Acta Neurol Scand 2016: 133: 192–201 DOI: 10.1111/ane.12445
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Serum soluble CD40 ligand levels after acute intracerebral hemorrhage Lin X-F, Ten X-L, Tang X-B, Chen J. Serum soluble CD40 ligand levels after acute intracerebral hemorrhage. Acta Neurol Scand 2016: 133: 192–201. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Soluble CD40 ligand (sCD40L) is associated with inflammation. This study aimed to assess the prognostic value of sCD40L for clinical outcomes of acute intracerebral hemorrhage (ICH) patients. Materials and methods – The serum sCD40L levels of 110 patients and 110 age- and gender-matched healthy controls were measured using sandwich immunoassays. The relationships between serum sCD40L levels and 1-week mortality, 6-month mortality, 6month overall survival, 6-month unfavorable outcome (modified Rankin Scale score >2), and ICH severity including hematoma volume and National Institutes of Health Stroke Scale (NIHSS) score were assessed using multivariate analysis. Results – Compared with healthy controls, ICH patients had higher serum sCD40L levels. Serum sCD40L levels were correlated positively with hematoma volumes and NIHSS scores using a multivariate linear regression. Multivariate analysis results indicated that sCD40L was identified an independent predictor of 1-week mortality, 6-month mortality, 6-month unfavorable outcome and 6-month overall survival. sCD40L also showed high predictive performances for 1-week mortality, 6-month mortality and 6-month unfavorable outcome based on receiver operating characteristic curve. Conclusions – Elevated serum sCD40L levels are independently associated with ICH severity and clinical outcomes. And sCD40L has potential to be a good prognostic biomarker of ICH.
Introduction
Acute spontaneous intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular accident that is a major cause of human suffering, hospitalization, chronic disability, and death (1–3). National Institutes of Health Stroke Scale (NIHSS) on admission and ICH volume are known to be associated with clinical outcome after ICH (4). ICH occurs when a blood vessel in the brain parenchyma ruptures. The introduction of blood components, including thrombin, heme, leukocytes, and platelets, into the brain creates the basis for a secondary injury due to microglial activation and neuroinflammation, resulting in the recruitment of leukocytes into a normally immune privileged site and the production of proinflammatory cytokines including tumor necrosis factor-alpha, interleukin-1beta, and 192
X.-F. Lin1, X.-L. Ten2, X.-B. Tang3, J. Chen4 1 Department of Neurosurgery, The Central Hospital of Jinhua City, Jinhua, China; 2Department of clinical laboratory, Jinhua People’s Hospital, Jinhua, China; 3 Department of Emergency Medicine, Jinhua People’s Hospital, Jinhua, China; 4Department of Neurology, Jinhua People’s Hospital, Jinhua, China
Key words: intracerebral hemorrhage; prognosis; severity; soluble CD40 ligand Xiao-Feng Lin, Department of Neurosurgery, The Central Hospital of Jinhua City, 351 Mingyue Street, Jinhua 321000, China Tel.: +86 0579 82318024 Fax: +86 0579 82338512 e-mail: [email protected] Accepted for publication May 11, 2015
interleukin-6 (5). Brain contains large amounts of tissue factor, the major initiator of the coagulation cascade, and is rich in phospholipids. Brain injury after ICH leads to the shedding of procoagulant phospholipids and the activation of tissue factor. Tissue factor activates the blood coagulation system in which thrombin is generated from prothrombin. However, excessive activation of the blood coagulation process can induce a blood coagulation disorder due to excessive consumption of blood coagulation factor and, in severe cases, induces disseminated intravascular coagulation disorder. This activation of tissue factors affects the blood coagulation disorder by inducing changes in blood coagulation factors, therefore enhancing the risk of hematoma growth (6). Overall, inflammation and hypercoagulability play crucial roles in the pathophysiology of ICH (7, 8).
