been well described. The aim of this study was to investigate and compare the 1-year prognostic influences of fibrinogen and CRP levels on outcome in ischemic stroke.
Methods—Fibrinogen and CRP were determined within 24 hours after stroke and related to 1-year outcome in 128 patients with first-ever ischemic stroke. The Kaplan-Meier technique was applied in survival analysis. Multiple logistic regression analysis was used to evaluate the associations between risk factors and outcome.
Results—The
probabilities of death or new vascular event were 21.1%, 27.9%, and
51.7% (P=0.0172,
2 for trend), respectively, in patients
stratified by tertiles of fibrinogen (<3.78, 3.78 to 6.17, and >6.17
g/L). The probabilities of a primary end point were 12.1%, 29.7%, and
54.8% (P=0.0004),
respectively, after stratification of patient data by tertiles of CRP
level (<5, 5 to 33, and >33 mg/L). In multiple logistic regression
analysis, higher CRP levels (odds ratio, 2.39; 95% CI, 1.28 to
4.49; P=0.0066) and stroke
severity on the Canadian Neurological Stroke Scale (odds ratio, 2.37;
95% CI, 1.01 to 5.58;
P=0.0472) were independently
associated with death or new vascular
event.
Conclusions—Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.
Key Words: C-reactive protein • fibrinogen • prognosis • risk factors • stroke, ischemic
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is an association between increased fibrinogen levels and early signs of atherosclerosis in asymptomatic individuals.1 2 Elevated fibrinogen levels might therefore be an indicator of, and contribute to, the formation and progression of atherosclerotic plaques. Increased fibrinogen levels have also been identified as an important risk factor for future cardiovascular events in several prospective long-term studies of apparently healthy individuals3 4 5 6 7 and patients with stable coronary artery disease.8 9 10
Fibrinogen also acts as an acute-phase protein and increases after stroke,11 and elevated fibrinogen levels are associated with an increased risk of further cardiovascular events in stroke survivors.11 12 An increased fibrinogen level is associated with mortality after myocardial infarction13 (MI) and in patients with claudication.14
There are other signs of inflammation in ischemic stroke, such as increased levels of inflammatory cytokines15 and C-reactive protein (CRP).16 17 18 19 In a recent study increased CRP levels were associated with a more severe short-term prognosis in patients with ischemic stroke.20 Furthermore, a strong correlation between fibrinogen and CRP levels was found in a large prospective study of patients with angina pectoris.21
The aim of this study was to investigate and compare the 1-year prognostic influences of fibrinogen and CRP levels on outcome in a well-defined population of patients with first-ever ischemic stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied all patients who were admitted to the Villa Pini d’Abruzzo Care Center (Chieti, Italy) with a diagnosis of ischemic stroke and included in the Villa Pini Stroke Data Bank between March 1 and December 31, 1998. The Villa Pini d’Abruzzo Care Center is an acute, rehabilitation, and long-term care center. This center has no specific selection criteria for the admission of stroke patients. The Villa Pini Data Bank is an ongoing hospital-based stroke data bank started on March 1, 1998, in the Department of Neurology and Neurorehabilitation to continue for at least 5 years. Informed consent was obtained from all patients included or their legal representative. The study was approved by our institutional committee.
