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April2015 Vol.52 Issue:      2 Table of Contents
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Pentraxin 3 is Increased Early in Blood of Patients with Cerebral Stroke and Predicts its Severity

Tamer  Belal1, Mervat Mashaly2, Ibrahim E. Elmenshawi1

Departments of Neurology, Clinical Microbiology Unit1, Clinical Pathology2, Mansoura University; Egypt


Background: Pentraxin-3 is a novel biomarker of inflammation in atherosclerosis and cardiovascular diseases that is not studied well in cerebral stroke. Objective: to assess plasma level of pentraxin-3 in patients with acute cerebral stroke whether hemorrhagic or ischemic. Methods: patients admitted to neurocritical neurology department with acute stroke within 24-48 hours of stroke were recruited and subjected for pentraxin- 3 assay and their clinical data and severity were measured using validated tests. Statistical analyses were performed in the SPSS statistical package programme (version 16, SPSS, Chicago, IL). Results: A hundred and forty acute stroke patients were enrolled. The median of pentraxin-3 was significantly high in both stroke types when compared to control. Patients with hypertension, diabetes mellitus and hypercholesterolemia have significantly higher pentraxin-3 level. Pentraxin level was significantly correlated with severe stroke and large infarcts. pentraxin-3 was also the only predictor of severe hemorrhagic stroke (NIHSS more than 14) on multivariate regression analysis for severe stroke (Beta=1.59, SE=0.422 &P=0.000). Conclusion: pentraxin-3 level is a novel biomarker for stroke and its severity and correlated with atherosclerosis risk factors and its pathological role in stroke should be more clarified. [Egypt J Neurol Psychiat Neurosurg.  2015; 52(2): 111-117]

 Key Words: Pentraxin 3, stroke, severity

Correspondence to Ibrahim Elmenshawi. Neurology Department, Mansoura University, Egypt.

Tel.: +201005447704




Pentraxin 3 (PTX3) is a member of the pentraxin family that includes the traditional C-reactive protein(CRP) but unlike it ,is expressed locally at atherosclerosotic patches and have been considered a biomarker of atherosclerotic cardiovascular diseases and correlated with its severities1. PTX-3, as an acute phase reactant, is induced by pro-inflammatory cytokines (inteleukin1 beta & tumor necrosis factor) and has anti-inflammatory effect through binding and activation of complement system2. Intracranial and extracranial atherosclerosis is not only a major cause for ischemic strokes but also for hemmorhagic ones due to rupture of unstable atherosclerotic plaques3. Although PTX-3 was reported to be expressed in atherosclerotic plaques and high levels were seen in patients with carotid artery atherosclerosis4, its pathological role in acute stroke situation is still not fully studied or understood. The aim of this study was to evaluate PTX-3 in acute stroke patients and its prognostic value.



This prospective study was conducted on patients with acute stroke admitted to neuro-critical care unit, Mansoura University Hospital within the first 24 hours of symptom onset. Thirty two, age and sex matched, healthy subjects, not having any evidence of stroke or previous history of transient ischemic attacks, were served as a control.

Stroke was ascertained and classified into ischemic or hemorrhagic by brain computed tomography and/ or magnetic resonance imaging done on hospital admission.

Ischemic stroke cases were further classified into 5 subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST): cardioembolic infarct (CEI), large-artery atherosclerosis (LAAS), lacunar infarct (LAC), stroke of undetermined etiology (UDE), and stroke of other determined etiology (ODE)5.

Infarct volumes were measured by brain CT according to the formula 0.5*A*B*C where (A) is the largest diameter of the infarct and (B) is its largest perpendicular diameter, while (C) was determined by summing the thicknesses of the slices in which the lesion was visible.  The infarcts were classified as large when the volume > 1.5 cm and small when the volume was < 1.5 cm. 6

On admission, stroke severity was assessed by the National Institute of Health Stroke Scale (NIHSS) and stroke was categorized as mild (NIHSS 0–7), moderate (NIHSS 8–14), or severe (NIHSS >14) 7.

Seven days following the onset of stroke, we evaluated the outcome of patients using modified Rankin Scale (MRS). Poor outcome was considered to be >2 by MRS score8.