sCD40L and intracerebral hemorrhage CD40 ligand (CD40L) is a member of the tumor necrosis factor family. Multiple lines of recently collected evidences point to prothrombotic and proinflammatory properties of CD40L and its soluble counterpart (sCD40L) on binding to their cell surface receptor CD40 (9–15). In humans, elevated circulating sCD40L levels have been found in severe sepsis (16), acute coronary syndrome (17, 18), and ischemic stroke (19–21). sCD40L is attracting increasing attention as a potential prognostic predictor of patients with influenza virus-associated encephalopathy (22), ST-segment elevation myocardial infarction (23), severe sepsis (16), and traumatic brain injury (24). These data suggest that sCD40L may represent a potential biomarker of neurological outcome in ICH. Up to now, the role of sCD40L in ICH has hardly been studied. Thus, this study was designed to determine serum sCD40L levels of acute ICH patients and also evaluate relationship between serum sCD40L levels and clinical outcomes of ICH. Materials and methods Study population
In this prospective study, all patients with acute spontaneous basal ganglia hemorrhage admitted to the Jinhua People’s Hospital within the first 24 h from stroke from September 2010 to September 2013 were enrolled. Patients with the following criteria were excluded: previous ischemic or hemorrhagic stroke, severe head trauma, use of antiplatelet or anticoagulant medication, presence of other prior systemic diseases including autoimmune diseases, uremia, liver cirrhosis, malignancy, and chronic heart or lung disease, recent infection (within a month), a surgical procedure, and missing of follow-up. Control group included age- and gender-matched healthy individuals. This study was performed with the approval of the Human Investigations Committee at the Jinhua People’s Hospital, and written informed consent was obtained from study subject or the relative. Clinical and radiological evaluation
For each patient, the following baseline characteristics were collected: sex, age, hypertension, diabetes mellitus, initial systolic blood pressure and diastolic blood pressure, and NIHSS score (assessed immediately after admission). Early neurological deterioration (END) was defined as an increase of ≥4 points in the NIHSS score or
death at 24 h from symptoms onset (25). All patients underwent at least two cranial CT scans: an initial CT scan within 1 h of admission and follow-up CT scan at 24 h from symptoms onset. All CT scans were performed according to the neuroradiology department protocol and were reviewed by investigators blinded to the clinical information. Hematoma volumes were measured according to the ABC/2 method. For the bedside ABC/2 method, the CT slice with the largest area of hemorrhage was identified. The largest diameter (A) of the hemorrhage on this slice was measured. The largest diameter 90° to A on the same slice was measured next (B). Finally, the approximate number of 10-mm slices on which the ICH was seen was calculated (C). C was calculated by a comparison of each CT slice with hemorrhage to the CT slice with the largest hemorrhage on that scan. If the hemorrhage area for a particular slice was greater than 75% of the area seen on the slice where the hemorrhage was largest, the slice was considered one hemorrhage slice for determining C. If the area was approximately 25% to 75% of the area, the slice was considered half a hemorrhage slice; and if the area was less than 25% of the largest hemorrhage, the slice was not considered a hemorrhage slice. These CT hemorrhage slice values were then added to determine the value for C. All measurements for A and B were made with the use of the centimeter scale on the CT scan to the nearest 0.5 cm. A, B, and C were then multiplied and the product divided by 2, which yielded the volume of hemorrhage in cubic centimeters (26). Hematoma growth was defined as hematoma enlargement >33% at 24 h (27). Clinical endpoints
For follow-up, structure telephone interviews were performed by one doctor, blinded to clinical information and biomarker levels. Participants were followed up until death or completion of 6 months after stroke. An unfavorable outcome was defined as a modified Rankin Scale score >2 at 6 month. The endpoints were death within 1 week and 6 months and unfavorable outcome within 6 months after ICH. Determination of serum sCD40L concentrations
All blood samples from the patients at admission and from the healthy controls at study entry were collected in serum separator tubes (Vacuette, Greiner Bio-One, Kremsmu¨nster, Austria) and centrifuged within 30 min at 1000*g for 15 min. The 193
Lin et al. come, and 6-month overall survival of acute ICH patients. Therefore, it is hypothesized that sCD40L may be a useful prognostic biomarker of acute ICH.
13.
Acknowledgement
14.
The authors thank all staffs in Department of Neurosurgery, Department of clinical laboratory, Department of Emergency Medicine, and Department of Neurology, Jinhua People’s Hospital (Jinhua, China), for their technical support.