Cerebral infarction was defined as a focal neurological deficit of sudden onset that persisted beyond 24 hours in surviving patients, documented by brain CT or by MRI indicating the presence of infarction or the absence of hemorrhage.22
Study Protocol, Data Collection, and
Follow-Up
All patients were screened according to a strict
protocol consisting of complete medical history, full neurological
examination, standardized blood tests, at least 1 and usually 2 CT
scans of the brain or MRI, duplex scanning of the carotid arteries, and
a cardiac analysis that included standard 12-lead ECG and
transthoracic echocardiography and, if
indicated, 24-hour ECG monitoring and transesophageal
echocardiography. The nature and time course of
symptoms were recorded by means of a detailed checklist. Initial
stroke severity and disability were assessed by the Canadian
Neurological Stroke Scale (CNSS) and Barthel Index,
respectively.23 24
Finally, patients were classified into 4 subgroups of different presumed etiology: atherothrombotic, cardioembolic, small-vessel occlusive (lacunar), or undetermined cause, as previously described, on the basis of standard criteria.22 25 26 27
Cerebrovascular risk factors, such as never, current, or
previous cigarette smoking, alcohol abuse (>100 g/d),
hypercholesterolemia (history of
hypercholesterolemia and/or fasting total
cholesterol level >200 mg/dL),
hypertriglyceridemia (history of
hypertriglyceridemia and/or fasting
triglycerides level >180 mg/dL), arterial
hypertension (history of hypertension and/or systolic blood
pressure >150 mm Hg and/or diastolic pressure
>90 mm Hg, out of the acute phase, treated or not), diabetes
mellitus (diagnosis according to the criteria of the National Diabetes
Data Group28 ) were screened,
together with associated medical diseases. A special effort was made to
assess the presence of cardiovascular comorbidity such
as arrhythmias and impulse conduction disorders (as present
when documented in a standard 12-lead ECG), valvulopathies (diagnosed
by echocardiography), left ventricular
hypertrophy (as present when documented in a standard
12-lead ECG), coronary heart disease (angina pectoris or
previous Q-wave and non-Q-wave MI diagnosed by history and chart
review), and peripheral arterial disease (in
presence of a history of intermittent claudication or previous
arterial intervention or Doppler ultrasonography
documentation). For statistical analysis, carotid ultrasound
measurements were grouped into 2 categories: stenosis 0% to
50% and 51% to occlusion. Routine laboratory investigations included
a complete blood count, erythrocyte sedimentation rate, blood urea,
creatinine, total cholesterol and HDL
subfraction, triglycerides, glucose, electrolytes, liver
enzymes, serological tests for syphilis, ferritin, transferrin, and
plasma fibrinogen. For the specific purpose of the study, the following
acute-phase inflammation markers were included in the screening
procedures of stroke patients: CRP, serum C3c (C3) and C4 (C4)
complement fractions, and serum
1-glycoprotein.
To avoid confounding factors, we excluded patients with history of recent clinical infection; concurrent major renal, hepatic, and cancerous disease; surgery or major trauma in the previous month; and obvious signs and clinical evidence of in-hospital–acquired infection. Previous infections were monitored with an exhaustive medical history focusing on signs and symptoms of potentially clinical infection during the last 4 weeks before stroke, together with the review of patient’s hospital access schedule. All fasting blood samples were processed by the Villa Pini clinical laboratory according to the manufacturer’s instructions (Behering Institute). Elevated results were verified by repeated analysis. Blood samples were taken at admission, within 24 hours after qualifying stroke. All patients were followed up regularly as outpatients for 1 year. During the follow-up period, every effort was made to continuously monitor new vascular events. Follow-up was obtained through periodic follow-up visits, direct contact with the patient or the patient’s family or physician, and chart review, if necessary. We were able to obtain current information on all included patients.
The primary end point was the combination of death of any cause (vascular and nonvascular death) and any new nonfatal vascular event (transient ischemic attack, recurrent stroke, unstable angina, or acute MI, whichever came first) during the 1-year follow-up. Transient ischemic attack was defined as an episode of focal cerebral dysfunction, presumably ischemic in origin, lasting <24 hours and followed by a return to normality. Recurrent stroke was defined as any new cerebrovascular event after the initial one, with an increased handicap at the time of the event, persisting >24 hours. Unstable angina was defined as the appearance of ischemic chest pain at rest documented with typical ischemic changes on ECG, requiring admission to the hospital. Acute MI was diagnosed in the presence of chest pain lasting >20 minutes, characteristic ECG alterations, and plasma creatine kinase–MB elevation greater than twice the normal or previous elevated value. Vascular death included sudden death or death from MI, congestive heart failure, systemic embolism, and other cardiovascular causes (including pulmonary embolism and peripheral arterial disease) or as a consequence of the qualifying stroke or of a new fatal stroke in the absence of other intervening causes. Nonvascular death included cancer, pneumonia, sepsis, and other less frequent causes of death not included in the vascular death.
