Pentraxin 3 is considered an important inflammatory marker is known to increase
in patients with ischemic stroke, but the relationship between pentraxin 3 and
intracerebral hemorrhage mortality is unclear. The purpose of this study is to investigate
the level of pentraxin 3 in serum and its impact on prognosis in 307 patients
with intracerebral hemorrhage. During the 5-year follow-up, the mortality rate of
patients with intracerebral hemorrhage was 22.5%. The serum pentraxin 3
level of the brain-dead patients was higher than that of the control group
Spontaneous intracerebral hemorrhage (ICH) refers to primary intraparenchymal bleeding, accounting for 10%-15% of all stroke, and the mortality rate in the acute phase is as high as 30%-40% . After ICH, the hematoma compresses the surrounding brain tissue mechanically, which causes primary injury. Meanwhile, the hematoma components such as red blood cells and their degradation products can stimulate cytotoxicity, excitotoxicity, oxidative stress response and inflammatory response, leading to secondary injury , brain edema, destruction of the blood-brain barrier (BBB), neuronal apoptosis. Inflammatory reaction runs through all stages of ICH injury and plays a vital role in it. As part of the inflammatory response, inflammatory cytokines and immune cells play variable roles in ICH’s progress .
After ICH, inflammatory mechanisms involve activation of microglia, infiltration of inflammatory cells and release of cytokines and inflammatory chemokines, leading to cell death and aggravating brain injury . This higher frequency of pro-inflammatory genes in ischemic stroke could explain the immunoinflammatory activation of the acute phase of stroke . One study  indicated that the level of serum inflammatory factors in patients with ICH is significantly increased, and they participate in the pathological process of brain injury. However, the dynamic changes in inflammatory response factors after ICH are not clear. A series of cells participate in the production of pentraxin 3 (PTX3), including myeloid dendritic cells, monocytes, macrophages, vascular endothelial cells, smooth muscle cells, renal epithelial cells, fibroblasts, adipocytes, glia, cumulus cells, mesenchymal cells and synovial cells . PTX3 commonly would not be expressed in brain tissue but can be increased significantly after exposure to pro-inflammatory factors .
PTX3 is a member of the pentraxin superfamily, was first recognized as a cytokine-inducing gene in endothelial cells and fibroblasts in the early 1990s. Pentraxin family proteins can be classified into two groups according to the primary structure subunits: short-chain pentraxin and long-chain pentraxin. The former includes C-reactive protein (CRP) and serum amyloid P (SAP), while PTX3 belongs to the latter. PTX3 is a product of the acute-phase reaction of injured tissues, mainly from the heart and blood vessels. Compared with CRP from the liver, PTX3 is likely to be a more sensitive and specific biological predictor of tissue injury. Many kinds of cells in vivo can secrete PTX3, reflecting the inflammation in vascular endothelial cells. Pentraxins are a multifunctional protein superfamily playing an important role in an inflammatory response.
PTX3 is a multifunctional protein superfamily member, which plays a vital
role in the inflammatory reaction . According to the previous study , PTX3
increases in sepsis and various infectious diseases, and its increase is related
to the severity of these diseases. Also, plasma PTX3 levels were detected to
increase in various disease states, such as ischemic heart disease, vasculitis
and pulmonary contusion, in which inflammation plays an important role and is
associated with disease activity [10, 11]. PTX3 is produced by inflammatory
cytokines such as Toll-like receptor agonists, interleukin-1
PTX3 is proven to increase in many inflammatory diseases, and the serum PTX3 level is associated with sepsis development. After 6 hours of chest pain in patients with acute myocardial infarction (AMI), PTX3 level in plasma approaches peak level earlier than CRP. Therefore, PTX3 is seen as a better indicator than CRP, creatine kinase (CK), Troponin T (TnT), N terminal pro B-type natriuretic peptide (NT-proBNP) [12, 13]. It is also known that the PTX3 level is correlated with the severity and mortality of patients with systemic inflammatory response syndrome .
