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January2014 Vol.51 Issue:      1 Table of Contents
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Elevated Plasma Fibrinogen Levels Predict Poor Clinical Outcome after Acute Ischemic Stroke

Dina M. Abdelgawad, Ahmed A. Elbassiouny, Romany A. Youssef,

Nahed Salah Eldin, Mahmoud H. Elrakawy

Department of Neuropsychiatry, Ain Shams University; Egypt



ABSTRACT

 Background: Fibrinogen is a powerful predictor of vascular events in health populations and patients with cardiovascular disease. There is great evidence suggesting that patients suffering ischemic stroke has significantly higher plasma fibrinogen levels, these levels are associated with increased risk of ischemic stroke as well as significant prognostic influence in stroke patients. Objective: The objective of this study is to correlate the plasma fibrinogen levels with clinical outcome in patients with acute ischemic stroke. Methods: Thirty-five consecutive patients with acute ischemic stroke were evaluated within the first 48 hours of onset of symptoms and after three months duration. Serum fasting plasma fibrinogen level was measured within 48 hours of onset of symptoms. Results: Plasma fibrinogen levels were high in patients with ischemic stroke and ranged from 1.8 to 8.2 g/l with a mean of 5.33 g/l (S.D ±1.77). Twenty-five patients (71%) patient had plasma fibrinogen level >4.5 g/l and ten patients (29%) with fibrinogen levels ≤ 4.5 g/l. High fibrinogen levels were associated with poor outcome three months post stroke and the most prevalent risk factor was hypertension. Conclusion: There is association between plasma fibrinogen level and ischemic stroke. Elevated fibrinogen levels were predictive of poor outcome. [Egypt J Neurol Psychiat Neurosurg.  2014; 51(1): 61-67]

 Key Words: Stroke, fibrinogen, hypertension.

Correspondence to Dina Abdelgawad, Department of Neuropsychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Email: dina.zamzam1@hotmail.com





INTRODUCTION

 

Stroke is the fourth leading cause of death, and a leading cause of long-term severe disability. Nearly half of older stroke survivors experience moderate to severe disability.1 Acute ischemic stroke (AIS) most commonly occurs when a blood vessel is obstructed by either thrombosis or embolism leading to irreversible brain injury and subsequent focal neurologic deficits.2 Fibrinogen (Fg) is a high molecular weight plasma adhesion protein and a biomarker of inflammation.3   Many cardiovascular and cerebrovascular disorders are accompanied by increased blood content of fibrinogen. Increased levels of fibrinogen result in changes in blood rheological properties such as increases in plasma viscosity, erythrocyte aggregation, platelet thrombogensis, alterations in vascular reactivity and compromises in endothelial layer integrity.4 These alterations exacerbate the complications in peripheral blood circulation during cardiovascular diseases such as hypertension, diabetes and stroke.5

Cerebrovascular disorders associated risk factors and mortality all show seasonal variation. This finding suggests a major role of inflammation in association with the seasonal variation of fibrinogen.6

 

As fibrinogen concentrations remain associated with ischemic stroke prognosis after adjustment for many known prognostic risk factors, including age, stroke severity, and neuro-radiological findings, it follows that a prognostic prediction model that adds fibrinogen would provide more accurate assessment of ischemic stroke prognosis.7

Aim of the work: The objective of this study is to correlate the plasma fibrinogen levels with clinical outcome in patients with acute ischemic stroke better management.

 

PATIENTS AND METHODS

 

A prospective study carried out in the neurology department, El Sahel Teaching Hospital, between January and September 2010. Thirty-five patients were included, aged over 40 years, to avoid collagen disorders. All patients suffered of acute ischemic stroke with-in 48 hours of onset. Patients with history of other medical diseases, or severely disabled patients (National Institutes of Health Stroke Scale (NIHSS)8 above 14 were excluded to avoid poor clinical outcome.

