Journal of Vascular Surgery
Volume 46, Issue 3 , Pages 449-454, September 2007

Fibrinogen and high-sensitive C-reactive protein as serologic predictors for perioperative cerebral microembolic lesions after carotid endarterectomy

  • Peter Heider, MD

      Affiliations

    • Department of Vascular Surgery, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
    • Corresponding Author InformationReprint requests: Dr Peter Heider, Rechts der Isar Medical Center, Technical University of Munich, Ismaninger Str 22, D-81675 Munich, Germany.
    • ,
  • Holger Poppert, MD

      Affiliations

    • Department of Neurology, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
    • ,
  • Oliver Wolf, MD

      Affiliations

    • Department of Vascular Surgery, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
    • ,
  • Thomas Liebig, MD

      Affiliations

    • Department of Neuroradiology, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
    • ,
  • Jaroslav Pelisek, PhD

      Affiliations

    • Department of Vascular Surgery, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
    • ,
  • Tibor Schuster, PhD

      Affiliations

    • Institute of Epidemiology and Medical Statistics, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany.
    • ,
  • Hans H. Eckstein, MD

      Affiliations

    • Department of Vascular Surgery, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany

Received 23 March 2007; accepted 14 May 2007.

Article Outline

Background

Neurologic deficit caused by cerebral ischemia defines the outcome of carotid endarterectomy (CEA). Although few patients have clinically evident neurologic deficit, diffusion-weighted imaging (DWI) presents a number of cases with ischemic brain lesions. This study should elucidate preoperative risk factors for perioperative microemboli that cause brain infarction.

Methods

We studied 183 patients (58 women, 69.2 ±12.7 years; 125 men, 69.3 ± 8.9 years) with high-degree carotid artery stenosis. DWI was performed before and after CEA to analyze new cerebral ischemia. Blood samples were obtained before operation to measure fibrinogen and C-reactive protein (CRP), and preoperative high-sensitive CRP (hsCRP) was analyzed in 30 consecutive patients.

Results

Postoperative DWI revealed new ipsilateral ischemic lesions in 41 patients (22.4%), and eight (4.4%) showed new neurologic deficit. Preoperative fibrinogen levels were higher in patients with new lesions (397.6 mg/dL ± 104.7 mg/dL) than in those without (324.7 mg/dL ± 74.2 mg/dL, P < .001). Preoperative levels of hsCRP were also higher in patients with new lesions (7.9 mg/dL ± 5.2 mg/dL) than in those without (2.8 mg/dL ± 2.6 mg/dL, P = .004). Significant association was found between fibrinogen and CRP (Spearman ρ = 0.402; P < .001) as well as hsCRP (Spearman ρ = 0.603, P = .003). No association was found between postoperative lesions and CRP (P = .833).

Conclusion

The present study demonstrates that preoperative levels of fibrinogen and hsCRP are independent determinants for new periprocedural cerebral ischemic lesions caused by microembolic events. There is still not sufficient evidence to recommend measurement of CRP as a prognostic marker for perioperative cerebral lesion.

 

The main purpose of carotid endarterectomy (CEA) is the prevention of stroke.1 CEA in symptomatic patients is associated with a high incidence for the appearance of diffusion-weighted imaging (DWI) lesions and brain infarction, but the cause for microembolic events remain notional.2 Many studies have shown that raised levels of inflammatory markers increase the risk of coronary heart disease and the risk of ischemic or hemorrhagic stroke.3, 4 Recent studies indicate a strong association between high-sensitive C-reactive protein (hsCRP) levels and subsequent cardiac events after interventional cardiac therapy.5 Elevated fibrinogen is an important predictor of future coronary events in individuals with a history of coronary heart disease.6

The role of plasma fibrinogen as central protein in the coagulation system has been documented by clinical evidence: fibrous plaques are rich in fibrinogen and degradation products, which are involved in mechanisms of endothelial cell injury and platelet aggregation.7 It triggers the formation of progressive atherosclerotic plaques. The relationship between high plasma fibrinogen levels, the thin fibrous cap of atheroma, and a greater incidence of plaque rupture and thrombosis are well known. In patients with elevated fibrinogen levels, high numbers of inflammatory cells are concentrated in the shoulder and cap of plaques.8

Studies on the association between several inflammatory markers and postoperative cerebral lesion after CEA are limited, however. The aim of our study was to assess whether levels of fibrinogen, CRP, and hsCRP are useful as predictive values of postoperative ischemic events in patients after CEA.