Statistical Analysis
The Kaplan-Meier technique (log-rank test) was
applied in survival analysis. The distribution of CRP was
positively skewed, and therefore the data were log transformed to
evaluate the associations among CRP and fibrinogen and CNSS score, with
the use of Pearson’s correlation coefficients. Univariate
and forward stepwise multiple logistic regression analyses were
used to evaluate the independent contribution of the risk factors to
the risk of a primary end point. Added to this model were age (cutoff
point 70 years), CNSS score, diabetes mellitus,
hypercholesterolemia (>200 mg/dL), history of
smoking, coronary heart disease, atrial fibrillation,
arterial hypertension, tertiles of fibrinogen, tertiles of
CRP, and aspirin use (yes/no). CNSS score was dichotomized above and
below median value to provide approximately equal numbers of subjects
in each group. Differences in proportions were evaluated by
2 analysis, unpaired
t test for continuous normally
distributed variables, and Mann-Whitney
U test for nonnormally
distributed variables. Continuous variables are described as
mean or median values with 25th and 75th percentiles, according to
manner of distribution. Values of
P<0.05 were considered
statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Between March 1 and December 31, 1998, 185 patients with clinical signs attributable to ischemic stroke were identified. After comprehensive evaluation, 128 were included in the present study. Fifty-seven patients (30.8%) were excluded because they did not fulfill the inclusion criteria for the present study: hemorrhagic stroke (n=10); subarachnoid hemorrhage (n=2); recurrent stroke (n=5); vasculitis (n=1); concurrent major renal (n=1), hepatic (n=2), or cancerous diseases (n=3); surgery (n=1); or major trauma in the previous month (n=1). History of recent clinical infection and obvious signs and clinical evidence of in-hospital–acquired infection after index stroke were registered in 17% of patients (n=31). Sixty-four percent (n=20) of patients with recent clinical infection had a relevant comorbidity that was also able to increase acute reactants.
Among 128 patients, there were 53 men and 75 women
(male/female ratio, 0.7). The mean±SD age was 73.1±9.2 years. CT was
performed in 113 patients (88.3%) and MRI or both in all remaining
patients. Baseline characteristics are presented in
Table 1
. Fifty-one patients had cardioembolic stroke, 46
had atherothrombotic stroke, 22 had small-vessel occlusive stroke, and
in 9 patients the diagnosis was other/uncertain. The CRP values (median
and 25% to 75% interquartile ranges) within 24 hours were 13 mg/L (5
to 33 mg/L; normal range, 0 to 5 mg/L); 33 patients (25.8%) had normal
CRP level on admission. The mean fibrinogen level was 4.76 g/L (3.78 to
6.17 g/L; normal range, 2 to 4 g/L). No significant differences were
found between stroke types and levels of CRP and fibrinogen at
admission. However, patients with acute thrombosis of precerebral
arteries (n=12) had the highest levels of CRP (30 mg/L; 8 to 50 mg/L)
in our stroke patients.
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During the follow-up period all patients received a secondary preventive treatment with aspirin (50%), ticlopidine (22%), or warfarin (28%), with strict control of recognized vascular risk factors. Forty patients (31.3%) had a primary end point within 1 year of stroke onset; 18 were men, and 22 were women; 32 (80%) were older than 70 years. Twenty patients died: 16 (80%) died because of vascular death (qualifying stroke or a new fatal stroke in 6, cardiovascular causes in 10) and 4 because of nonvascular death (in 1, gastric cancer 9 months later; in 2, pneumonia 3 and 7 months later; and in 1, hemorrhagic shock 4 months later). Twenty patients experienced a new vascular event: transient ischemic attack in 1, MI in 3, recurrent stroke in 7, and occurrence of unstable angina requiring new admission to hospital in 9.
The mean fibrinogen level was significantly higher in
patients who had a primary end point during the follow-up period: 5.39
(4.61 to 6.18) g/L versus 4.46 (4.02 to 4.90) g/L
(P=0.0259;
t test). The patients were
stratified into tertiles based on fibrinogen levels with cutoff limits
of <3.78, 3.78 to 6.17, and >6.17 g/L. In survival analysis,
an increased probability of death or new vascular event (21.1%,
27.9%, and 51.7%; P=0.0182,
log-rank test; P=0.0172,
2 for trend) was found in the upper
tertiles
(Figure 1).