Patients were subjected to; (a) full clinical evaluation including history of hypertension, diabetes mellitus and dyslipidemia, (b) the NIHSS8 and Barthel index9: at base line and follow up after three months, (c) Fasting Plasma fibrinogen level was measured during the first 48 hours from the onset of  symptoms by Caluss method in hematology lab with reference value from 1.5 g/l to 3.5 g/l and a cutoff point of 4.5 g/l10, and (d) Computerized tomography of the brain was done at base line and after three days of onset to confirm recent infarction.

 

Statistical Analysis

Statistical analysis was carried out using SPSS (21.0). Results are presented as percentage, mean ±SD. Chi-square test  was used to study the association between each 2 variables or comparison between 2 independent groups as regards the categorized data Continuous variables were compared using t test, and categorical variables were analyzed with χ2 test. Correlation analyses were performed using Pearson correlation for non-categorized data. Logistic Stepwise Multi-Regression analysis was used to search for a panel (independent parameters) that can predict the target parameter (dependant variable). Results were considered statistically significant at p value ≤ 0.05 and highly significant p value ≤0.005.

 

RESULTS

 

Thirty-five patients; 12 males (34%) and 23 females (66%) with acute ischemic stroke were included.  Age ranged between 40 and 84 years with a mean of 57.57 years ±10.65. The most prevalent risk factor was hypertension 24 (68.6%) followed by dyslipidemia 22 (62.9%), and diabetes mellitus 15 (42.9%). Five patients did not have any risk factor, eight patients had one risk factor and 22 patients had more than one risk factor. The plasma fibrinogen level of the patients ranged from 1.8g/l to 8.2 g/l with a mean of 5.33 g/l ±1.7. Among hypertensive patients 21 (84%) had a plasma fibrinogen level > 4.5lg/l. while only 4 non-hypertensive patients (16%) had a plasma fibrinogen level > 4.5 g/l (p<0.01). Among diabetic patients 12 (48%) had a plasma fibrinogen level > 4.5g/l while 13 non-diabetic patients (52%) had a plasma fibrinogen level > 4.5 g/l (p>0.05). Among dyslipidemic patients 16 (64%) had a plasma fibrinogen level >4.5 g/l. While 9 non-dyslipidemic patients (36%) had a plasma fibrinogen level >4.5 g/l (p>0.05). Also fibrinogen level did not correlate with neither the number of risk factors nor the size or site of lesions (p>0.05) (Table 1).

Our patients where classified according to NIHSS into 7 patients (20%) with mild disability (scored 0-6) and 28 patients (80%) with moderate disability (scored 7 -14). After three months, 12 patients (34.3%) completely recovered, 14 patients (40%) had mild disability and 9 patients (25.7%) had moderate disability (Figure 1). Fibrinogen levels at the onset of stroke correlates positively with the (NIHSS), p=0.004 (Figure 2).

After 3 months twelve patients improved, 7 patients (70%) had a plasma fibrinogen level <4.5 g/l. Fourteen patients had mild disability, only two of them had a plasma fibrinogen levels <4.5 g/l, while other patients had a plasma fibrinogen levels >4.5 g/l. There was statistically significant positive correlation between high fibrinogen level and disability detected by NIHSS, p=0.01 (Figure 3).

Our patients were categorized according to Barthel index into severely dependent (score 0–50), mildly dependent (score 51–95). Twenty six patients (74.3%) were severely dependent and nine patients (25.7%) were mildly dependent. After three months 12 patients (34.3%) improved (scored 95), and 17 patients (48.6%) were severely dependent.

Fibrinogen levels at the onset inversely correlate with the Barthel Index (r=8.615, p=0.003). Four patients with severe disability had a plasma fibrinogen level <4.5 g/l, while 22 patients had a plasma fibrinogen level >4.5 g/l.

After three months there was significant inverse correlation (r=9.563, p=0.008), with fibrinogen levels. Twelve patients had better Barthel Index after 3 months, seven patients (70%) had a plasma fibrinogen level <4.5 g/l while 5 patients (20%) had a plasma fibrinogen level >4.5 g/l. One patient with moderate dependency had a plasma fibrinogen level <4.5 g/l while 16 patients (64%) had a plasma fibrinogen level >4.5 g/l (Table 2).