The presence of baseline vascular risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, and smoking, was determined. Hypertension was defined as blood pressure ≥ 140/90 mmHg; or current antihypertensive therapy. Diabetes mellitus was defined as fasting blood glucose level ≥ 126 mg/dl or a history of treatment with antidiabetics. Dyslipidemia was defined as a total cholesterol level ≥ 200 mg/dl.

Subjects admitted more than 24h after symptoms onset, or with recent inflammatory conditions, such as major trauma, surgery, or obvious acute infectious disease, acute coronary syndrome, cerebrovascular events, autoimmune disease, liver cell failure, and chronic renal failure were excluded from this study.


Blood sampling & laboratory measurements:

For PTX-3 measurement: 2 ml of venous blood were collected within 24 - 48 hours of hospitalization into tubes containing ethylene diamine tetraacetic acid (EDTA). Within 30 minutes of collection, tubes were centrifuged at 1500×g  for 10 min. Plasma samples were stored frozen at – 20o C until the analysis were performed.

For blood glucose & cholesterol measurements: after an overnight fasting, 2ml of venous blood were withdrawn into dry plastic tubes and allowed to clot then the serum was separated by centrifugation at 3000 r/min for 10 min and immediately analyzed.

Plasma PTX-3 levels were determined using enzyme-linked immunosorbent assay (ELISA) according to the manufacture's procedure (R&D Systems, Inc, USA) 9.

Blood glucose and cholesterol concentrations were measured on a Cobas Integra 400 chemistry autoanalyzer (Roche Diagnostics, Basel, Switzerland) using commercially available reagents and an enzyme-based kit.


Statistical Analysis

Statistical analyses were performed in the SPSS statistical package programme (version 16, SPSS, Chicago, IL). Normality was measured with Kolmogorov Smirmov test. The results were expressed as percentages for categorical variables and as mean ± SD in normal distributed variables or median (range) in non-normal distributed variables. The two-tailed Mann–Whitney U test was used to compare the median values of parameters in patient and control groups. Spearman & Pearson correlation coefficient test (r) was used to test a positive or negative relationship between two variables. Results were considered significant if P values ≤ 0.05. A receiver operating characteristic (ROC) analysis was performed to define a cut-off value of plasma PTX3 for ischemic, hemorrhagic stroke and the associated specificity and sensitivity levels. To test how much of the total variation in the stroke severity can be explained by the plasma PTX3 level we calculated R square by Simple linear regression analysis.




A hundred and forty acute stroke patients were enrolled. Their demographic, risk factors, & clinical variables as well as PTX-3 levels are presented in table 1. Plasma pentraxin-3 level were significantly higher in stroke patients when compared to control (P=0.000). Although, both ischemic and hemorrhagic groups showed significantly higher levels than control subjects, the PTX3 level was significantly higher among the ischemic group (P=0.000).

There were no significant gender differences of plasma PTX-3 level in each stroke type. Significantly higher PTX-3 levels were noticed in patients with comorbidity of hypertension (P=0.000), diabetes mellitus (P=0.000) or hypercholesterolemia (P=0.001) in both stroke types. On the other hand, patients with ischemic stroke who smoke have significantly higher PTX3 level when compared to non-smokers, a finding that was not seen among patients with hemorrhagic stroke.

Stroke severity among both types of strokes are shown in table 2 while ischemic stroke classification and infarcts volumes are shown in table 3. PTX-3 was significantly higher among cardioembolic (P=0.000) and atherosclerotic ischemia (P=0.002) but not in lacunar ischemia and those with undetermined etiology.

The level of PTX3 was significantly higher in patients with severe stroke both clinically (in both stroke types) and radiologically by infarct volume in the ischemic group as shown in Figures (1) and (2).  Also, Correlation between plasma PTX3 level and stroke severity (as measured by NIHSS) was significantly strong positive in ischemic stroke patients (r=0.91, P=0.000) and significantly moderate positive in hemorrhagic stroke patients (r=0.60, p=0.000) as shown in Figures (3) and (4)..

