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Original Article

Study of Fibrinogen Level in Acute Ischemic Stroke Patients in Medical Intensive Care Unit

Samir, Ghada M.1; Khalil, Osama A.1; Fawzy, Mohamed S.2; Sadek, Ayman M.E.M.1,∗

Author Information
The Egyptian Journal of Critical Care Medicine: December 2020 - Volume 7 - Issue 2 and 3 - p 51-56
doi: 10.1097/EJ9.0000000000000009
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Abstract

1 Introduction

Stroke is a common cause of disability and death worldwide, with devastating emotional and socioeconomic effects on patients, their families, and the health care system.1

Ischemic stroke is a common type of cerebrovascular accidents in Egypt, accounting for 59% to 93%.2

Inflammation is a risk factor of atherosclerosis and during the ischemic events. Many inflammatory markers as fibrinogen and high sensitive C-reactive protein (hs-CRP) have been reported as predictable markers for stroke severity and outcome.3

Fibrinogen is a major determinant of whole blood and plasma viscosity. Elevated levels are associated with atherosclerosis and coronary heart disease, peripheral vascular disease, and carotid stenosis.4

While elevated fibrinogen level is associated with other cardiovascular risk factors including age, smoking, elevated blood pressure, and high cholesterol, the relationship with stroke persisted even after correction of these confounders.5

Our aim in this work is to estimate fibrinogen levels in patients with ischemic stroke, to study its relation to other risk factors (age, sex, hypertension, diabetes mellitus, and smoking), to find out the most important predictor of ischemic stroke, and to find out its relation to in-hospital clinical outcome and possible predictive cutoff value.

2 Subjects and methods

2.1 Study design and setting

We conducted an observational cohort study in the period from August 2017 to March 2018 in medical intensive care unit of Zagazig University.

2.2 Participants and sampling

Sixty-four subjects with high cardiovascular risk (≥20%), according to atherosclerotic cardiovascular disease 2013 Risk estimator,6 were classified into two groups: group (1) was 32 ischemic stroke subjects diagnosed clinically and radiologically by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) brain, and group (2) was 32 nonstroke controls with matched age, sex, and risk factors (15 patients had hypertensive encephalopathy, 12 patients had hyperosmolar hyperglycemic state, 3 patients had meningitis, and 2 patients had postictal confusion), as presented in the flow chart diagram (Fig. 1). The estimated sample size was 64 patients at 80% power and 95% confidence interval (Dean AG. Epi Info, version 6: a word-processing, database, and statistics program for public health on IBM-compatible microcomputers.).

Figure 1
Figure 1:
Flow chart diagram of the study participants.

2.3 Inclusion criteria and exclusion criteria

We included patients with the following criteria: age > 18 years old, in both genders, who met the clinical and radiological diagnostic criteria of acute ischemic stroke.7 We excluded patients with the following criteria: hemorrhagic stroke, traumatic, and space-occupying lesions of cerebrovascular disease and diseases known to cause elevated serum fibrinogen level were also excluded such as liver disease, renal failure, and patients with past or recent myocardial infarction. In addition, we excluded other conditions that led to increase in the fibrinogen level such as pregnancy or hormonal contraception.

2.4 Ethical clearance

We carried this work in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments. We took an informed consent from the patients who participated in the study or their relatives. Approval for performing the study was obtained from internal medicine and medical biochemistry departments, Zagazig University Hospitals after taking Institutional Review board approval (IRB No. 2970).

2.5 Process

All patients were subjected to full history and thorough clinical examination. Routine laboratory investigations were done at the hospital clinical laboratory such as complete blood picture, liver tests, kidney function tests, fasting blood sugar and two hours postprandial blood sugar (FBS and PPBS), lipid profile, and coagulation profile. Radiological investigations were done as needed at radiology department such as CT or MRI brain, chest X-Ray, pelvi-abdominal ultrasound, and electrocardiography for all patients. We calculated the APACHE II score within 48 hours of admission. We measured serum fibrinogen level at medical biochemistry department 48 hours after admission using COATRON M1-TECO GMBH and FIBROTEK FIB fibrinogen assay kit produced by R2 Diagnostics, Inc. south bend, Indiana USA, with a normal range of 250–350 mg/dL. We followed up group (1) of patients for two weeks to estimate hospital outcome.

