physiologie de la coagulation - adrhec …€¦ · physiologie de la coagulation pr yesim dargaud...
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PHYSIOLOGIE DE LA COAGULATIONPHYSIOLOGIE DE LA COAGULATION
Pr Yesim DARGAUD
DIU d’Hémostase Biologique et Biochimie de l’Hémostase Lyon, 2015 01 26
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Timing of hemostasis
Blood Blood CoagulationCoagulation
• activation of clotting factors
Blood Blood CoagulationCoagulation
• activation of clotting factors
FibrinolysisFibrinolysis
• activation of fibrinolytic factors
FibrinolysisFibrinolysis
• activation of fibrinolytic factors
PrimaryPrimaryHemostasisHemostasis
• vasoconstriction(immediately)
PrimaryPrimaryHemostasisHemostasis
• vasoconstriction(immediately)
IIII
NNNN
JJJJ clotting factors(seconds)
• fibrin formation(minutes)
clotting factors(seconds)
• fibrin formation(minutes)
fibrinolytic factors(immediately)
• clot lysis(hours)
fibrinolytic factors(immediately)
• clot lysis(hours)
(immediately)
• platelet adhesion(seconds)
• platelet aggregation(minutes)
(immediately)
• platelet adhesion(seconds)
• platelet aggregation(minutes)
JJJJ
UUUU
RRRR
YYYY
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Voie IntrinsèqueTCA
FXI FXIa
FXII, KHPM, PK
FIX FIXaFVIIIa
FVIIa + FT
1. Modèle Plasmatique en « Cascade »
FVIIIa
FX FXaFVa
FII FIIa
Thrombine
Fibrinogène Fibrine
Voie extrinsèqueTP
FX
Ce modèle n’expliquepas pourquoi saignentles hémophiles
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Voie Intrinsèque
FX FXIa
FXII, KHPM, PK
FIX FIXaFVIIIa Voie extrinsèque
FVIIa + FT
TCA allongé mais pas de signe hémorragique
TCA allongé mais hémorragie d’intensité variable
TCA allongé et syndrome hémorragique sévère
FVIIIa
FX FXaFVa
FII FIIaThrombine
Fibrinogène Fibrine
Voie extrinsèque
FX
Pourquoi les hémophiles saignent ?
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Tissue FactorTissue Factor
ExtracellularExtracellularExtracellularExtracellular
TransTrans--membranemembrane
IntracellularIntracellular
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FVIIa
[FVII] = 10nM[FVIIa] = 1-2% [FVII] ~0.1nM FIX
FIXa
FX
Surfaces Cellulaires et Génération de Thrombine
FVIIa
FT
Site actif
Phase d’initiation
FVIIa FVIIaFIXa
FXa
Cellules exprimantle facteur tissulaire
Monroe DM et al. Blood Coag Fibrinolysis 1996 Allen GA et al. Blood Coag Fibrinolysis 2001 Monkovic et al. Biochemistry 1990
Thrombine
FT
Monocytes activ.C. endoth. activ.Fibroblastes FXa
FII
(IIa: 10-17 – 10-14 mol/L)
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A, Numeric simulations of the earliest events leadi ng to catalyst formation with a tissue factor insult.
Mann K G Circulation 2011;124:225-235
Copyright © American Heart Association
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150
250
300
thro
mbi
n (n
M)
The amount of thrombin formed is more important
than the moment of clotting
0
50
thro
mbi
n
time (min)time (min)00 1515 3030
Initiation phaseInitiation phase
First traces of IIa≤ 10nM
5% of prothrombin converted to IIa
Clot formationClot formationTF
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Mann KG et al Haemostaseology 2009
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Thrombine
Amplification
FVIIa
FT
FXa
CellulesExprimant le FT
FXaFII
FV *
FIXa
FXIa
VIIIa
FX
Fibrine
Oliver JA et al. Blood 2002 Hultin B. Blood 19 85 Hoffman et al. Thromb Haemost 2005
Activation plaquettaire (PAR 1)
collagène
VWF
Plaquette
collagène
VWF
Plaquette
FVa
collagène
VWF
Plaquette
T
V W FRoberts et al. 2006
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105 - 106 fois plus actif
Propagation
FIXaFXFVIIIa
FIXa
FX
Plaquetteactivée
PAR
GPIIb IIIa
Tenase
50 fois plus actif
>90% du FXa est produit par le complexe FVIIIa-FIXa sur les plaquettes activées
Mann KG et al. Thromb Haemost 2003 Hockin MF et al J Clin Biochem 2002
FXa
FVIIaFT
FX
GPIb IX V
PAR
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Amplification Cascade Model
• This preceding model can be interpreted as follows:
If each of 100 individual Factor VIIa enzymes
catalyzed the activation of 100 Factor Xa enzymes,
and each one of these 10,000 Factor Xa enzymes
catalyzed 100 thrombin activations, and so on -
there is a resulting million-fold activation from there is a resulting million-fold activation from
the start of the pathway to fibrinogen cleavage.