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A significantly higher median level of CRP was found in
patients who had a primary end point during the follow-up period (22.5
[11.2 to 72.0] versus 10.0 [4.0 to 23.0] mg/L;
P=0.0002; Mann-Whitney
U test). Stratification of the
patients into tertiles on the basis of CRP (<5, 5 to 33, and >33
mg/L) revealed an increased probability of death or new vascular event
in patients with increased CRP levels: 12.1%, 29.7%, and 54.8%
(P=0.0007, log-rank test;
P=0.0004,
2 for trend)
(Figure 2). There was a clearly increased risk only for
patients above a threshold of CRP and fibrinogen: for neither factor is
there any evidence of moderate elevation (middle tertile) conferring
greater risk. Fibrinogen concentrations were correlated with baseline
levels of CRP (r=0.45;
P<0.0001) and with stroke
severity, assessed with the CNSS
(r=-0.33;
P<0.0001). Levels of CRP also
correlated with CNSS score
(r=-0.35;
P<0.0001).
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We also assessed the relative risk of a primary end point
and the distribution of patients into tertiles according to levels of
fibrinogen and CRP. The relative risk of death or subsequent vascular
events was 4.18 (95% CI, 1.46 to 11.97) in individuals with a
fibrinogen level in the highest tertile compared with those with a
level in the lowest tertile and 8.50 (95% CI, 2.62 to 27.58;
Table 2) for CRP.
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Univariate predictors of a primary end point were age over 70 years (odds ratio [OR], 2.62; 95% CI, 1.01 to 6.35; P=0.0337), CNSS score (OR, 3.4; 95% CI, 1.53 to 7.58; P=0.0028), coronary heart disease (OR, 2.80; 95% CI, 1.30 to 6.07; P=0.0089), tertiles of fibrinogen (OR, 2.08; 95% CI, 1.19 to 3.62; P=0.0098), and tertiles of CRP (OR, 2.89; 95% CI, 1.58 to 5.29; P=0.0006).
To elucidate whether fibrinogen and CRP levels were
independently associated with the risk of death or new vascular event,
logistic multiple regression analyses were performed, with
other risk factors at inclusion also taken into account. In order of
strength of significance, a risk of death or new vascular event was
significantly associated with increased CRP level (OR, 2.39; 95% CI,
1.28 to 4.49; P=0066) and
stroke severity on CNSS (OR, 2.37; 95% CI, 1.01 to 5.58;
P=0.0472)
(Table 3). An increased fibrinogen level was not an
independent risk factor for the primary end point, even after exclusion
of CRP from the model.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite improved treatment of ischemic stroke during the past decade, there remains a substantial risk of death or new vascular events during the first year after the acute episode. The identification of new risk markers could improve (1) risk stratification and selection of individuals who might benefit from intensified therapy and (2) the understanding of pathophysiological mechanisms. Increased concentrations of acute-phase proteins, such as fibrinogen and CRP, have been reported in ischemic stroke,11 12 16 17 18 29 but there are not head-to-head comparisons between acute-phase reactants.
Our study included a small number of patients; however, we adopted strict enrollment criteria to have a homogeneous population: all patients were selected to avoid possible confounding factors able to increase CRP and fibrinogen. We found 2 distinctive patterns in our stroke population: a low rate of stroke of unknown cause (7%) and a very high rate of primary end point within 1 year (31%). Although either pattern was largely due to the older age of our population, other reasons should be considered: diligent case ascertainment with complete screening procedures and a compulsive follow-up, higher proportions of atherogenic risk factors, and cardiovascular comorbidity could explain both results.
The findings of this study might not apply to the whole spectrum of stroke patients; however, demographic characteristics, risk factor distribution, and prognosis of our sample are similar to that of a recent Italian population-based stroke registry.30
The present study revealed a relation between elevated CRP levels and 1-year risk of death or a new vascular event in ischemic stroke. One limitation of the study was that the venous blood samples were obtained at inclusion, within 24 hours after stroke, when a putative acute-phase response and accompanying infection might play a major role. However, inclusion of the delay from stroke onset to time of blood sample had no major influence on the results in regression analysis. Furthermore, the prognostic importance of elevated CRP levels is independent of the influence of fibrinogen on 1-year outcome.
Elevated CRP levels were associated with a probability of death or new vascular event in the present investigation. However, there was no relation between increased fibrinogen levels and the risk of primary end point in our investigation. The possibility that absence of associations with fibrinogen reflects a chance finding must be considered. The failure to replicate existing large study findings might be an indication of less reliable results. However, we found a strong association between CRP and hard end points for a relatively small number of patients, suggesting a persuasive association. Furthermore, increased fibrinogen levels were not an independent risk factor for death or new vascular event after exclusion of CRP levels from the multiple regression model. Thus, fibrinogen levels might be of less importance than has been suggested from previous experiences.11 12 29 Because there are close relations between acute-phase proteins, it might be suggested that CRP, rather than fibrinogen, contributes to the increased risk of new events in ischemic stroke.