2.6 Statistical methods

We used SPSS program version 18 for Windows (SPSS Inc., Chicago, Illinois, USA). Data were expressed in the form of mean ± SD for continuous variables and as number and percentage for categorical variables. Continuous data were tested for normality using the Shapiro-Wilk test.

All normally distributed data were interpreted using the Independent Student t test, while nonnormally distributed data were explored using the Mann-Whitney U test. One-Way ANOVA (F) was used to compare normally distributed variables in three groups. Percentage of categorical variables was compared using the Chi-squared (χ2) test.

Spearman's rank correlation coefficient (Spearman's rho) was calculated to assess the correlations between fibrinogen level in patients with acute ischemic stroke and various study parameters.

Receiver operating characteristic curve analysis was used to establish the optimal cutoff value of fibrinogen level with maximum sensitivity and specificity.

An alpha level below 0.05 was considered for statistical significance.

3 Results

Group (1) included 32 ischemic stroke subjects, 14 males and 18 females. Their ages ranged from 45 to 80 years with mean values ± SD (66.28 ± 8.76) years: 10 of them are smokers, 14 patients have diabetes, 20 patients have hypertension, 8 patients have a history of old stroke, 4 patients have Atrial Fibrillation, and 4 patients have no risk factors. According to hospital outcome, 7 died before 15 days, 14 discharged through 15 days, and 11 stayed in the hospital >15 days.

Group (2) included 32 nonstroke controls, 15 males and 17 females. Their ages ranged from 45 to 80 years with mean values ± SD (64.91 ± 9.19) years: 4 of them are smokers, 12 patients have diabetes, 15 patients have hypertension, and 5 patients have no risk factors.

Between all the demographic, cardiovascular risk factors, and biochemical parameters in this study, High-Density Lipoprotein (HDL)-Cholesterol, Low-Density Lipoprotein(LDL)-Cholesterol, White Blood Cells, Platelets, and fibrinogen showed a significant difference between acute ischemic stroke patients (group 1) and nonstroke control patients (group 2) (Table 1).

Table 1 - Comparison of demographic, cardiovascular risk factors, and biochemical data between groups
Group 1 (n = 32) Group 2 (n = 32) Test


Frequency Percentage Frequency Percentage χ2 P
Sex Male 14 43.7% 15 46.9% 0.002 .999
Female 18 56.2% 17 53.1%
Smoking status NonSmoker 22 65.6% 28 87.5% 2.29 .131
Smoker 10 34.4% 4 12.5%
Diabetes No 18 56.2% 20 62.5% 0.065 .799
Yes 14 43.7% 12 37.5%
Hypertension No 12 37.5% 17 53.1% 1.009 .315
Yes 20 62.5% 15 46.9%
Atrial fibrillation No 28 87.5% 32 100% 2.4 .121
Yes 4 12.5% 0 0%
Mean ± SD Mean ± SD t
Age (y) 66.28 ± 8.76 64.91 ± 9.19 0.61 .542
Triglycerides (mg/dL) 129.73 ± 55.73 120.40 ± 19.34 0.894 .375
HDL-Cholesterol (mg/dL) 39.10 ± 7.77 45.37 ± 7.25 3.33 .001
Mean ± SD Mean ± SD MW
LDL- Cholesterol (mg/dL) 126.32 ± 39.62 107 ± 25.75 338.5 .019
Cholesterol (mg/dL) 188.54 ± 45.43 176.41 ± 29.96 453.50 .432
WBCs (x 109) 10.23 ± 3.16 7.30 ± 1.68 235.50 .002
Hemoglobin (g/dL) 13.23 ± 1.38 13.06 ± 1.1 437.50 .317
Platelets (x 109) 234.31 ± 49.81 277.13 ± 48.79 274 .001
Fasting blood sugar (mg/dL) 126.63 ± 32.66 111.78 ± 17.26 388 .095
2h postprandial blood sugar (mg/dL) 183.03 ± 47.57 163 ± 28.38 394.50 .115
Creatinine (mg/dL) 0.93 ± 0.37 0.89 ± 0.17 484 .705
INR 1.09 ± 0.17 1.05 ± 0.14 465.50 .517
Fibrinogen (mg/dL) 538.31 ± 42.57 332.88 ± 52.18 715.5 <.001
HDL, High-Density Lipoprotein; INR, International Normalized Ratio; LDL, Low-Density Lipoprotein; MW, Mann-Whitney U test; WBC, White blood cell.
Chi-squared test.
Independent t test.
Mann-Whitney U test.Bold are significant P value

Considering factors affecting hospital outcome in the group (1), only diabetes mellitus had an impact on the outcome (Table 2).