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Material and methods 

Patient population 

We evaluated 183 patients with high-degree carotid artery stenosis (91 asymptomatic, 92 symptomatic patients) intended for CEA. The degree of stenosis was evaluated by color-coded duplex ultrasound imaging following European Carotid Surgery Trial (ECST) criteria. All CEA were performed by experienced vascular surgeons from January 2004 to June 2006. All patients underwent neurologic examination ≤2 days before and after the procedure.

The study was performed according to the Guidelines of the World Medical Association Declaration of Helsinki and was approved by the Hospital Review Board of the Interdisciplinary Center for Vascular Diseases. All patients gave informed consent.

Magnetic resonance imaging (MRI) was performed using a 1.5 Tesla whole-body imaging system (Magnetom Symphony Quantum gradient, Siemens Medical Systems, Erlangen, Germany) with a dedicated head coil. DWI was performed 1 day before and after CEA. The whole brain DWI was done with an isotropic echo-planar sequence with b-values of 0.500 and 1000 s/mm2, repetition time, 4006 milliseconds; echo time, 83 milliseconds; number of averages, two; slice thickness, 4 to 6 mm; 128 × 128 matrix size, and 220 × 220 mm2 field of view. Sagittal, coronal, and transverse views were obtained.

All MRI results were reviewed by two experienced neuroradiologists without knowledge of vascular status and side of operation and blinded to each other’s findings. An acute DWI lesion (Fig 1) was only diagnosed if an increased signal intensity was visible on two planes, if a corresponding decreased signal intensity was detected in the apparent diffusion coefficient image, and if both neuroradiologists agreed on their findings.

Clinical history and physical examination were taken with special attention to cardiovascular risk factors, as summarized in Table I. Routine laboratory values, urinalysis results, and chest radiographs were used to exclude any inflammatory or infectious diseases. Severe cardiac disease, coagulopathy, or any operation ≤6 months was an exclusion criterion. Blood samples for measurement of fibrinogen, CRP, and hsCRP were taken from an antecubital vein a day before operation and were immediately analyzed.

Table I. Patient characteristics
Data⁎AsymptomaticSymptomaticTotalPWithout post-op DWI lesionWith post-op DWI lesionP
Patients91(49.7)92(50.3)183.96†142(77.6)41(22.4).082†
Female29(31.9)29(31.5)58(31.7) 49(34.5)9(21.9)
Male62(68.1)63(68.5)125(68.3) 93(65.5)32(78.0)
Age, mean68.8±11.169.7±9.469.2±10.3.572‡68.7±11.169.2±7.360.674§
Risk factors
Number, mean2.2±1.12.2±0.92.2±1.0.785†2.5±0.992.1±1.01.024§
Hypertension81(89.0)82(89.1)161(87.9).474∥106(86.9)36(87.8).505†
Diabetes24(26.4)23(25.0)47(25.7).761∥26(21.3)17(41.5).018†
Hypercholesterolemia50(54.9)59(64.1)109(59.6).314∥70(57.4)25(61.0).944†
Tobacco use40(43.9)41(44.6)81(44.3).899∥53(43.4)23(56.1).253†
Renal disease5(5.5)2(2.2)7(3.8).16∥5(4.1)1(2.4).516†
Coronary heart disease36(39.6)35(38.0)71(38.8).687∥47(38.5)10(24.4).065†
Medication
Thrombocyte aggregation inhibitors85(93.4)89(96.7)174(95.1).564∥116(95.1)41(100).436†
β-Blocker55(60.4)60(65.2)115(62.8).561∥70(57.4)29(70.7).293†
ACE inhibitors48(52.7)43(46.7)91(49.7).366∥59(48.4)20(48.8).963†
Lipid-lowering agents45(49.5)55(59.8)100(54.6).179∥66(54.1)25(61.0).693†
Degree of stenosis(PSV)361.6±111.6347.4±138.0354.8±124.7.519‡347.4±138.0353.2±140.0.978§
Post-op DWI lesions13(14.3)28(30.4)41(25.2).008‡
New neurologic symptoms2(2.2)6(6.5)8(4.4).242‡
Pre-op symptomatic patient 64(45.1)28(68.3).008§

DWI, Diffusion-weighted image; ACE, angiotensin-converting enzyme; PSV, peak systolic velocity.

⁎Categoric data are presented as numbers(%); continuous data are presented as mean ± standard deviation.

†P obtained with χ2 test.

‡P obtained with Kruskal-Wallis test.

§P obtained with Mann-Whitney U test.

∥P obtained with the Fisher exact test.