The pathophysiological reason for an association between CRP and prognosis is uncertain. However, it is possible that some patients had unrecognized conditions, such as chronic infections and cancer, that elevate inflammation marker levels and also increase the risk of new vascular events or death. Several chronic infections are linked with cardiovascular and cerebrovascular ischemia. The pathogenic link between infection and vessel injury and ischemia is insufficiently understood at present.31 Elevated CRP levels may affect coagulation through the important role of tissue factor expression.32 Previous data showed that activation of coagulation factors in stroke patients increased mortality, and fibrinogen has a putative role.33 34 It is likely, however, that the explanation is more complicated. In this study we found a strong association between fibrinogen and CRP without any association between fibrinogen and outcome, suggesting that the effects of higher CRP levels are independent from fibrinogen. The mechanisms that can lead to initiation of such inflammatory reaction may be multiple and to date are largely unexplained.35
CRP may reflect inflammation related to the pathobiology of ischemic stroke.15 18 36 However, many patients (25%) in our series had normal levels of CRP after stroke, implying that ischemic stroke itself does not induce a full-blown acute-phase response. The high CRP values may reflect the extent of ischemic area.15 18 Obviously, necrosis triggers a rise of circulating CRP. Thus, the extent of necrosis in part determines the CRP response. In agreement, CRP correlates with stroke severity in our patients. However, this explanation is not consistent with the observation that CRP response after stroke predicts clinical outcome such as 1-year risk of death or new vascular event, irrespective of stroke severity.
CRP may reflect amount and activity of circulating proinflammatory cytokines.19 35 These patients might be predisposed to intense activation of inflammation in response to a variety of stimuli, such as stroke. Stroke patients in whom the inflammation system reacts most intensely may be at greater risk for subsequent events. CRP levels would identify those patients whose inflammation system responds most actively to stimuli. These might be the patients at highest risk for subsequent vascular events or death, in whom more aggressive therapy and clinical surveillance might be appropriate.
Taken together, all explanations for the associations between CRP and stroke agree that CRP levels are indirectly linked to the extent and severity of the atherosclerotic processes. None of these explanations consider that CRP may directly participate in tissue damage and in clinical complications in vascular disease. Recently, we observed that patients with activated complement system, detected by total C3 and C4 serum levels, had a significantly higher occurrence of new vascular events or death.20 Notably, CRP displays the ability of ligand bound to activate the complement system.37 Thus, CRP may constitute a cerebrovascular risk factor because it promotes complement activation. Further studies should reveal whether CRP contributes to tissue damage and clinical complications in cerebrovascular disease.
In conclusion, increased CRP levels and, less convincingly, elevated fibrinogen levels are associated with a guarded prognostic significance in ischemic stroke. CRP levels should be measured as a baseline characteristic and used in subgroup analysis in future studies of interventions in ischemic stroke to help refine the choice of therapy.
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Acknowledgments |
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We thank the clinical and laboratory staff for skillful assistance and excellent technical help.
Received May 30, 2000; revision received September 22, 2000; accepted September 22, 2000.