Table 2 - Impact of demographic and cardiovascular risk factors among the group 1 patients on hospital outcome
Deceased (n = 7) Stayed > 14 days (n = 11) Stayed < 14 days (n = 14) Test P



Mean ± SD Mean ± SD Mean ± SD F



Age (y) 66.29 ± 7.83 69.91 ± 7.89 62.43 ± 8.81 2.76 .08



Freq-uency Percen-tage Freq-uency Percen-tage Freq-uency Percen-tage χ2
Sex Male 3 42.9% 5 45.5% 6 42.9% 0.02 .99
Female 4 57.1% 6 54.5% 8 57.1%
Smoking status None 5 71.1% 8 72.7% 8 57.1% 0.80 .67
Smoker 2 28.6% 3 27.3% 6 42.9%
Diabetes No 1 14.3% 8 72.7% 9 64.3% 6.59 .04
Yes 6 85.7% 3 27.3% 5 35.7%
Hypertension No 0 0% 6 54.5% 6 42.9% 5.74 .06
Yes 7 100% 5 45.5% 8 57.1%
Old stroke No 6 85.7% 10 90.9% 8 57.1% 4.29 .12
Yes 1 14.3% 1 9.1% 6 42.9%
Atrial fibrillation No 6 85.7% 9 81.8% 13 92.9% 0.71 .70
Yes 1 14.3% 2 18.2% 1 7.1%
One-way ANOVA.
Chi-squared test.

In the group (1), significant positive correlations were found between age, FBS and 2 hours PPBS, systolic blood pressure, APACHE II score, all serum cholesterol components on one hand, and in fibrinogen level on the other hand (Table 3).

Table 3 - Correlation coefficient between fibrinogen level in patients with acute ischemic stroke and study parameters
Fibrinogen level in patients with ischemic stroke (n = 32)

r P
Age 0.428 .015
Fasting blood sugar 0.398 .024
2h Postprandial blood sugar 0.358 .042
Systolic blood pressure 0.606 <.001
APACHE II 0.380 .032
Total cholesterol 0.387 .028
Triglycerides 0.135 .461
LDL - Cholesterol 0.382 .031
HDL - Cholesterol 0.388 .028
HDL, High-Density Lipoprotein; LDL, Low-Density Lipoprotein.
Spearman's rank correlation coefficient.

A cutoff value of fibrinogen ≥439 mg/dL with a sensitivity of 92.31%, specificity of 75.36%, and accuracy 84.34% may be used as a predictor for acute ischemic stroke. A cutoff value of fibrinogen ≥ 557 mg/dL with a sensitivity of 85.71%, specificity of 96%, and accuracy 93.75% seems to be a guide for prediction of mortality in the group (1) (Table 4).

Table 4 - Specificity and sensitivity of fibrinogen in predicting ischemic stroke (n = 64) and its mortality (n = 32)
Sensitivity Specificity Positive predictive value Negative predictive value Area under curve

Cutoff values of Fibrinogen (95% confidence interval) Accuracy
Ischemic Stroke ≥439 mg/dL 92.31% 75.36% 79.3% 90.6% 0.86 84.34%
Mortality ≥577 mg/dL 85.71% 96% 85.7% 96% 0.966 93.75%

Figures 2 and 3 demonstrated the receiver operating characteristic curves of the previous table with an excellent area under the curve of both cutoff values of fibrinogen for prediction of acute ischemic stroke (0.86) and its mortality (0.966).

Figure 2
Figure 2:
ROC curve of fibrinogen as a predictor of acute ischemic stroke. ROC, receiver operating characteristic.
Figure 3
Figure 3:
ROC curve of fibrinogen as a predictor of mortality. ROC, receiver operating characteristic.