Plasma fibrinogen activity was measured quantitatively by the Clauss method, where fibrinogen is converted from a soluble protein to an insoluble polymer by the action of thrombin, resulting in the formation of a fibrin clot. The thrombin clotting time is inversely proportional to the fibrinogen concentration of the plasma. Thus, measuring the clotting time of dilute plasma when excess thrombin is added compared with a standardized fibrinogen preparation results in quantitative determination of fibrinogen concentration (Dade Behring, Schwalbach, Germany).

Measurement of CRP was performed on serum using an ultrasensitive assay based on a particle-enhanced turbidimetric immunoassay technique (Dade Behring). The assay was performed according to manufacturer instructions. Blood samples were mixed with the antiserum solution. The CRP reacts specifically with latex particles coated with antihuman CRP antibody to yield insoluble aggregates. The increase in turbidity that accompanies aggregation is proportional to the CRP concentration and was determined using an automated nephelometer (BNII System, Dade Behring).

In 30 consecutive asymptomatic and symptomatic patients, we also collected blood samples before operation for hsCRP enzyme-linked immunosorbent assay (ELISA) analysis. The samples were centrifuged at 1600 rpm for 10 minute. The obtained serum was stored at −70°C until laboratory testing. According to the results of Pai et al,9 who investigated the stability of plasma markers in different time ranges, the range from sample collection until freezing was held to a maximum of 2 hours. The hsCRP ELISA is based on the principle of solid-hase enzyme-linked immunosorbent assay (LifeDiagnostics, West Chester, Pa), with an analytical sensitivity of <0.01 mg/dL and intraassay and interassay coefficients of variation of 4.2% and 4.1%, respectively.

Statistical analysis 

Data were analyzed with SPSS 13.0 (SPSS Inc, Chicago Ill). Values of continuous variables are expressed as mean ± standard deviation. Groups were compared by the Mann-Whitney Utest or matched signed rank test. Correlations between continuous variables were calculated using Spearman rank correlation coefficient. To investigate the relationship between binary outcome and measured covariates, the logistic regression model was used. Calculations of odds ratios with 95% confidence intervals (CI) were performed and illustrated with forest plots. Accuracy for prediction was additional assessed by receiver operating curve (ROC) analyses; thereby, area under the curve (AUC) and optimal cutoff values of explanatory variables were calculated. All tests were considered significant at P = .05.

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Results 

Clinical characteristics of the patients are given in Table I. Both groups were similar with regard to all analyzed risk factors, medications, and degree of stenosis measured as peak systolic velocity (PSV). Logistic regression analysis showed no significant effect on the likelihood of occurring new cerebral lesions (Fig 2).

  • View full-size image.
  • Fig 2. 

    Forest plot for new cerebral ischemic lesions subject to patient characteristics, risk factors, medication, and degree of stenosis. OR, Odds ratio; CI, confidence interval; ACE, angiotensin-converting enzyme.

Preoperative DWI was performed in all patients, and 13 (14.3%) of the 91 preoperatively asymptomatic patients and 28 (30.4%) of the 92 preoperatively symptomatic patients showed new postoperative cerebral ischemic lesions. All lesions occurred ipsilateral to the operated side. New neurologic deficits developed in eight patients, two (2.2%) within the prior asymptomatic group and six (6.5%) within the symptomatic group (P = .242). We saw two transient ischemic attacks (TIAs) in the asymptomatic group, and five TIAs and one permanent minor stroke in the symptomatic group.

Mean serum levels of CRP (0.79 ± 0.71 mg/L vs 0.84 ± 1.0 mg/L) and fibrinogen (331.2 ± 84.5 mg/dL vs 349.9 ± 90.99 mg/dL) relating to asymptomatic and symptomatic patients showed no significant difference (Table II). Significant association was found between levels of fibrinogen and CRP (Spearman rho 0.402; P < .001) as well as hsCRP (Spearman rho 0.603; P = .003) whereas no association was found between postoperative lesions and CRP (P = .833). Focusing on cerebral events, the group with new lesions had significantly higher levels of fibrinogen (397.6 ± 104.7 mg/dL vs 324.1 ± 75.1 mg/dL, P = .001) and hsCRP (7.9 ± 5.2 mg/dL vs 2.8 ± 2.6 mg/dL, P = .004). CRP (1.0 ± 1.48 mg/L vs 0.8 ± 0.66 mg/L, P = .625) showed no significant difference (Fig 3, Fig 4, Fig 5).