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M. Di Napoli and P. Singh Is Plasma Fibrinogen Useful in Evaluating Ischemic Stroke Patients?: Why, How, and When Stroke, May 1, 2009; 40(5): 1549 - 1552. [Full Text] [PDF]
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C. Altamura, R. Squitti, P. Pasqualetti, C. Gaudino, P. Palazzo, F. Tibuzzi, D. Lupoi, M. Cortesi, P. M. Rossini, and F. Vernieri Ceruloplasmin/Transferrin System Is Related to Clinical Status in Acute Stroke Stroke, April 1, 2009; 40(4): 1282 - 1288. [Abstract] [Full Text] [PDF]
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C. R.W. Kuhlmann, L. Librizzi, D. Closhen, T. Pflanzner, V. Lessmann, C. U. Pietrzik, M. de Curtis, and H. J. Luhmann Mechanisms of C-Reactive Protein-Induced Blood-Brain Barrier Disruption * Supplemental Methods Stroke, April 1, 2009; 40(4): 1458 - 1466. [Abstract] [Full Text] [PDF]
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 T. T. Papas, C. K. Maltezos, N. Papanas, G. Kopadis, J. Marakis, E. Maltezos, and E. Bastounis High-Sensitivity CRP Is Correlated With Neurologic Symptoms and Plaque Instability in Patients With Severe Stenosis of the Carotid Bifurcation Vascular and Endovascular Surgery, June 1, 2008; 42(3): 249 - 255. [Abstract] [PDF]
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 P. S. Mullenix, S. R. Steele, M. J. Martin, B. W. Starnes, and C. A. Andersen C-reactive Protein Level and Traditional Vascular Risk Factors in the Prediction of Carotid Stenosis Arch Surg, November 1, 2007; 142(11): 1066 - 1071. [Abstract] [Full Text] [PDF]
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 H. Tsukui, A. Abla, J. J. Teuteberg, D. M. McNamara, M. A. Mathier, L. M. Cadaret, and R. L. Kormos Cerebrovascular accidents in patients with a ventricular assist device J. Thorac. Cardiovasc. Surg., July 1, 2007; 134(1): 114 - 123. [Abstract] [Full Text] [PDF]
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 M. S. V. Elkind, W. Tai, K. Coates, M. C. Paik, and R. L. Sacco High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med, October 23, 2006; 166(19): 2073 - 2080. [Abstract] [Full Text] [PDF]
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P. Htun, S. Fateh-Moghadam, B. Tomandl, R. Handschu, K. Klinger, K. Stellos, C. Garlichs, W. Daniel, and M. Gawaz Course of Platelet Activation and Platelet-Leukocyte Interaction in Cerebrovascular Ischemia Stroke, September 1, 2006; 37(9): 2283 - 2287. [Abstract] [Full Text] [PDF]
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C. Ladenvall, K. Jood, C. Blomstrand, S. Nilsson, C. Jern, and P. Ladenvall Serum C-Reactive Protein Concentration and Genotype in Relation to Ischemic Stroke Subtype Stroke, August 1, 2006; 37(8): 2018 - 2023. [Abstract] [Full Text] [PDF]
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 C. W. Hogue Jr, C. A. Palin, R. Kailasam, J. S. Lawton, A. Nassief, V. G. Davila-Roman, B. Thomas, and R. Damiano C-reactive protein levels and atrial fibrillation after cardiac surgery in women. Ann. Thorac. Surg., July 1, 2006; 82(1): 97 - 102. [Abstract] [Full Text] [PDF]
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D. Tanne, R. F. Macko, Y. Lin, B. C. Tilley, S. R. Levine, and for the NINDS rtPA Stroke Study Group Hemostatic Activation and Outcome After Recombinant Tissue Plasminogen Activator Therapy for Acute Ischemic Stroke Stroke, July 1, 2006; 37(7): 1798 - 1804. [Abstract] [Full Text] [PDF]
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 C. W. Hogue Jr, T. Hershey, D. Dixon, R. Fucetola, A. Nassief, K. E. Freedland, B. Thomas, and K. Schechtman Preexisting cognitive impairment in women before cardiac surgery and its relationship with C-reactive protein concentrations. Anesth. Analg., June 1, 2006; 102(6): 1602 - 1608. [Abstract] [Full Text] [PDF]
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P. M. Bokesch, G. A. Izykenova, J. B. Justice, K. A. Easley, and S. A. Dambinova NMDA Receptor Antibodies Predict Adverse Neurological Outcome After Cardiac Surgery in High-Risk Patients Stroke, June 1, 2006; 37(6): 1432 - 1436. [Abstract] [Full Text] [PDF]
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 L. Allard, P. R. Burkhard, P. Lescuyer, J. A. Burgess, N. Walter, D. F. Hochstrasser, and J.-C. Sanchez PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke Clin. Chem., November 1, 2005; 51(11): 2043 - 2051. [Abstract] [Full Text] [PDF]