Simple linear regression analysis showed that plasma PTX3 level can explain 83.4% & 63.1% of ischemic & hemorrhagic stroke severity as measured clinically by NIHSS. Moreover, PTX3, hypertension and smoking were significant predictors of severe ischemic stroke type as measured by NIHSS on multivariate regression linear analysis while only PTX-3 was the only significant predictor for hemorrhagic stroke on the same analysis (Beta=1.59, SE=0.422 & P=0.000).

Our study showed that at a cutoff value of 3.18 ng/ml, PTX3 has specificity, sensitivity, negative and positive predictive values of  78.13%, 98.6%, 92.6% & 95.17% respectively for detecting patients with acute cerebral stroke (AUC, 0.96; 95%  CI,  0.93 – 0.99) as done by Receiver operating characteristic (ROC) curve (Figure 5).


Table 1. Clinical results of the studied stroke patients and control subjects.



All stroke patients (n=140)







Age ♦

63.5 (39 – 87)

62 (48 - 87)

65 (39 – 85)

65 (39 – 81)

Sex    n (%)




68 (48.6%)

72 (51.4%)


28 (40%)

42 (60%)


40 (57.1%)

30 (42.9%)


20 (62.5%)

12 (37.5%)

Smoking status n (%)






8 (5.7%)

74 (52.9%)


32 (45.7%)




26 (37.1%)

8 (11.4%)

36 (51.4%)


2 (6.3%)

4 (12.5%)


Hypertension n (%)

98 (70%)

40 (57.1%)

58 (82.9%)


Diabetes Mellitus n (%)

80 (57.1%)

44 (62.9%)

36 (51.4%)

6 (18.8%)

Hypercholestermia  n (%)

70 (70%)

26 (37.1%)

44 (62.9%)

6 (18.8%)

NIHSS at admission♦

25 (5 – 35)

22 (5 – 35)

26 (5 – 34)


Pentraxin 3 level (ng/ml)♦

9.18 (3.14 -21.63)

12.12 (3.31-21.63)

8.14 (3.14-12.20)

2.35 (1.57 -4.80)

♦ median (range)


Table 2. Stroke clinical severity assessment.



Hemorrhagic stroke


Ischemic stroke

N (%)










MR scale-mild



MR scale-severe




Table 3. Type of ischemia and infarcts size in patients with ischemic stroke.




Pentraxin-3 (ng/ml)

Type of ischemia












Undetermined etiology



Infarct size



Small (less than 1.5 cm)



Large (more than 1.5 cm)

44 (62.9%)





Figure 1. Pentraxin-3 (PTX-3) in different stroke severity assessment scales in patients with ischemic stroke.





Figure 2. Pentraxin-3 (PTX-3) in different stroke severity assessment scales in patients with hemorrhagic stroke.




Figure 3. Correlation between plasma PTX3 and NIHSS in ischemic stroke patients.




Figure 4. Correlation between plasma PTX3 and NIHSS in hemorrhagic stroke patients.




Figure 5. Receiver operating characteristic (ROC) curve of PTX3.





Stroke is a world health problem with great direct and indirect cost on countries' economy. Over the last two decades, stroke has begun to be both preventable and treatable disease rather than a direct aging consequence that end with disability or death. This was achieved by better identification of people at risk of stroke and mechanisms that makes them susceptible for stroke or the likelihood of severe disability thereafter10.

Pentraxin-3 is one of the pentraxin family that is well-identified as acute inflammatory cardiovascular biomarker and was incriminated in the pathogenesis of acute coronary syndrome , congestive heart failure, sleep apnea syndrome, heart valvular disease, and atherosclerosis11. Atherosclerosis exerts a state of chronic inflammation of the arterial wall and stroke itself leads to perpetuation of this inflammatory response that produce PTX-3 locally to prevent more platelet adhesion and stimulate antiapoptotic mechanism and help regeneration by mediating neurogenesis and angiogenesis12. The aim of this study was to explore the role of PTX-3 in patients with cerebral stroke. We found significantly higher PTX-3 in all stroke patients whether hemorrhagic or ischemic type. Zanier et al has detected elevated PTX-3 in all subarachnoid hemorrhage in plasma and CSF with acute peak in the first 48 hours and another peak with the development of vasospasm13. Sezer et al. reported also significantly higher PTX-3 in patients with acute ischemic stroke when compared to control subjects14.