There are few studies on the relationship between PTX3 and brain injury. Several
recent studies have suggested that PTX3 is closely related to ischemic stroke
. PTX3 levels in patients with acute ischemic stroke increased obviously and
positively correlated with stroke severity . A study  has shown that high
levels of PTX3 imply poor long-term outcomes in patients with acute ischemic
stroke and are more sensitive than CRP. However, some other studies have shown
that plasma PTX3 levels were not associated with ischemic stroke [17, 18]. After
ICH, the expression levels of TNF-
From January 2014 to December 2016, a total of 307 patients with ICH were prospectively recruited into this study at the Department of Neurosurgery of the First Affiliated Hospital of Xi’an Medical University. Their symptom occurred within 12 hours before admission. Inclusion criteria: All ICH patients included in the study met the diagnostic criteria formulated by the 4th National Academic Conference on Cerebrovascular Diseases and were confirmed by a CT scan of the brain. Exclusion criteria: (i) traumatic intracranial hemorrhage or hemorrhage caused by infarction, tumors and cerebrovascular malformations; (ii) patients with evident damaged liver or kidney functions or malignant tumors; (iii) patients with chronic inflammatory diseases (rheumatological diseases, IBD), taking immunosuppressive agents, hormones or inflammatory inhibitors for within a month; (iv) patients with atrial fibrillation; (v) patients with coagulation dysfunction and menstrual women. Another 132 volunteers were selected as the control group in the physical examination center. All subjects in this study signed informed consent after understanding the purpose and risk of this study. The ethics committee has approved this study of the First Affiliated Hospital of Xi’an Medical University.
We collected the clinical data of patients at admission, including gender, age, laboratory data, Glasgow coma scale (GCS), National Institute of Health Stroke Scale (NIHSS), Hematoma evacuation and initial systolic blood pressure. Venous blood samples were drawn within 24 h of symptoms and were examined for WBC, glucose, total cholesterol, and CRP levels. The risk factor information was also collected, such as hypertension, diabetes, previous stroke, hypercholesterolemia, smoking history, and heart diseases.
Blood samples were centrifuged in sterile test tubes for 10 minutes (4
The patients discharged from the hospital were followed up by outpatient service or telephone, and the survival status of 1, 3 and 5 years was recorded.
Statistical analysis was performed by SPSS software version 16.0 (SPSS Inc.,
Chicago, IL). Data were expressed in the format of mean
The 307 patients with ICH included 181 males and 126 females aged 67.22
|Controls (n = 132)||All (n = 307)||P||All (n = 307)|
|Alive (n =238)||Deceased (n = 69)||P|
|Age (years, mean
|Hypertension (n%)||-||254 (82.7)||-||195 (81.9)||59 (85.5)||0.833|
|Diabetes (n%)||-||75 (24.4)||-||54 (22.7)||21 (30.4)||0.312|
|Previous stroke (n%)||-||33 (10.7)||-||12 (5.0)||11 (15.9)||0.006|
|Hypercholesterolemia (n%)||-||88 (28.7)||-||65 (27.3)||23 (33.3)||0.474|
|Current smoking (n%)||-||181 (58.9)||-||132 (55.5)||49 (71.0)||0.252|
|Atrial fibrillation (n%)||-||65 (21.2)||-||49 (20.6)||16 (23.2)||0.709|
|Hematoma Evacuation (n%)||-||236 (76.8)||-||187 (78.6)||49 (56.5)||0.631|
|Initial systolic blood pressure (mmHg)||-||163.58
|Total cholesterol (mmol/L)||4.26
|C-reactive protein (mg/L)||2.0 (0.11-12.1)||3.2 (0.43-21.2)||0.076||2.1 (0.43-6.85)||8.66 (2.09-21.2)|
|Pentraxin 3 (ng/mL)||3.19 (0.03-8.97)||8.99 (0.11-30.97)||5.29 (0.11-12.32)||19.34 (2.95-30.97)|
Data are presented as the mean (standard deviation), median, range or percentage.
SD: Standard Deviation; GCS: Glasgow coma scale; NIHSS: National Institute of Health Stroke Scale.
The serum PTX3 levels in patients with ICH [8.99 (0.11-30.97) ng/mL] were
significantly higher than those in control group [3.19 (0.03-8.97) ng/mL,
CRP and other biomarkers are commonly used markers of inflammation but suffer from its lack of specificity for infections. PTX3 tends to increase from the onset of the event. Compared with other inflammatory indexes, it has higher specificity . It is an independent predictor of severe sepsis and mortality after adjusting for potential confounders . Higher PTX3 levels were found in non-survivors than survivors and are associated with a two-fold increase in mortality.