15.
Conflict of interest
16.
The authors have no conflict of interest. 17.
References 1. AGUILAR MI, FREEMAN WD. Spontaneous intracerebral hemorrhage. Semin Neurol 2010;30:555–64. 2. HOBOHM C, FRITZSCH D, BUDIG S, CLASSEN J, HOFFMANN KT, MICHALSKI D. Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis. Acta Neurol Scand 2014;130:338–45. NAESS H. Function3. TVEITEN A, LJØSTAD U, MYGLAND A, ing of long-term survivors of first-ever intracerebral hemorrhage. Acta Neurol Scand 2014;129:269–75. 4. CHEUNG CM, TSOI TH, HON SF et al. Using the National Institutes of Health Stroke Scale (NIHSS) to predict the mortality and outcome of patients with intracerebral haemorrhage. Hong Kong Med J 2008;14: 367–70. 5. TAYLOR RA, SANSING LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013;2013:746068. 6. VAN DREDEN P, HUE G, DREYFUS JF, WOODHAMS B, VASSE M. Procoagulant phospholipids and tissue factor activity in cerebrospinal fluid from patients with intracerebral haemorrhage. Adv Hematol 2014;2014:576750. 7. ZHOU Y, WANG Y, WANG J, ANNE STETLER R, YANG QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol 2014;115:25–44. 8. HU X, FANG Y, YE F et al. Effects of serum D-dimer levels on early mortality and long-term functional outcome after spontaneous intracerebral hemorrhage. J Clin Neurosci 2014;21:1364–7. 9. ZHOU L, STORDEUR P, DE LAVAREILLE A et al. CD40 engagement on endothelial cells promotes tissue factordependent procoagulant activity. Thromb Haemost 1998;79:1025–8. 10. HEZI-YAMIT A, WONG PW, BIEN-LY N et al. Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades. Proc Natl Acad Sci USA 2005;102: 12077–82. 11. MILLER DL, YARON R, YELLIN MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J Leukoc Biol 1998;63:373– 9. 12. SLUPSKY JR, KALBAS M, WILLUWEIT A, HENN V, KRO€ CZEK RA, MULLER -BERGHAUS G. Activated platelets induce tissue factor expression on human umbilical vein
200
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
endothelial cells by ligation of CD40. Thromb Haemost 1998;80:1008–14. PRASAD KS, ANDRE P, HE M, BAO M, MANGANELLO J, PHILLIPS DR. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 2003;100:12367–71. ANDRE P, PRASAD KS, DENIS CV et al. CD40L stabilizes arterial thrombi by a beta3 integrin–dependent mechanism. Nat Med 2002;8:247–52. ANTONIADES C, BAKOGIANNIS C, TOUSOULIS D, ANTONOPOULOS AS, STEFANADIS C. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009;54:669–77. LORENTE L, MARTIN MM, VARO N et al. Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis. Crit Care 2011;15:R97. AUKRUST P, MULLER F, UELAND T et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999;100:614–20. VARO N, DE LEMOS JA, LIBBY P et al. Soluble CD40L: risk prediction after acute coronary syndromes. Circulation 2003;108:1049–52. GARLICHS CD, KOZINA S, FATEH-MOGHADAM S et al. Upregulation of CD40-CD40 Ligand (CD154) in patients with acute cerebral ischemia. Stroke 2003;34:1412–8. FERRO D, LOFFREDO L, POLIMENI L et al. Soluble CD40 ligand predicts ischemic stroke and myocardial infarction in patients with nonvalvular atrial fibrillation. Arterioscler Thromb Vasc Biol 2007;27:2763–8. DAVI G, TUTTOLOMONDO A, SANTILLI F et al. CD40 ligand and MCP-1 as predictors of cardiovascular events in diabetic patients with stroke. J Atheroscler Thromb 2009;16:707–13. ICHIYAMA T, MORISHIMA T, SUENAGA N, KAJIMOTO M, MATSUBARA T, FURUKAWA S. Analysis of serum soluble CD40 ligand in patients with influenza virus-associated encephalopathy. J Neurol Sci 2005;239:53–7. PUSUROGLU H, AKGUL O, ERTURK M et al. Predictive