 

Table 1. Correlations of Fibrinogen.

 

 

Fibrinogen

χ2

p

Hypertension

9.665

0.002*

Diabetes mellitus

0.945

0.331

Dyslipidemia

0.049

0.825

Number of risk factors

2. 838

0.242

Size of lesion

0.135

0.714

Affected circulation

0.875

0.350

* Significant at P<0.01

 

 

Figure 1. NIHSS among patients at base line and after 3 months

 


Figure 2. NIHSS and fibrinogen level at onset.

 

 

Figure 3. Follow up NIHSS regarding fibrinogen level.

 

 

 

Figure 4. Barthel index at onset and after 3 months.

Table 2. Barthel index according to fibrinogen level at onset and after 3 months.

 

 

Fibrinogen

Total

 

<4.5

>4.5

Barthel index

Moderately dependent

n

6

3

9

r

8.615

% within Fibrinogen

60.0%

12.0%

25.7%

Severely dependent

n

4

22

26

p

% within Fibrinogen

40.0%

88.0%

74.3%

0.003*

Follow up

Barthel index

Improved

n

7

5

12

r

% within Fibrinogen

70.0%

20.0%

34.3%

9.563

Mildly dependent

n

2

4

6

 

% within Fibrinogen

20.0%

16.0%

17.1%

Severely dependent

n

1

16

17

P

% within Fibrinogen

10.0%

64.0%

48.6%

0.008*

Total

n

10

25

35

 

% within Fibrinogen

100.0%

100.0%

100.0%

* Significant at P<0.01

 


DISCUSSION

 

Fibrinogen is a clotting factor that may accelerate the thrombotic process and could act as a marker of inflammation.3 The objective of this study is to correlate the plasma fibrinogen levels with clinical outcome in patients with acute ischemic stroke. Thirty-five patients with acute ischemic stroke were recruited and evaluated clinically including functional assessment by Barthel index and NIHSS and CT brain within the first 48 hours of onset of symptoms and after three months duration. Fasting plasma fibrinogen level was measured during the first 48 hours of onset. The present study found that the plasma fibrinogen level was high in the patients with ischemic stroke and ranged from 1.8 to 8.2 g/l with a mean of 5.33 g/l ±1.77. This is in agreement with Tanne and colleague11, who found mean baseline plasma fibrinogen levels were also higher in patients experiencing any cerebrovascular event (375±71mg/dl), and Di Napoli and colleagues12, who found that the mean plasma fibrinogen level was 4.76g/L (3.78 to 6.17 g/L) among stroke patients .This is in agreement with an Egyptian study carried by Abdel-Ghani and colleagues13, which revealed high serum fibrinogen in patients suffering acute ischemic stroke .Variation in the level of fibrinogen among these studies may be due to variation in ethnicity,  method of fibrinogen assay,  age and sex of patients selected for these studies.

Similar to our results, Folsom and colleagues14, Kafle and Shrestha15, who reported a positive association between fibrinogen levels and prevalent hypertension in both men and women. This may be explained by the relationship between fibrinogen and increased viscosity and peripheral vascular resistance. Hyper-insulinemia and insulin resistance is common among hypertensive patients and hyper-insulinemia decreases fibrinolytic activity hence increases fibrinogen levels in hypertensive patients.16 Fogari and colleagues17, did not confirm these results. This may be attributed to small sample size, different blood pressure levels, and interference of antihypertensive treatments.