Our results showed that patients with hypertension, diabetes mellitus and hypercholestrolemia have higher PTX-3 level. This is in agreement with Parlak et al who beautifully investigated the relationship between systolic and diastolic blood pressure and PTX-3 level. They found higher PTX-3 level in both systolic and diastolic hypertension. Moreover, on regression analysis PTX-3 levels strongly affected blood pressure causing increase in both of them15. Also Karakas et al found a correlation between PTX-3 and metabolic syndrome and its level increase with increasing the number of metabolic syndrome criteria and severity16. Cigarette smoking increases pulmonary PTX-3 expression in an IL-1 dependant manner17. The later has an established role in the atherosclerosis state of chronic inflammation. Our results showed that cigarette smokers with ischemic stroke but not hemorrhagic one has higher PTX-3 when compared to ischemic stroke non-smokers.

A higher level of PTX-3 was found with severe stroke as measured clinically by NIHSS and by the infarct volume and type. This is in agreement with sezer et al (14) that showed similar trends and Ryu et al.18, who showed that higher levels of PTX-3 are independently associated with increased mortality.

This is the only study, to our knowledge, that comprised PTX-3 assessment in both hemorrhagic and ischemic stroke and shedding light on its role as a cause of severe forms of stroke; clinically and radiologically and its relationship with the common stroke risk factors. The limitations of our study were the small number of patients to explore different severity forms of stroke and also the fact that we didn't follow up the mortality and the long-term disability of patients with high PTX3 level.

More studies in this field are essential as PTX3 is emerging biomarker and a possible target for stroke prevention and treatment.


[Disclosure: Authors report no conflict of interest]




1.        Spagnoli LG, Bonanno E, Sangiorgi G and Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med. 2007;48(11):1800-1815

2.        Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 2008;28(1):1-13.

3.        Arenillas JF. Intracranial atherosclerosis: current concepts. Stroke 2011;42(1 suppl):S20-23

4.        Shindo A,  Tanemura H, Yata K, Kazuhide H,  Shibata M, Umeda Y,  Asakura F,2  Toma N, Sakaida H, Fujisawa T, Taki W and  Tomimoto H. Inflammatory Biomarkers in Atherosclerosis: Pentraxin 3 Can Become a Novel Marker of Plaque Vulnerability. PLoS One. 2014; 9(6): e100045.

5.        Chen PH, Gao S, Wang YJ, Xu AD, Li YS, Wang D. Classifying Ischemic Stroke, from TOAST to CISS. CNS Neurosci Ther. 2012; 18: 452-456.

6.        Pantano P, Caramia F, Bozzao L, Dieler C, von Kummer R. Delayed increase in infarct volume after cerebral ischemia: Correlations with thrombolytic treatment and clinical outcome. Stroke. 1999; 30:502-507

7.        Adams Jr HP, Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke WR, et al. Baseline NIH stroke scale score strongly Predicts outcome after stroke: a report of the trial of org10172 in acute stroke treatment (TOAST). Neurology. 1999; 53(1): 126–131.

8.        Van Sweiteen JC, Kodstaal PJ, Visser MC, Schouten HJ, Van Gijn J:inter observer agreement for the assessment of the handicap in stroke patients. Stroke. 1988;19(5):604-607

9.        Bottazzi B, Bastone A, Doni A, Garlanda C, Valentino S, Deban L, Maina V, Cotena A, Moalli F, Vago L, Salustri A, Romani L, Mantovani A. The long pentraxin PTX3 as a link among innate immunity, inflammation, and female fertility.J Leukoc Biol. 2006;79(5):909-912

10.     National collaborating centre for chronic conditions (UK).Stroke: National clinical guidline for diagnosis and initial management of acute stroke and transient ischemic attack (TIA). London: Royal College of physians (UK); 2008. (NICE clinical guidelines, No.68.)1, Introduction.

11.     Inoue K, Kodama T, Daida H: Pentraxin 3. A novel biomarker for inflammatory cardiovascular disease. int J Vasc Med. 2012;(2012) Article ID 657025, 6pages.