value of elevated soluble CD40 ligand in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Coron Artery Dis 2014;25:558–64. -RIVERO AF et al. LORENTE L, MARTIN MM, GONZALEZ Serum soluble CD40 Ligand levels are associated with severity and mortality of brain trauma injury patients. Thromb Res 2014;134:832–6. DU Q, YANG DB, SHEN YF et al. Serum leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage. Peptides 2013;45:35–9. KOTHARI RU, BROTT T, BRODERICK JP et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304–5. BROTT T, BRODERICK J, KOTHARI R et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. BILGIR F, BILGIR O, KEBAPCILAR L et al. Soluble CD40 ligand, high sensitive C-reactive protein and fetuin-A levels in patients with essential thrombocythemia. Transfus Apher Sci 2012;46:67–71. FOY TM, ARUFFO A, BAJORATH J, BUHLMANN JE, NOELLE RJ. Immune regulation by CD40 and its ligand GP39. Annu Rev Immunol 1996;14:591–617. € U, SUKHOVA GK et al. Functional MACH F, SCHONBECK CD40 ligand is expressed on human vascular endothelial
sCD40L and intracerebral hemorrhage Table 1 The factors correlated with serum soluble CD40 ligand levels Characteristics
r value
P value
Gender (male/female) Age (years) Hypertension Diabetes mellitus NIHSS score Hematoma volume (ml) Presence of intraventricular hemorrhage Hemorrhage growth Early neurological deterioration Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Plasma D-dimer level (mg/l) Blood white blood cell count (9109/l) Blood hemoglobin level (g/l) Blood platelet count (9109/l) Prothrombin time (s) Thrombin time (s) Partial thromboplastin time (s) Plasma fibrinogen level (g/l)
0.061 0.117 0.094 0.276 0.601 0.521 0.324 0.202 0.200 0.022 0.074 0.018 0.078 0.260 0.261 0.227 0.170 0.173 0.101 0.068 0.125 0.025 0.010
0.525 0.223 0.326 0.003
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Serum soluble CD40 ligand levels after acute intracerebral hemorrhage Lin X-F, Ten X-L, Tang X-B, Chen J. Serum soluble CD40 ligand levels after acute intracerebral hemorrhage. Acta Neurol Scand 2016: 133: 192–201. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Soluble CD40 ligand (sCD40L) is associated with inflammation. This study aimed to assess the prognostic value of sCD40L for clinical outcomes of acute intracerebral hemorrhage (ICH) patients. Materials and methods – The serum sCD40L levels of 110 patients and 110 age- and gender-matched healthy controls were measured using sandwich immunoassays. The relationships between serum sCD40L levels and 1-week mortality, 6-month mortality, 6month overall survival, 6-month unfavorable outcome (modified Rankin Scale score >2), and ICH severity including hematoma volume and National Institutes of Health Stroke Scale (NIHSS) score were assessed using multivariate analysis. Results – Compared with healthy controls, ICH patients had higher serum sCD40L levels. Serum sCD40L levels were correlated positively with hematoma volumes and NIHSS scores using a multivariate linear regression. Multivariate analysis results indicated that sCD40L was identified an independent predictor of 1-week mortality, 6-month mortality, 6-month unfavorable outcome and 6-month overall survival. sCD40L also showed high predictive performances for 1-week mortality, 6-month mortality and 6-month unfavorable outcome based on receiver operating characteristic curve. Conclusions – Elevated serum sCD40L levels are independently associated with ICH severity and clinical outcomes. And sCD40L has potential to be a good prognostic biomarker of ICH.
