thrombin activity in ischemic stroke · 2019. 5. 30. · thrombin concentration dependent dual...
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Thrombin Activity in Ischemic Stroke
Director, Stroke and Cognition Institute Rambam Health Care Campus
President, Israeli Neurological Association
Prof. David Tanne
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Coagulation pathway
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Intravenous rt-PA
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Activation and Expression of PARs in the CNS
Noorbakhsh et al. Nature Reviews. 2003; 981-90
PAR: Protease-Activated Receptor
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PAR-1 at Node of Ranvier Shavit et al., Brain 2008
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Thrombin
Concentration dependent dual effect of thrombin in
the brain
Low concentrations (~ pM) -neuroprotective effects
High concentrations (~nM) -deleterious effects
Thrombin regulates cellular activity through PAR1 &
PAR4 activation
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Intraluminal MCA occlusion by
Monofilament Suture
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Thrombin Activity in Ischemic vs. Healthy Brains
Slice #
Slice #3
Slice #11
24h following MCAo
Each group n=6
0
5
10
15
20
25
30
35
40
3 4 5 6 7 8 9 10 11
Control RControl LStroke RStroke L
Thrombin activity
(mU/ml)
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Thrombin Activity vs. Infarct Volume
R² = 0.66
0
1
2
3
4
5
6
7
-50 0 50 100 150 200
Thro
mb
in A
ctiv
ity
Isch
emic
H
em
isp
he
re [
mU
]
Infarct Volume[mm^3]
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Histochemical visualization of
Thrombin Activity
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Spatial Profile of Thrombin Activity-PMCAo
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Spatial Profile of Thrombin Activity-tMCAo
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PAR1 Levels in the Ischemic Core
Decrease Upon MCAo
*p=0.055, **p=0.004
Is=Ischemic; Co= contralateral.
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Inverse Correlation Between
Thrombin Activity and PAR1 levels
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PAR1
antagonist
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Stroke
Ischemia
Impairment of astrocyticglutamate transporters
Increase in [Glu]e
Cell Death
Ischemic LTP a form of synaptic scaling that protects the penumbra zone from excitotoxicity.
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Thrombin inhibitor PAR1 antagonistPAR1 antagonist
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Thrombin activity in hippocampal
slices undergoing OGD
Thrombin concentration in
hippocampal slices undergoing OGDProthrombin mRNA in hippocampal
slices undergoing OGD
Conditions were no blood is present
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• In the early phases of ischemic stroke a rise in [Thrombin]induces iLTP which protects the tissue from excitotoxicitywhile saturating the physiological mechanisms of synapticplasticity.
• As time goes on, the rise in [Thrombin] causes synapticdysfunction and impairment in inhibition.
• In the late phases of ischemic stroke, [Thrombin]high altersinhibition, promotes excitability and induces seizures.
• Persistent [Thrombin]high induces apoptosis and cell deathwhich consequently promotes circuit reorganization andpredisposes to post-stroke epilepsy.
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Factor X Prothrombin
Upregulation of Coagulation Factors Gene Expression in the Ischemic Hemisphere
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IP
administration
immediately
after pMCAo
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Apixaban Decreases infarct volumes Following MCAo
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Coagulation factors are synthetized in the brainand they play a major role in the
pathophysiology of ischemic stroke from the early phases to the late consequences.
Thank you
Take Home Message