The present study found that plasma fibrinogen levels were not significantly elevated among diabetic patients (P>0.05). This is in agreement with Missov and colleagues.18 Meanwhile our study disagreed with James and colleagues.19

The main finding of the present study was the high association between plasma fibrinogen level and poor outcome after ischemic stroke. This is consistent with Di Napoli and colleagues12, and Del Zoppo and colleagues10, who found that baseline fibrinogen level ≥4.5 g/dl, was significantly associated with poor functional outcome 90 days after ischemic stroke taking into consideration the variability of age and treatment of stroke. Tanne and colleagues20, reported that patients with high fibrinogen levels two hours from the onset of ischemic stroke tended to deteriorate rapidly (P=0.05), and high 24-hours fibrinogen levels were associated with 40% increased mortality 90 days after stroke. This could be due to high fibrinogen level, which forms blood clots made of thinner and tightly packed fibers, more resistant to fibrinolysis. Therefore, fibrinogen levels in the early post stroke period may have implications on the efficacy of thrombolytic treatment.21    

Conclusion

This study suggests that fibrinogen is a powerful predictor of vascular events. Plasma fibrinogen levels are associated with poor clinical outcome three months following acute ischemic stroke.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

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2.      Bansal S, Sangha S, Khatri P. Drug Treatment of Acute Ischemic Stroke. Am J Cardiovasc. 2013; 13:57-69.

3.      Sato S, Nakamura M, Iida M, Naito Y, Kitamura A, Okamura T, et al. Plasma fibrinogen and coronary heart disease in urban Japanese. Am J Epidemiol. 2000; 152:420-3.

4.      Bas M ,  Kirchhartz  N, Hochfeld J, Tüllmann C, Kumpf S, Suvorava T, et al. Potential role of vasomotor effects of fibrinogen in bradykinin induced angioedema. J Allergy Clin Immunol. 2008; 121:969-75.

5.      Lominadze DDean WLTyagi SCRoberts AM. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease. Acta Physiol. 2010; 198(1):1-13.

6.      Su TC, Chen SY, Chan CC. Progress of ambient air pollution and cardiovascular disease research in Asia. Prog Cardiovasc Dis. 2011; 53(5):369-78.

7.      Tombul T, Atbas C, Anlar O. Hemostatic markers and platelet aggregation factors as predictive markers for type of stroke and neurological disability following cerebral infarction. J Clin Neurosci. 2005; 12(4):429-34.

8.      Lyden PD, Lu M, Levine S, Brott TG, Broderick J. A modified National Institutes of Health Stroke Scale for use in stroke clinical trials: preliminary reliability and validity. Stroke. 2001; 32:1310-7.

9.      Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study. Int Disabil Stud. 1988; 10:61-3.

10.    del Zoppo GJ, Levy DE, Wasiewski WW, Pancioli AM, Demchuk AM, Trammel J, et al. Hyperfibrinogenemia and functional outcome from acute ischemic stroke. Stroke. 2009; 40:1687-91.

11.    Tanne D, Haim M, Goldbourt U, Boyko V, Doolman R, Adler Y, et al. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke. 2003; 34:632-6.

12.    Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32:917-24.

13.    Abdel-Ghani MO, Gaballa MR, Lechner H, Moustafa M. Hamorheology in cerebrovascular stroke [MD thesis]. Cairo: Ain Shams University; 1986.

14.    Folsom AR, Rosamond WD, Shahar E, Cooper LS, Aleksic N, Nieto FJ, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1999; 100:736-42.

15.    Kafle DR, Shrestha P. Study of fibrinogen in patients with diabetes mellitus. Nepal Med Coll J. 2010; 12(1):34-7.

16.    Sechi LA, Zingaro L, Catena C, De Marchi S. Relation of fibrinogen level and hemostatic abnormalities with organ damage in hypertension. Hypertension 2000; 36:978-85.

17.    Fogari R, Zoppi A, Malamani GD, Marasi G, Vanasia A, Villa G. Effects of different antihypertensive drugs on plasma fibrinogen in hypertensive patients. Br J Clin Pharmacol. 1995; 39(5):471-6.

18.    Missov RM, Stolk RP, van der Bom JG, Hofman A, Bots ML, Pols H, et al. Plasma fibrinogen in NIDDM: the Rotterdam study. Diabetes Care. 1996; 19:157-9.

19.    Stec JJ, Silbershatz H, Tofler GH, Matheney TH, Sutherland P, Lipinska I, et al. Association of Fibrinogen with Cardiovascular Risk Factors and Cardiovascular Disease in the Framingham Offspring Population. Circulation. 2000; 102:1634-8.