12.     Rodriguez-Grande B, Varghese L, Molina-Holgado F, Rajkovic O, Garlanda C, Denes A, Pinteaux E. Pentraxin 3 mediates neurogenesis and angiogenesis after cerebral ischemia. J Neuroinflammation. 2015;12.doi:10.1186/s12974-014-0227-y

13.     Zanier E, Brandi G, Peri G, Lounghi L, Sigurta A, Valaperta S, et al. Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm. Intensive Care Med. 2011; 37(2):302-309

14.      Sezer S, Ucar F, Uloosoy E, Erdogan S, Bilen S, Zungun C, et al. Serum amyloid A, fetuin-A, and pentraxin-3 levels in patients with ischemic stroke: Novel prognostic biomarker?.Turk J Med Sci. 2014;44:16-23

15.     Parlak A, Aydogan U, Dikliler MA, Kut A, Cakir E, Saglam K. Elevated pentraxin-3 levels are related to blood pressure levels in hypertensive patients: an observational study. Anadolu Kardiyol Derg. 2012;12(4):298-304

16.     Karakas MF, Buyukkaya E, Kurt M, Motor S, Akcay AB, Karakas E,et al. Serum pentraxin-3 levels are associated with the severity of metabolic syndrome. Med Princ Pract. 2013;22(3):274-279

17.     Pauwels NS, Bracke KR, Maes T, Van Pottelberge GR, Garlanda C, Mantovani A, et al. Cigarette smoke induces PTX3 expression in pulmonary veins of mice in an IL-1 dependant manner. Resp Res. 2010;11:134

18.     Ryu WS, Kim  CK, Kim BJ, Kim c, Lee SH, Yoon BW: Pentraxin 3: a novel and independent prognostic marker in ischemic stroke. Atherosclerosis. 2012;220(2):581-586.



الملخص العربي


زيادة مستوي البنتراكسين-٣ في مرضي السكتات الدماغية ومتنبئا بخطورتها


خلفية البحث: البنتراكسين-٣ هو أحد الدلالات الجديدة المصاحبة لتصلب الشرايين وأمراض الأوعية الدموية للقلب.

الهدف من البحث: هذا البحث يهدف الي رصد مستوي البنتراكسين-٣ في دم مرضي السكتات الدماغية الحادة ومحاولة الربط بينة وبين خطورة المرض. طريقة البحث: تم تحديد مستوي البنتراكسين-٣ في دم مرضي السكتات الدماغية بنوعيها؛ الاحتشاء والنزيف المخي في المرضي الذين تم وصولهم لقسم الحالات الحرجة التابع لقسم المخ والأعصاب بمستشفي جامعة المنصورة خلال ٢٤-٤٨ ساعة من حدوثها. تم تجميع عوامل الخطورة لتصلب الشرايين في هؤلاء المرضي واستخدام طرق إكلينيكية وإشعاعية لقياس خطورة المرض وبحث علاقتها مع مستوي البنتراكسين بالدم. نتائج البحث:  زيادة في مستوي البنتراكسين -٣ في مرضي السكتات الدماغية بنوعيها بدلالة احصائية عند مقارنتهم بأشخاص لا يختلفون عنهم إحصائيا في السن والجنس. كانت الزيادة أيضا ملحوظة إحصائيا مع مرض زيادة ضغط الدم، البول السكري وزيادة الكوليسترول بالدم أما مدخني السجائر فكانت الزيادة ذات دلالة احصائية في مرضي الاحتشاء وليس النزيف المخي. وكان من أهم نتائج البحث هو وجود علاقة طرديه ذات دلالة احصائية بين مستوي البنتراكسين -٣ بالدم وزيادة حدة السكتة الدماغية حسب قياسها بمقياس معهد الصحة والسكتات القومي الامريكي ومقياس رانكين المعدل. وفي حين أن زيادة مستوي البنتراكسين-٣ كانت ذات دلالة احصائية مع الاحتشائات المخية الناتجة عن تصلب الشرايين ومرضي القلب والاحتشائات الكبيرة بالأشعة المقطعية فإن هذه الزيادة كانت هي المتنبأ الوحيد لحدوث نزيف المخ وليس عوامل الخطورة في هذا البحث. الاستنتاجات : هذا البحث يؤكد علي أهمية قياس مستوي البنتراكسين-٣ بالدم ودراسة دوره المرضي في مرضي السكتات الدماغية.


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