Considering the above-observed result that the deceased patients had
significantly higher PTX3 levels than survivors, the ROC curves were
plotted to evaluate the performance of serum PTX3 in predicting alive and
deceased patients. The AUC value of PTX3 levels was 0.801 for survived versus
Survival curves of Pentraxin 3 tertiles. The percent survival was
different according to the PTX3 tertiles (P
The Cox proportional hazard regression test’s univariate analysis showed that PTX3 levels were significantly associated with higher mortality. The hazard ratio (HR) was 3.684 (95% confidence interval (CI): 1.276-5.966) (Table 2). The multivariable analysis also revealed a high association between PTX3 levels and mortality (Fig. 2).
Receiver operating characteristic curves of PTX3 and CRP. Receiver
operating characteristic curves for comparison alive and deceased. P for
|Predictors||Univariate analysis||Multivariable analysis|
|Crude HR||95% CI||P||Adjusted HR||95% CI||P|
|Age (per 1-year)||4.651||2.881-7.632||3.671||1.558-4.297||0.002|
|GCS (increase per unit)||3.116||1.007-4.358||1.524||1.006-2.334||0.003|
|NIHSS (increase per unit)||2.158||1.071-4.307||1.456||1.015-2.489||0.006|
|Glucose (per 1 mmol/L)||1.029||0.961-1.789||0.097||-||-||-|
|Total cholesterol (mmol/L)||0.563||0.325-1.074||0.051||-||-||-|
|WBC (per 1000/mm
|CRP (per 1 log unit)||1.346||1.009-3.214||1.091||1.004-1.978||0.029|
|PTX3 (increase per log unit)||3.684||1.276-5.966||2.776||1.198-3.651|
|GCS: Glasgow coma scale; NIHSS: National Institute of Health Stroke Scale; CRP: C-reactive protein; PTX: Pentraxin.|
Univariate and multivariate analysis showed that PTX3 level is a significant
independent factor associated with the overall survival of ICH deceased, besides
age, admission GCS and admission NIHSS [HR (95% CI) = 6.551 (1.782-8.965),
P = 0.001, Table 3]. The Kaplan-Meier curves showed that patients’ overall
survival with ICH decreased with PTX3 levels
|NO. of patients||Overall Survival (%)||Univariate analysis||Multivariate analysis|
|1 year||3 year||5 year||P||HR (95% CI)||P|
|Age (year)||0.032||2.557 (1.098-4.681)||0.019|
|Admission GCS||0.002||0.567 (0.013-0.953)||0.007|
|Admission NIHSS||0.006||1.965 (1.027-3.589)||0.010|
|Previous stroke||0.027||1.457 (0.473-2.226)||0.095|
|CRP (mg/L)||0.018||1.187 (0.971-2.457)||0.123|
|PTX3 (ng/mL)||0.003||6.551 (1.783-8.965)||0.001|
|GCS: Glasgow coma scale; NIHSS: National Institute of Health Stroke Scale; CRP: C-reactive protein; PTX: Pentraxin.|
We took a single venous blood sample for each patient at the arrival to detect the PTX3 levels and chose a straightforward prognosis data model consisting of survival and death to derive a clear conclusion. We found that plasma levels of PTX3 increased in patients with ICH, especially in the deceased patients. Usually, the basic levels of PTX3 in serum is low, but it may increase 3-5 times the baseline level within 6 or 8 hours under inflammatory conditions [6, 22]. The levels of PTX3 in the healthy control group were 3.19 (0.03-8.97) ng/mL, while in the ICH group was 8.99 (0.11-30.97) ng/mL in the brain-dead group was the highest at 19.34 (2.95-30.97). We also found leukocytosis in peripheral blood. The number of neutrophils in peripheral blood within 72 hours after ICH was associated with poor prognosis . However, it had no association with long-term prognosis.
In conclusion, inflammation played an important role in secondary brain injury after ICH. Inflammatory signals trigger the infiltration of peripheral inflammatory cells and release inflammatory mediators, leading to cell death and brain damage. We demonstrated the correlation between the expression levels of PTX3, CRP and prognosis after ICH. Compared with CRP, PTX3 is a robust and independent predictor of long-term mortality in ICH patients. Higher levels of PTX3 were independently associated with increased mortality after ICH.
All authors had full access to all the data and took responsibility for the data integrity and data analysis accuracy. All authors contributed to the conception and design during the acquisition, analysis and interpretation of the results, including drafting and critical review of the manuscript to improve the content and the final approval of the published version.
All subjects in this study signed informed consent after understanding the purpose and risk of this study. The ethics committee has approved this study of the First Affiliated Hospital of Xi’an Medical University.
We thank two anonymous reviewers for improving the quality of the paper.
None of the authors report any conflicts of interest.