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 D. Feinbloom and K. A. Bauer Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2043 - 2053. [Abstract] [Full Text] [PDF]
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M. Di Napoli, M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H. C.A. Emsley, S. Forconi, S. J. Hopkins, L. Masotti, et al. Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members Stroke, June 1, 2005; 36(6): 1316 - 1329. [Abstract] [Full Text] [PDF]
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K. Sander, D. Sander, H. Audebert, and R. L. Haberl Systemic Inflammatory Response Depends on Initial Stroke Severity but Is Attenuated by Successful Thrombolysis * Response Stroke, February 1, 2005; 36(2): 232 - 232. [Full Text] [PDF]
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 S. C. Smith Jr, J. L. Anderson, R. O. Cannon III, Y. Y. Fadl, W. Koenig, P. Libby, S. E. Lipshultz, G. A. Mensah, P. M Ridker, and R. Rosenson CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Clinical Practice Discussion Group Circulation, December 21, 2004; 110(25): e550 - e553. [Full Text] [PDF]
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P. M. Rothwell, S. C. Howard, D. A. Power, S. A. Gutnikov, A. Algra, J. van Gijn, T. G. Clark, M. F.G. Murphy, C. P. Warlow, and for the Cerebrovascular Cohort Studies Collaborati Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke Stroke, October 1, 2004; 35(10): 2300 - 2305. [Abstract] [Full Text] [PDF]
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H. J. Audebert, M. M. Rott, T. Eck, and R. L. Haberl Systemic Inflammatory Response Depends on Initial Stroke Severity but Is Attenuated by Successful Thrombolysis Stroke, September 1, 2004; 35(9): 2128 - 2133. [Abstract] [Full Text] [PDF]
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C. Wojcik and M. Di Napoli Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy Stroke, June 1, 2004; 35(6): 1506 - 1518. [Abstract] [Full Text] [PDF]
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 M. Di Napoli and A. Arakelyan POEMS Syndrome, Fibrinogen, and Ischemic Stroke: A Critical Point of View Arch Neurol, January 1, 2004; 61(1): 155 - 155. [Full Text] [PDF]
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K. Kang, K. Chu, and J.-K. Roh POEMS Syndrome, Fibrinogen, and Ischemic Stroke: A Critical Point of View--Reply Arch Neurol, January 1, 2004; 61(1): 155 - 156. [Full Text] [PDF]
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F. Biancari, J. Lahtinen, S. Lepojarvi, P. Rainio, E. Salmela, R. Pokela, M. Lepojarvi, J. Satta, and T. S. Juvonen Preoperative C-reactive protein and outcome after coronary artery bypass surgery Ann. Thorac. Surg., December 1, 2003; 76(6): 2007 - 2012. [Abstract] [Full Text] [PDF]
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M. Di Napoli and F. Papa Angiotensin-Converting Enzyme Inhibitor Use Is Associated With Reduced Plasma Concentration of C-Reactive Protein in Patients With First-Ever Ischemic Stroke Stroke, December 1, 2003; 34(12): 2922 - 2929. [Abstract] [Full Text] [PDF]
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 M. Di Napoli and F. Papa Association Between Blood Pressure and C-Reactive Protein Levels in Acute Ischemic Stroke Hypertension, December 1, 2003; 42(6): 1117 - 1123. [Abstract] [Full Text] [PDF]
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L. Mascitelli and F. Pezzetta Anti-inflammatory Effects of Alcohol Arch Intern Med, October 27, 2003; 163(19): 2393 - 2393. [Full Text] [PDF]
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R. Kleemann, H. M.G. Princen, J. J. Emeis, J. W. Jukema, R. D. Fontijn, A. J.G. Horrevoets, T. Kooistra, and L. M. Havekes Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol-Lowering Effect in APOE*3-Leiden Transgenic Mice: Evidence for Antiinflammatory Effects of Rosuvastatin Circulation, September 16, 2003; 108(11): 1368 - 1374. [Abstract] [Full Text] [PDF]
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 D. G. Hackam and S. S. Anand Emerging Risk Factors for Atherosclerotic Vascular Disease: A Critical Review of the Evidence JAMA, August 20, 2003; 290(7): 932 - 940. [Abstract] [Full Text] [PDF]