Introduction
Acute spontaneous intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular accident that is a major cause of human suffering, hospitalization, chronic disability, and death (1–3). National Institutes of Health Stroke Scale (NIHSS) on admission and ICH volume are known to be associated with clinical outcome after ICH (4). ICH occurs when a blood vessel in the brain parenchyma ruptures. The introduction of blood components, including thrombin, heme, leukocytes, and platelets, into the brain creates the basis for a secondary injury due to microglial activation and neuroinflammation, resulting in the recruitment of leukocytes into a normally immune privileged site and the production of proinflammatory cytokines including tumor necrosis factor-alpha, interleukin-1beta, and 192
X.-F. Lin1, X.-L. Ten2, X.-B. Tang3, J. Chen4 1 Department of Neurosurgery, The Central Hospital of Jinhua City, Jinhua, China; 2Department of clinical laboratory, Jinhua People’s Hospital, Jinhua, China; 3 Department of Emergency Medicine, Jinhua People’s Hospital, Jinhua, China; 4Department of Neurology, Jinhua People’s Hospital, Jinhua, China
Key words: intracerebral hemorrhage; prognosis; severity; soluble CD40 ligand Xiao-Feng Lin, Department of Neurosurgery, The Central Hospital of Jinhua City, 351 Mingyue Street, Jinhua 321000, China Tel.: +86 0579 82318024 Fax: +86 0579 82338512 e-mail: [email protected] Accepted for publication May 11, 2015
interleukin-6 (5). Brain contains large amounts of tissue factor, the major initiator of the coagulation cascade, and is rich in phospholipids. Brain injury after ICH leads to the shedding of procoagulant phospholipids and the activation of tissue factor. Tissue factor activates the blood coagulation system in which thrombin is generated from prothrombin. However, excessive activation of the blood coagulation process can induce a blood coagulation disorder due to excessive consumption of blood coagulation factor and, in severe cases, induces disseminated intravascular coagulation disorder. This activation of tissue factors affects the blood coagulation disorder by inducing changes in blood coagulation factors, therefore enhancing the risk of hematoma growth (6). Overall, inflammation and hypercoagulability play crucial roles in the pathophysiology of ICH (7, 8).
sCD40L and intracerebral hemorrhage CD40 ligand (CD40L) is a member of the tumor necrosis factor family. Multiple lines of recently collected evidences point to prothrombotic and proinflammatory properties of CD40L and its soluble counterpart (sCD40L) on binding to their cell surface receptor CD40 (9–15). In humans, elevated circulating sCD40L levels have been found in severe sepsis (16), acute coronary syndrome (17, 18), and ischemic stroke (19–21). sCD40L is attracting increasing attention as a potential prognostic predictor of patients with influenza virus-associated encephalopathy (22), ST-segment elevation myocardial infarction (23), severe sepsis (16), and traumatic brain injury (24). These data suggest that sCD40L may represent a potential biomarker of neurological outcome in ICH. Up to now, the role of sCD40L in ICH has hardly been studied. Thus, this study was designed to determine serum sCD40L levels of acute ICH patients and also evaluate relationship between serum sCD40L levels and clinical outcomes of ICH. Materials and methods Study population
In this prospective study, all patients with acute spontaneous basal ganglia hemorrhage admitted to the Jinhua People’s Hospital within the first 24 h from stroke from September 2010 to September 2013 were enrolled. Patients with the following criteria were excluded: previous ischemic or hemorrhagic stroke, severe head trauma, use of antiplatelet or anticoagulant medication, presence of other prior systemic diseases including autoimmune diseases, uremia, liver cirrhosis, malignancy, and chronic heart or lung disease, recent infection (within a month), a surgical procedure, and missing of follow-up. Control group included age- and gender-matched healthy individuals. This study was performed with the approval of the Human Investigations Committee at the Jinhua People’s Hospital, and written informed consent was obtained from study subject or the relative. Clinical and radiological evaluation