Table II. Mean serum levels compared in asymptomatic and symptomatic patients
Data⁎AsymptomaticSymptomaticPWithout post-op DWI lesionWith post-op DWI lesionP
Fibrinogen (mg/dL)331.2±84.5349.9±90.99.149†320.2±74.77397.6±104.7<.001‡
CRP(mg/dL)0.79±0.710.84±1.0.703†0.8±0.661.0±1.48.625‡
HsCRP(mg/dL)3.85±3.35.38±5.4.436†2.8±2.627.9±5.24.004‡

⁎Data are presented as the mean ± standard deviation.

†P obtained with Kruskal-Wallis test.

‡P obtained with Mann-Whitney U test.

  • View full-size image.
  • Fig 3. 

    Box plots demonstrate the mean values of fibrinogen (mg/dL) in patients with (1) and without (0) new cerebral lesion (P < .001). The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; and the whiskers mark the 90th and 10th percentiles.

  • View full-size image.
  • Fig 4. 

    Box plots demonstrate the mean values of C-reactive protein (mg/dL) in patients with (1) and without (0) a new cerebral lesion (P = .625). The top and bottom borders of the box mark the 75th and 25th percentiles, respectively; and the whiskers mark the 90th and 10th percentiles.

  • View full-size image.
  • Fig 5. 

    Box plots demonstrate the mean values of high-sensitive CRP (mg/dl) in patients with (1) and without (0) new cerebral lesion (P = .004). The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; and the whiskers mark the 90th and 10th percentiles.

In logistic regression analysis, hsCRP (P = .048) and fibrinogen (P < .001) showed a significant effect on the likelihood of new cerebral lesions occurring, but CRP was not significant (P = .100). Accuracy for prediction assessed by ROC analysis showed an AUC of 0.879 for hsCRP, with an optimal cutoff value of 4.16 (sensitivity, 0.75; specificity, 0.77), and an AUC of 0.884 for fibrinogen with a cut-off value of 364 (sensitivity, 0.88; specificity, 0.71). The odds ratio for a new lesion was 4.49 (95% CI, 2.12 to 9.49) by categorized fibrinogen and 11.0 (95% CI, 1.42 to 85.2) by hsCRP, noting that fewer measurements resulted in a large CI for the estimated effect of hsCRP. The odds ratio achieved by CRP with a cutoff value 0.75 was 1.75 (95% CI, 0.81 to 3.80), thus corresponding to a weak but not significant trend (Fig 6). The positive and negative predictive value was 63.6% and 90.9% for fibrinogen and 85.7% and 86.7% for hsCRP.

  • View full-size image.
  • Fig 6. 

    Odds ratios (OR) and 95% confidence intervals (CI) for new cerebral lesions for fibrinogen, C-reactive protein (CRP), and high-sensitive C-reactive protein (hsCRP) in patients after carotid endarterectomy.

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Discussion 

In earlier studies, we observed a significant correlation between the number and volume of cerebral lesions in DWI and the occurrence of brain infarction in follow-up MRI. These findings indicate that the severity of new postoperative neurologic events correlates with DWI lesion size.2 Assuming that a loss of brain tissue impairs the result of CEA, we elucidated the influence of pre-existing activity of atherosclerosis represented by acute-phase proteins. Inflammatory processes play a pivotal role in the pathogenesis of atheroma development to ultimate rupture of unstable atherosclerotic plaques.5

Atherosclerosis is typically associated with low-grade vascular inflammation that can be measured. Dosa et al5 evaluated plasma fibrinogen and serum hsCRP during CEA. The study indicated that removal of atherosclerotic plaques from the carotid arteries markedly decreased the production of acute-phase proteins owing to the decrease of inflammatory burden or the removal of the advanced plaques able to produce these proteins.5 Increased hsCRP levels may be related to the presence of macrophages and T-lymphocytes in carotid plaque, which is associated with instability that leads to ischemic events. Kondo et al10 demonstrated that plasma hsCRP is a marker of carotid atherosclerosis activity.

Rerkasem et al11 investigated levels of inflammatory markers between patients with symptomatic carotid stenosis and those who were asymptomatic. Plasma hsCRP was elevated in symptomatic compared with asymptomatic patients. Their study showed that hsCRP was of prognostic value in a number of cardiovascular conditions.11 In contradiction to these results, we could detect patients in both asymptomatic and symptomatic groups with a higher expression of acute-phase reactants and new postoperative cerebral lesions. Our results also contradict those of Choi et a1,12 who found that a higher hsCRP level was associated with a higher risk score of coronary heart disease but not with carotid atherosclerosis. We also found a significant interaction between serum levels and activity of carotid atherosclerosis expressed in postoperative ischemic lesions.12

