Thrombin Activity in Ischemic Stroke

Director, Stroke and Cognition Institute Rambam Health Care Campus

President, Israeli Neurological Association

Prof. David Tanne

Coagulation pathway

Intravenous rt-PA

Activation and Expression of PARs in the CNS

Noorbakhsh et al. Nature Reviews. 2003; 981-90

PAR: Protease-Activated Receptor

PAR-1 at Node of Ranvier Shavit et al., Brain 2008

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

Intraluminal MCA occlusion by

Monofilament Suture

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)

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]

Histochemical visualization of

Thrombin Activity

Spatial Profile of Thrombin Activity-PMCAo

Spatial Profile of Thrombin Activity-tMCAo

PAR1 Levels in the Ischemic Core

Decrease Upon MCAo

*p=0.055, **p=0.004

Is=Ischemic; Co= contralateral.

Inverse Correlation Between

Thrombin Activity and PAR1 levels

PAR1

antagonist

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.

Thrombin inhibitor PAR1 antagonistPAR1 antagonist

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

• 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.

Factor X Prothrombin

Upregulation of Coagulation Factors Gene Expression in the Ischemic Hemisphere

IP

administration

immediately

after pMCAo

Apixaban Decreases infarct volumes Following MCAo

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

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