impact of the neutrophil response to granulocyte colony-stimulating factor on the risk of hemorrhage...

Impact of the Neutrophil Response

to Granulocyte Colony-Stimulating

Factor on the Risk of Hemorrhage when

Used in Combination with Tissue

Plasminogen Activator during the Acute

Phase of Experimental Stroke

Vita Kusuma Rahmawati

Gautier et al, Journal of Neuroinflammation 2014, 11: 96

Journal Reading

1VIT

Introduction

• Granulocyte colony stimulating factor (G-

CSF) is a hematopoietic cytokine initially

used in the treatment of neutropenia for its

effects on proliferation and maturation of

the granulocyte cell line.

• G-CSF displayed a neuroprotective effect

when used during experimental stroke by

both decreasing the infarct size and

improving motor function recovery.3VIT

Introduction

• However, the tPA-therapeutic window is

limited due to induced-hemorrhages.

• The objective of this work was to analyze

the impact of G-CSF on the risk of

hemorrhage when used in combination

with tPA during the acute phase of an

experimental ischemic stroke.

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Method

• Blood samples were collected before

surgery (MCA occlusion).

• Samples received G-CSF or 0.9% saline

subcutaneously just before tPA.

tPA (+)

20

tPA (-)

2013 evaluation of infarct,

hemorrhage, and neutrophil infiltration

7 vasoreactivity analysis

Non MCA-occlusion:

4 receiving G-CSF treatment

4 receiving 0.9% saline treatment

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Method

Neutrophil count on peripheral blood before surgery, 24 h, and 72 h of reperfusion

Evaluation of infarct and hemorrhage (quantifying infarct volume)

Myeloperoxidase immunohistochemistry analysis (assaying MPO which expressed by neutrophil cells)

Vasoreactivity analysis (measuring lumen diameter)

MMP-9 analyzed on gelatin zymography

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Statistycal Analysis

SAS software

version 9.3

P<0.05

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Results

• Physiological Parameters

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Results

• Neutrophil response to G-CSF treatment

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Results

• Effect of G-CSF treatment on the risk of hemorrhage

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Results • Effect of G-CSF treatment on the risk of hemorrhage

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Results

• Effect of G-CSF treatment on the risk of hemorrhage

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Results

• Effect of G-CSF treatment on endothelial

function of cerebral vessel

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Results

• Effect of G-CSF treatment on endothelial

function of cerebral vessel

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Results • Effect of G-CSF treatment on neutrophil infiltration and

cerebral infarction size

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Results • Effect of G-CSF treatment on neutrophil infiltration and

cerebral infarction size

16VIT

Results

• Effect of G-CSF treatment on MMP-9

release from neutrophil degranulation

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Discussion

• G-CSF administered in combination with

tPA during the acute phase of cerebral

ischemia worsened the risk of

hemorrhage.

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Discussion

In Infarct Region

• The neuroprotective effect is probably

independent from G-CSF’s action on

neutrophils; directly related to G-CSF’s

effect on neurons: inducing neurogenesis,

anti-inflammatory, and anti-apoptotic

mechanisms.

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Discussion • In the Circulation

ischemia tPA treatment + G-CSF

Increase of peripheral neutrophilLeucocytosisMMP-9

Changes in arterial endothelial cells

Extravasation of RBC

Hemorrhage

BBB damage

Tissue injury

Edema formation

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Conclusion

The potential hemorrhagic risk in

administering G-CSF in combination with

tPA during the acute phase of cerebral

ischemia, probably though vascular

alterations mediated by the MMP-9 release

from peripheral neutrophils.

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Journal Search

Problem Intervention Comparison Outcome

Male

spontaneously

hypertensive rats

with middle

cerebral artery

occlusion

(MCAO) of

cerebral

ischemia

Tissue

Plasminogen

Activator (tPA) in

combination with

Granulocyte

Colony-

Stimulating

Factor (G-CSF)

Tissue

Plasminogen

Activator

Risk of

hemorrhage

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Design, Focus, and Worksheet

Design True experimental

Journal focus Prognosis

Worksheet Prognosis

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Journal Critical AppraisalRAMMBO Validity

Worksheet

Prognosis

Answer

Recruitment Was a defined

representative sample

of patients assembled

at a common (usually

early) point in the

course of their

disease?

Yes

Allocation How were patients

treated?

Yes

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Worksheet

Prognosis

Answer

Maintenance Was the comparable

status of the study

groups maintained

through equal

management?

Yes

28

p.3

VIT


Worksheet

Prognosis

Answer

Maintenance Was the follow up has

been done in enough and adequate time?

Yes

29

p.2

VIT


Worksheet

Prognosis

Answer

Maintenance Was 80% minimally of

the subject could

follow the follow up

until the end of the

research?

Yes

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Worksheet

Prognosis

Answer

Measurement

BlindingOutcome

Were the subjects and

assessors kept ‘blind’

to which treatment was

being received

and/or were the

measures objective?

Yes

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Journal Critical Appraisal

Importancy

Worksheet

Prognosis

Answer

Were the statistical and

clinical meaning from this

research can be known

well?

Yes

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Journal Critical AppraisalImportancy

Worksheet

Prognosis

Answer

What kind of measurement that

was used and how much the effect

of the intervention can related to

the outcome of the subject?

OR measurement, but not

described well in statistical

analysis.

35VIT


Importancy

Worksheet

Prognosis

Answer

Could the outcome of this

research were merely

accident?

p-value?

Confidence interval (CI)?

p-value: <0.05 and OR 1.4

with 95% CI, so the

outcome were not happen

accidentally.

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No Applicability Answer

1 Were the patient quite similar to the patients in the

study?

YES

2 Were the indicator in this study can be applied to the

management of patients in your neighborhood?

YES

3 Were the outcomes of this research important for your

patient?

YES

4 Will the potential benefit is greater than the potential

harm when this indicator is applied to your patients ?

YES

5 Will the results of this research can be integrated with

the values and expectations of your patients ?

YES

37VIT


CONCLUSION

• This journal can be classifed as a VALID

journal

• IMPORTANCY in this journal were not

described well

• Result from the research in this journal is

APPLICABLE in Indonesia

38VIT

impact of the neutrophil response to granulocyte colony-stimulating factor on the risk of hemorrhage...

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