Actually, acute coronary syndromes are thought to result from plaque rupture that is induced by the inflammatory process in the atherosclerotic tissue. Patients with non-ST elevation acute coronary syndromes who showed no event ≤6 months were characterized by a decrease in hsCRP levels from baseline to follow-up. Most events in the observation period of 3 years occurred in patients with follow-up hsCRP-levels >60% of the initial level. It was therefore hypothesized that a repeated measurement of hsCRP levels in CAD patients could help to discriminate those at high risk of further events.13 Thus determination of circulating hsCRP levels may be a useful additional marker of risk in patients with high-grade carotid stenosis.14 Zwaka et al15 showed hsCRP-dependent mediation of low-density lipoprotein uptake by macrophages, and Pasceri et al16 showed that hsCRP influences atherogenesis and induces adhesion molecule expression in human endothelial cells. Furthermore, Hashimoto et al17 found that hsCRP is an independent predictor of the rate of increase of carotid atherosclerosis.17

Tanne et al18 examined the association between CRP levels and the subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease and showed that the risk of stroke per 1000 person-years increased according to CRP levels. These findings demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients.18 Our findings contradicted these results: we could not detect significant difference in CRP levels that affected postoperative cerebral lesions.

The analysis of the EUROSTROKE project indicates that increased fibrinogen is a powerful predictor of stroke.3 However, an increase of 100 mg/dL in a patient’s fibrinogen level within the range tested (between 250 mg/dL and 562 mg/dL) was associated with a significantly increased risk of heart disease and stroke. Ma et al19 found that those with high fibrinogen levels, >343 mg/dL, had a twofold increase in the risk of myocardial infarction (MI). A multivariate analysis by Coppola et al20 revealed that fibrinogen plasma levels in patients after acute MI were the only independent predictor of mortality in a 42-month follow-up after acute MI.

Our results, together with other observations from recent studies, suggest that fibrinogen evaluation may be useful in identifying patients at higher risk of atherosclerosis-associated events.20 Finally, fibrinogen may also be more than a marker because it binds to platelets and contributes to platelet aggregation and fibrin formation. Further studies should elucidate the connection between serum levels and plaque morphology.

Elevated plasma levels of fibrinogen and hsCRP have been shown to predict future risk of plaque rupture and ischemic stroke, particularly in men and in young and middle-aged individuals.4 Patients with high fibrinogen levels after ischemic stroke had higher mortality rates than patients with lower fibrinogen levels.21 Although we also found an association between hsCRP and fibrinogen, we could not detect any influence of sex on the laboratory values or new postoperative DWI events. HsCRP has been reported to reflect inflammation related to the pathology and biology of ischemic stroke.22

Elevated levels of fibrinogen and hsCRP in patients with carotid artery stenosis vs controls imply that these acute-phase reactants are markers of plaque stability. This is supported by the fact that carotid artery stenosis is a predictor of widespread atherosclerosis23 and that atherosclerosis is an inflammatory process. In atherosclerosis, macrophages produce cytokines such as interleukin-1 and 6 and tumor necrosis factor, all of which stimulate hepatocytes to produce fibrinogen and hsCRP. Furthermore, our findings are in accordance with those by Levenson et al24 that fibrinogen was elevated in subjects with silent atherosclerosis, particularly in those with disease in several arterial beds.24 Finally, within the Copenhagen City Heart Study, patients with ischemic heart disease and thus atherosclerosis had elevated fibrinogen.25

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Conclusion 

Our data demonstrate that elevated levels of the inflammatory markers fibrinogen and hsCRP are associated with increased risk of new cerebral ischemic lesions after CEA. Our observation also suggests the possibility that the tested inflammatory markers may provide a method of identifying people for whom a specific antiinflammatory therapy before operation is necessary, a hypothesis requiring direct testing in randomized clinical trials.

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Author contributions 


Conception and design: HP

Analysis and interpretation: HP, LT

Data collection: HP, PH

Writing the article: HP, PJ

Critical revision of the article: HP, PJ

Final approval of the article: HP

Statistical analysis: ST

Obtained funding: EH

Overall responsibility: HP, EH

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We thank Felicitas Altmayr for her technical support and Bernhard Holzmann, MD, from the Department of Surgery, Technical University of Munich, for providing the laboratory setting.

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References 

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 Competition of interest: none.

 Financial support for this study was provided by the Commission of Clinical Research, Rechts der Isar Medical Center, Technical University of Munich (Kommission für Klinische Forschung, KKF-Nr.: 8744652).

PII: S0741-5214(07)00963-9

doi:10.1016/j.jvs.2007.05.035

Journal of Vascular Surgery
Volume 46, Issue 3 , Pages 449-454, September 2007

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