4 Discussion

Stroke was responsible for 5.3 million deaths or 1 in 11 deaths worldwide. The absolute number of people affected by stroke has been increasing since 1990, along with numbers of disabled stroke patients and deaths due to stroke. It is estimated that if current trends continue, by 2030 there with be 70 million stroke survivors and 20 million annual stroke deaths worldwide.8

Inflammation is a risk factor in the development of atherosclerosis and during the ischemic events, which is identified by inflammatory markers as fibrinogen and hs-CRP. Increased concentration of hs-CRP helped in the prediction of cerebrovascular mortality.9

We could not find a significant difference in serum fibrinogen level regarding gender or smoking, supporting the results of Bruno et al.10 who estimated fibrinogen levels once in 1525 patients (669 men and 856 women) with noninsulin-dependent diabetes mellitus. On the contrary, Giansante et al.11 found higher fibrinogen values in male smokers in 516 normal subjects, but it was reversed in nonsmokers. However, his study included pregnant women and women who used oral contraceptives.

This study showed that there was a statistically significant increase in serum fibrinogen level in stroke groups in comparison with a nonstroke group (P < .001), which was supporting Abdelgwad et al.12 who measured fibrinogen in 35 patients with acute ischemic stroke within the first 48 hours of the onset of symptoms and after 3 months duration, and found that high fibrinogen concentration was linked to poor outcome 3 months after stroke.

This study showed that there was a statistically significant increase in LDL and a statistically significant decrease in HDL in the stroke group in contrast to nonstroke group, which was concordant with Imran et al.13 who assessed plasma fibrinogen levels among 107 ischemic stroke patients and 94 controls once within 7 days after the onset of symptoms, and found a statistically significant increase in LDL and decrease in HDL in stroke group compared to nonstroke group.

Our study showed a significant positive correlation between fibrinogen level and both FBS and PPBS bracing Saini et al.14 findings who interpreted that the glycosylated fibrinogen is less susceptible to degradation with plasmin. Abdelgwad et al.12 revealed that there was no mentionable association between plasma fibrinogen levels and FBS and PPBS among diabetic patients. Correlation between glycemic control and fibrinogen levels could be explained by the fact that glycosylated fibrinogen is less susceptible to plasmin degradation plus the insulin deficiency that leads to differential protein synthesis with increase in the fibrinogen synthesis.14

This study showed the statistically significant positive correlation between fibrinogen and hypertension, which was near to Kafle and Shrestha15 and Abdelgwad et al.12 results of a positive correlation between fibrinogen levels and prevalent hypertension in both women and men.

Our study revealed that a cutoff value of serum fibrinogen ≥439 mg/dL could be considered as a predictable value in determining the development of ischemic stroke supporting the results of similar studies.13,16,17

Regarding the relation between fibrinogen level and in-hospital outcome, this study showed that 7 patients (21.9%) died within 15 days of admission with fibrinogen levels >557 mg, APACHE II score (11–18). Eleven patients (34.4%) had no improvement and stayed in the hospital with a disability for more than 15 days with APACHE II score (13–18) supporting the results of similar studies.18,19

One of the major limitation in our study was the measurement of fibrinogen after the occurrence of acute stroke that made it difficult to differentiate hyperfibrinogenemia as a cause or a result (as a one of acute phase reactants), in addition to the lack of serial daily measurement of fibrinogen with its impact on prognosis and outcome, necessitating a long-term prospective cohort study that followed high-risk individuals for the development of acute stroke with regular base checkup of fibrinogen level to validate these results and to determine the candidates for thrombolytic therapy. A second one was the measurement of fibrinogen 48 hours after intensive care unit admission without accurate linkage to the stroke onset. Finally, the association between imaging findings and Glasgow Coma Scale with the fibrinogen levels was not applied in this study.

In conclusion, high serum fibrinogen levels in high-risk individuals, especially the diabetics, may be used as a predictor for the occurrence of acute ischemic stroke and mortality from stroke.

Acknowledgments

We would appreciate the great help in statistics by Dr Usama Ragab, the assistant lecturer of internal medicine, Zagazig University.

References

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Keywords:

fibrinogen; intensive care unit; ischemic stroke

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.