20.    Tanne D, Macko RF, Lin Y, Tilley BC, Levine SR. for the NINDS rtPA Stroke Study Group. Hemostatic activation and outcome after recombinant tissue plasminogen activator therapy for acute ischemic stroke. Stroke. 2006; 37:1798-804.

21.    González-Conejero R, Fernandez-Cadenas I, Iniesta JA, Marti-Fabregas  J, Obach V Alvarez-Sabín J, et al. Role of fibrinogen levels and factor XIII V34L polymorphism in thrombolytic therapy in stroke patients. Stroke. 2006; 37:2288-93.


 

 


الملخص العربى

 

العلاقة بين معدل الفيبرنوجين فى البلازما والتحسن الاكلينيكى لمرض السكتة الدماغية الحادة

 

هناك ارتباط بين زيادة مستوى الفيبرنوجين فى البلازما والتطور الاكلينيكى بعد السكتة الدماغية الحادة وقد تبين أن المرضى الذين يعانون من انخفاض مستويات الفيبرنوجين الاوليه 4.5 جم/لتر كانو أفضل مال حتى عند  تصحيحها بالنسبة للعمر وشدة السكتة الدماغية الاوليه وأكدوا وجود علاقة بين الفيبرنوجين ومال المرض.

وقد كان الهدف من دراستنا تحديد نسبه الفيبرنوجين فى البلازما وتبين العلاقة بينها وبين التحسن الاكلينيكى لمرضى السكتة الدماغية الحادة.

وقد أجريت هذه الدراسة على 35 حاله من مرضى السكتة الدماغية (الارتوانيه الحادة) من قسم أمراض المخ والأعصاب بمستشفى الساحل التعليمى. وقد كان منهم 12 من الذكور و23من الإناث وتراوح العمر للمرضى من 41 سنه إلى 84 سنه.وقد تم قياس الفيبرنوجين خلال 48 ساعة من بداية الأعراض والمريض صائم وقياس معامل ان اى اش اس اس ومعامل بارثل للمريض فى البداية وبعد 3  شهور.

 

وقد جاءت النتائج كالاتى :

1.    أظهرت النتائج ان معدل الفيبرنوجين بين المرضى كان مرتفعا وتتراوح بين 1.8 جم/لتر الي 8,2 جم/لتر وهو معدل مرتفع بين مرضى السكتة الدماغية.

2.    أظهرت النتائج ان 80%من المرضى الذين يعانون من أعاقه متوسطه بعد السكتة بحسب ما حصلو عليه من درجات فى معامل ان اى اتش اس حصلو على درجات تتراوح بين (14-7) و20% يعانون من أعاقه بسيطة متوسطه بعد السكتة بحسب ما حصلوا عليه من درجات فى معامل ان اى اتش اس حصلوا على درجات تتراوح بين (0-6) وبعد 3 شهور تغيرت النتائج الى 34% تحسنوا تماما ولم تترك السكتة اى اثر عليهم و40% أعاقه بسيطة و 26% أعاقه متوسطه.

3.    وأظهرت النتائج أيضا ان 75%من المرضى اعتمدوا اعتمادا كبير على الاخرين فى حياتهم اليومية وذلك حسب درجاتهم فى معامل بارثل حيث حصلوا على درجات تتراوح بين (0-50) و 25%اعتمدوا اعتمادا بسيط وحصلو على درجات تتراوح بين (51-95) وبعد 3 شهور تغيرت النتائج الى 34% أصبحوا غير معتمدين على الاخرين وحصلوا على درجات اكبر من 95و 49% اعتماد كبير و 17% اعتماد بسيط.

 

التوصيات:

1.         قياس معدل الفيبرنوجين فى الدم لمرضى السكتة الدماغية حيث أنها يساعد على التنبؤ بالتحسن الاكلينيكى للمرضى.

2.         إجراء دراسات موسعه وعلى مجموعات اكبر من المرضى لتدعيم هذه النتائج.

 



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