For each patient, the following baseline characteristics were collected: sex, age, hypertension, diabetes mellitus, initial systolic blood pressure and diastolic blood pressure, and NIHSS score (assessed immediately after admission). Early neurological deterioration (END) was defined as an increase of ≥4 points in the NIHSS score or
death at 24 h from symptoms onset (25). All patients underwent at least two cranial CT scans: an initial CT scan within 1 h of admission and follow-up CT scan at 24 h from symptoms onset. All CT scans were performed according to the neuroradiology department protocol and were reviewed by investigators blinded to the clinical information. Hematoma volumes were measured according to the ABC/2 method. For the bedside ABC/2 method, the CT slice with the largest area of hemorrhage was identified. The largest diameter (A) of the hemorrhage on this slice was measured. The largest diameter 90° to A on the same slice was measured next (B). Finally, the approximate number of 10-mm slices on which the ICH was seen was calculated (C). C was calculated by a comparison of each CT slice with hemorrhage to the CT slice with the largest hemorrhage on that scan. If the hemorrhage area for a particular slice was greater than 75% of the area seen on the slice where the hemorrhage was largest, the slice was considered one hemorrhage slice for determining C. If the area was approximately 25% to 75% of the area, the slice was considered half a hemorrhage slice; and if the area was less than 25% of the largest hemorrhage, the slice was not considered a hemorrhage slice. These CT hemorrhage slice values were then added to determine the value for C. All measurements for A and B were made with the use of the centimeter scale on the CT scan to the nearest 0.5 cm. A, B, and C were then multiplied and the product divided by 2, which yielded the volume of hemorrhage in cubic centimeters (26). Hematoma growth was defined as hematoma enlargement >33% at 24 h (27). Clinical endpoints
For follow-up, structure telephone interviews were performed by one doctor, blinded to clinical information and biomarker levels. Participants were followed up until death or completion of 6 months after stroke. An unfavorable outcome was defined as a modified Rankin Scale score >2 at 6 month. The endpoints were death within 1 week and 6 months and unfavorable outcome within 6 months after ICH. Determination of serum sCD40L concentrations
All blood samples from the patients at admission and from the healthy controls at study entry were collected in serum separator tubes (Vacuette, Greiner Bio-One, Kremsmu¨nster, Austria) and centrifuged within 30 min at 1000*g for 15 min. The 193
Lin et al. come, and 6-month overall survival of acute ICH patients. Therefore, it is hypothesized that sCD40L may be a useful prognostic biomarker of acute ICH.
13.
Acknowledgement
14.
The authors thank all staffs in Department of Neurosurgery, Department of clinical laboratory, Department of Emergency Medicine, and Department of Neurology, Jinhua People’s Hospital (Jinhua, China), for their technical support.
15.
Conflict of interest
16.
The authors have no conflict of interest. 17.
References 1. AGUILAR MI, FREEMAN WD. Spontaneous intracerebral hemorrhage. Semin Neurol 2010;30:555–64. 2. HOBOHM C, FRITZSCH D, BUDIG S, CLASSEN J, HOFFMANN KT, MICHALSKI D. Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis. Acta Neurol Scand 2014;130:338–45. NAESS H. Function3. TVEITEN A, LJØSTAD U, MYGLAND A, ing of long-term survivors of first-ever intracerebral hemorrhage. Acta Neurol Scand 2014;129:269–75. 4. CHEUNG CM, TSOI TH, HON SF et al. Using the National Institutes of Health Stroke Scale (NIHSS) to predict the mortality and outcome of patients with intracerebral haemorrhage. Hong Kong Med J 2008;14: 367–70. 5. TAYLOR RA, SANSING LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013;2013:746068. 6. VAN DREDEN P, HUE G, DREYFUS JF, WOODHAMS B, VASSE M. Procoagulant phospholipids and tissue factor activity in cerebrospinal fluid from patients with intracerebral haemorrhage. Adv Hematol 2014;2014:576750. 7. ZHOU Y, WANG Y, WANG J, ANNE STETLER R, YANG QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol 2014;115:25–44. 