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M. Di Napoli Editorial Comment--How to Search for the Role of Genetic Polymorphisms in Stroke: Theory Versus Practice Stroke, August 1, 2003; 34(8): 1869 - 1870. [Full Text] [PDF]
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D. Acalovschi, T. Wiest, M. Hartmann, M. Farahmi, U. Mansmann, G. U. Auffarth, A. J. Grau, F. R. Green, C. Grond-Ginsbach, and M. Schwaninger Multiple Levels of Regulation of the Interleukin-6 System in Stroke Stroke, August 1, 2003; 34(8): 1864 - 1869. [Abstract] [Full Text] [PDF]
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K. Kang, K. Chu, D.-E. Kim, S.-W. Jeong, J.-W. Lee, and J.-K. Roh POEMS Syndrome Associated With Ischemic Stroke Arch Neurol, May 1, 2003; 60(5): 745 - 749. [Abstract] [Full Text] [PDF]
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M. Di Napoli and F. Papa C-Reactive Protein and Blood Pressure in the Acute Phase After an Ischemic Stroke Stroke, April 1, 2003; 34(4): 839 - 839. [Full Text] [PDF]
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M. Di Napoli, F. Papa, K. Winbeck, and D. Sander Clinical Use of C-Reactive Protein for Prognostic Stratification in Ischemic Stroke: Has the Time Come for Including It in the Patient Risk Profile? Stroke, February 1, 2003; 34(2): 375 - 376. [Full Text] [PDF]
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T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]
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 R. Kleemann, P. P. Gervois, L. Verschuren, B. Staels, H. M. G. Princen, and T. Kooistra Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation Blood, January 15, 2003; 101(2): 545 - 551. [Abstract] [Full Text] [PDF]
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L. Marquardt, A. Ruf, U. Mansmann, R. Winter, M. Schuler, F. Buggle, H. Mayer, and A. J. Grau Course of Platelet Activation Markers After Ischemic Stroke Stroke, November 1, 2002; 33(11): 2570 - 2574. [Abstract] [Full Text] [PDF]
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 S.E. GARIBALLA, T.P. HUTCHIN, and A.J. SINCLAIR Antioxidant capacity after acute ischaemic stroke QJM, October 1, 2002; 95(10): 685 - 690. [Abstract] [Full Text] [PDF]
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K. Winbeck, H. Poppert, T. Etgen, B. Conrad, and D. Sander Prognostic Relevance of Early Serial C-Reactive Protein Measurements After First Ischemic Stroke Stroke, October 1, 2002; 33(10): 2459 - 2464. [Abstract] [Full Text] [PDF]
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I. Iyigun, M. Di Napoli, and F. Papa C-Reactive Protein in Ischemic Stroke * Response Stroke, September 1, 2002; 33(9): 2146 - 2147. [Full Text] [PDF]
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M. Di Napoli and F. Papa Inflammation, Hemostatic Markers, and Antithrombotic Agents in Relation to Long-Term Risk of New Cardiovascular Events in First-Ever Ischemic Stroke Patients Stroke, July 1, 2002; 33(7): 1763 - 1771. [Abstract] [Full Text] [PDF]
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M. S. Elkind, J. Cheng, B. Boden-Albala, T. Rundek, J. Thomas, H. Chen, L. E. Rabbani, R. L. Sacco, and A. G. Thrift Tumor Necrosis Factor Receptor Levels Are Associated With Carotid Atherosclerosis * Editorial Comment Stroke, January 1, 2002; 33(1): 31 - 38. [Abstract] [Full Text] [PDF]
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G. Boysen and H. Christensen Early Stroke: A Dynamic Process Stroke, October 1, 2001; 32(10): 2423 - 2425. [Full Text] [PDF]
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M. Di Napoli and F. Papa Inflammation, Statins, and Outcome After Ischemic Stroke Stroke, October 1, 2001; 32 (10): 2446 - 2447. [Full Text] [PDF]
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 M. Di Napoli C reactive protein and acute phase of ischaemic stroke BMJ, June 30, 2001; 322(7302): 1605 - 1605. [Full Text]
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M. Di Napoli, G. Xi, R. F. Keep, Y. Hua, and J. T. Hoff Systemic Complement Activation in Ischemic Stroke Response Stroke, June 1, 2001; 32 (6): 1443 - 1448. [Full Text] [PDF]
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M. Di Napoli, F. Papa, and V. Bocola Periodontal Disease, C-Reactive Protein, and Ischemic Stroke Arch Intern Med, May 14, 2001; 161(9): 1234 - 1235. [Full Text] [PDF]
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