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Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, National Research Center for Hematology (Ministry of Health and Social Development of Russian Federation, Moscow). Alexey Tokarev, PhD. Mechanisms of regulation of the hemostatic system. - PowerPoint PPT Presentation
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Mechanisms of regulation of the
hemostatic system
• Platelet functioning (adhesion, activation, aggregation) – cell hemostasis• Blood clotting – plasma hemostasis• Blood flow – carrier
Alexey Tokarev, PhD
Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, National Research Center for Hematology
(Ministry of Health and Social Development of Russian Federation, Moscow)
Hemostatic plug (health) and thrombus (disease) formation
1/3
Platelet cross-flow distribution
Tokarev et al., Biophys. J., 2011b
wal
l wall
• Eulerian (PDEs)Modeling approach:
Tokarev et al. 2012. Rus. J Num. Anal. Math. Model.
• Lagrangian (particles)
Tosenberger et al. 2012. Rus. J Num. Anal. Math. Model.
Platelet adhesion
Tokarev et al., Biophys. J., 2011a
Plasma clotting
Fibrin mesh. SEM made by Jean-Claude Bordet (France).
Blood flow
Plug/ thrombus growth
Falati et al (2002)
plateletsplatelets+fibrin
fibrin
• Platelet activation, secretion, aggregation
Ohlmann (2000)
Some general questions:1.Biological: how plug/thrombus growth stops? Can this stopping result from the interaction between platelet and plasma subsystems?2.Methodological: How to mathematically model this complex system in a biology-adequate way? How to deal with platelet activation/signalling? How to connect intra-platelet signalling (detailed model of platelet activation) and changes in platelet properties (simple model of platelet activation)? 2/3
Some general questions:1.What is the mechanism of clotting propagation and stopping?2.How can we properly reduce the dimension of the large system of coupled PDEs (~30 eqs. down to 2-3 eqs.)?
Plasma clotting in non-stirring and slow-flow conditions
Reaction-diffusion PDEs (no flow) Reaction-diffusion-convection PDEs
Slow flow Boundary of fibrin clot (flow-resistant)
Injury
Dashkevich et al. Thrombin propagates in space during blood coagulation as a traveling wave: a new biological excitable medium. Submitted to PNAS.
0,001 2 3 40
50
100 Experiment Theory
Thr
ombi
n ac
tivity
, nM
Distance from the activator, mm
Thrombin concentration wave
3/3
Additional slides
Strong non-uniform platelet distribution across blood flow generally arises due to the finiteness of platelet own size
Tokarev et al., Biophys. J., 2011, 101 (8): 1835-1843.
Platelet
Erythrocyte
Excluded volume
wal
l wall
0,0 0,2 0,4 0,6
01
5
10
15
20 A
<P
>w
all t
o <
P>
axis r
atio
Inflow hematocrit/100%, 0
0,0 0,2 0,4 0,6
01
5
10
15
20 B
Pw
all t
o P
axis r
atio
Inflow hematocrit/100%, 0
Platelet adhesion from blood flow is controlled by near-wall rebounding collisions with erythrocytes
Tokarev et al., Biophys. J., 2011, 100 (4): 799-808.
Convection +
shear-induced
diffusion
Translocation/activation Detachment
Firm adhesion
Pushing out by RBC
Capture
Platelet activation time = const
Platelet activation - pathways
CRPconvulxine
collagen
vW f
G PVI
G PIb
FcR- Syc PLC-2
DAGIP 3
PLC-
PKC
Integrins1st affinity state
(adhesion)
ADPP2Y 1 P2Y 12
G q
G i2
AC
cAM P
PKA
G P1b-vW fTP
PI3K-
Ca2+
âî ëí à
Ca2+
-âî ëí à
Integrins2nd affinity state
(aggregation)
PAR 1
PAR 4
G 12/13
TP
IIa
T xA2
Shape Change
PG H 2
AA
PLA 2
ERK2M APk
p38M APk
Src
Src
100nM
10nM
Rho
Ca2+
50pM / 2s
5nM / 50s
TxS
COX-1
m em brane
???
PLC-
0.3uM 2uM
IP3
DAG
dencetubular system
Ca2+
(áåç Rap1b?)
AA
Âòî ê Ca2+
MEK
CalDAG-GEF1Ca2+
RAP1-GTP
Gz
2A
epinephrine
130/pl
1500/pl
PK
C
RhoA
???Akt/PKB
Gs
PGI2
Src
???
Raf
PI(3,4)P2?
PLC
PI3
K(I
I)?
PI3K-a)PI(3,4,5)P3 ?
PKCCa2+ RIAM
Talin
?
5-HT5-HT2AR
a-granules
Rab4-GTP
vWf,P-selectin
dense granules
TG
| |
RhoA-GTP
SERT
GEF
???- òî ëüêî ÷åðåç ADP?
Platelet activation – phenomenological behaviour
P 0 P 1 P 2
P flow
G PIb/v W f
P2Y 1
PAR 1
stress
TP
PAR 1*P2Y 12
PAR 4*(1+P2Y 12)
ADP
IIa
T xA 2
15 m in
stress
0.3uM2uM
50pM / 2s 5nM / 50s
-gr
collagen
PAR 4
FVa
PAR 1
PLA 2
Ca2+ext
?
P2+P2S0
P 2S 0
P S
PAR1*PAR4**(1+P2Y12)
P2Y 12