8. HU X, FANG Y, YE F et al. Effects of serum D-dimer levels on early mortality and long-term functional outcome after spontaneous intracerebral hemorrhage. J Clin Neurosci 2014;21:1364–7. 9. ZHOU L, STORDEUR P, DE LAVAREILLE A et al. CD40 engagement on endothelial cells promotes tissue factordependent procoagulant activity. Thromb Haemost 1998;79:1025–8. 10. HEZI-YAMIT A, WONG PW, BIEN-LY N et al. Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades. Proc Natl Acad Sci USA 2005;102: 12077–82. 11. MILLER DL, YARON R, YELLIN MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J Leukoc Biol 1998;63:373– 9. 12. SLUPSKY JR, KALBAS M, WILLUWEIT A, HENN V, KRO€ CZEK RA, MULLER -BERGHAUS G. Activated platelets induce tissue factor expression on human umbilical vein
200
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
endothelial cells by ligation of CD40. Thromb Haemost 1998;80:1008–14. PRASAD KS, ANDRE P, HE M, BAO M, MANGANELLO J, PHILLIPS DR. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 2003;100:12367–71. ANDRE P, PRASAD KS, DENIS CV et al. CD40L stabilizes arterial thrombi by a beta3 integrin–dependent mechanism. Nat Med 2002;8:247–52. ANTONIADES C, BAKOGIANNIS C, TOUSOULIS D, ANTONOPOULOS AS, STEFANADIS C. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009;54:669–77. LORENTE L, MARTIN MM, VARO N et al. Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis. Crit Care 2011;15:R97. AUKRUST P, MULLER F, UELAND T et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999;100:614–20. VARO N, DE LEMOS JA, LIBBY P et al. Soluble CD40L: risk prediction after acute coronary syndromes. Circulation 2003;108:1049–52. GARLICHS CD, KOZINA S, FATEH-MOGHADAM S et al. Upregulation of CD40-CD40 Ligand (CD154) in patients with acute cerebral ischemia. Stroke 2003;34:1412–8. FERRO D, LOFFREDO L, POLIMENI L et al. Soluble CD40 ligand predicts ischemic stroke and myocardial infarction in patients with nonvalvular atrial fibrillation. Arterioscler Thromb Vasc Biol 2007;27:2763–8. DAVI G, TUTTOLOMONDO A, SANTILLI F et al. CD40 ligand and MCP-1 as predictors of cardiovascular events in diabetic patients with stroke. J Atheroscler Thromb 2009;16:707–13. ICHIYAMA T, MORISHIMA T, SUENAGA N, KAJIMOTO M, MATSUBARA T, FURUKAWA S. Analysis of serum soluble CD40 ligand in patients with influenza virus-associated encephalopathy. J Neurol Sci 2005;239:53–7. PUSUROGLU H, AKGUL O, ERTURK M et al. Predictive value of elevated soluble CD40 ligand in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Coron Artery Dis 2014;25:558–64. -RIVERO AF et al. LORENTE L, MARTIN MM, GONZALEZ Serum soluble CD40 Ligand levels are associated with severity and mortality of brain trauma injury patients. Thromb Res 2014;134:832–6. DU Q, YANG DB, SHEN YF et al. Serum leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage. Peptides 2013;45:35–9. KOTHARI RU, BROTT T, BRODERICK JP et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304–5. BROTT T, BRODERICK J, KOTHARI R et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. BILGIR F, BILGIR O, KEBAPCILAR L et al. Soluble CD40 ligand, high sensitive C-reactive protein and fetuin-A levels in patients with essential thrombocythemia. Transfus Apher Sci 2012;46:67–71. FOY TM, ARUFFO A, BAJORATH J, BUHLMANN JE, NOELLE RJ. Immune regulation by CD40 and its ligand GP39. Annu Rev Immunol 1996;14:591–617. € U, SUKHOVA GK et al. Functional MACH F, SCHONBECK CD40 ligand is expressed on human vascular endothelial
sCD40L and intracerebral hemorrhage Table 1 The factors correlated with serum soluble CD40 ligand levels Characteristics
r value
P value
Gender (male/female) Age (years) Hypertension Diabetes mellitus NIHSS score Hematoma volume (ml) Presence of intraventricular hemorrhage Hemorrhage growth Early neurological deterioration Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mmHg) Diastolic arterial pressure (mmHg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Plasma D-dimer level (mg/l) Blood white blood cell count (9109/l) Blood hemoglobin level (g/l) Blood platelet count (9109/l) Prothrombin time (s) Thrombin time (s) Partial thromboplastin time (s) Plasma fibrinogen level (g/l)
0.061 0.117 0.094 0.276 0.601 0.521 0.324 0.202 0.200 0.022 0.074 0.018 0.078 0.260 0.261 0.227 0.170 0.173 0.101 0.068 0.125 0.025 0.010
0.525 0.223 0.326 0.003