• It is this amplification process that allows a clot
to form rapidly and also illustrates the magnitude
that one defect in these steps could have on the
whole process
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AmplificationAmplificationThe ‘snowball’ effectThe ‘snowball’ effect
FVIIa+TFFVIIa+TF
STARTSTART
ThrombinThrombin
STARTSTART
FINISHFINISHDargaud, 2012 01 24
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Thrombine
Thrombine
Thrombine
Thrombine
Thrombine
PropagationProthrombinase 300 000 foisplus active que le FXa seul pour transformer le FII en Thrombine
FVa
FIIFXa
Plaquette activée
FXaThrombine
Thrombine
ThrombineThrombine
Thrombine
Thrombine>96% de la thrombine est synthétisée pendant la phasede PROPAGATION sur des PLAQUETTES activées
activée
Lyon, 2013 01 22
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Pathways of prothrombin activation.
Mann K G Circulation 2011;124:225-235
Copyright © American Heart Association
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Butenas S et al. Arterioscler Thromb Vasc Biol 2009;29:1989-1996
Copyright © American Heart Association
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A numeric simulation of consecutive resupply of ele ctronic plasma reactants to a quiescent thrombus at 790, 1200, and 1800 seconds, which resu lts in a more intense thrombin
generation and provides higher concentrations of pr othrombinase (Xa=Va).
Mann K G Circulation 2011;124:225-235
Copyright © American Heart Association
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Phenotypic Hetrogeneity in the Blood Coagulation System..
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FII: 50-75-100-125-150 IU/dL
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Thrombin Formation *
CHEST. 2003;124(3_suppl):4S-10S.
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• An example is antithrombin, which
tightly binds and inactivates
thrombin - this complex is later
cleared from circulation in the
Anti-protease system
cleared from circulation in the
liver. The clinical administration
of heparin promotes the association
between antithrombin and thrombin.
This is the basis for use of heparin
as an anti-coagulant.
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Mann KG, Chest 2003
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Auto-regulation of thrombin
• Besides cleaving fibrinogen, thrombin
has forms complexes with an endothelial
cell protein receptor termed
thrombomodulin. Thrombomodulin and
calcium act as co-factors of thrombin calcium act as co-factors of thrombin
activation of Protein C, a Gla
containing protease. When activated,
Protein C in conjunction with another
protein co-factor, Protein S, will
proteolyze and inactivate Factors Va and
VIIIa.
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Gα
Surfaces Cellulaires et Régulation de la Génération de Thrombine
FXa
FVIIaFT
CellulesExprimant le FT
FXa FX a
AT
FVIIIactivé
AT½ vie ≤ 1 min
en milieu plasmatique
Monroe DM et al. Blood Coag Fibrinolysis 1996 Briede JJ et al. Thromb Haemost 2001Hoffman M et al. Thromb Haemost 2001 Monroe D. ATVB 2005
Thrombine
PCa
FVactivé
TM
T
EPCR
collagène
TT
T
x1000
x20
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A, A hypothetical construct displaying the potentia l molar concentrations of thrombomodulin in various regions of the vasculature.
Mann K G Circulation 2011;124:225-235
Copyright © American Heart Association
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PS+TFPI dep et APC+
PS
TFPI
PS+TFPI
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DIAGNOSIS ofbleeding disorders
aPTT, PT and other routinecoagulation assays
Global HaemostasisAssays
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150
250
300
thro
mbi
n (n
M)
The amount of thrombin formed is more important
than the moment of clotting
0
50
thro
mbi
n
time (min)time (min)00 1515 3030
Initiation phaseInitiation phase
First traces of IIa≤ 10nM
5% of prothrombin converted to IIa
Clot formationClot formationTF
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Fibrinogen ActivationPeptides cleaved by thrombin contain many Asp, Glu and sulfated-Tyrresidues, thus very highly negatively charged
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Eb
A A
a a
D D
a
B B
b b
Fibrinogène
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Eb
A A
a a
Thrombine
Libération des sites de polymérisations A et B
D
E
D
a
B B
b b
Monomère de fibrine
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D
E
D D
E
D
D
E
D D
E
D D
E
D D D D
D
E
D D
E
D
Polymérisation des monomères de fibrines
Fibrine soluble
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Factor XIIIa
• The "soft clot" of fibrin monomers is stabilized and converted into the final clot by covalent cross-linkages between specific glutamine residues on one monomer and lysine residues on another monomer. This peptide (amide) bond is catalyzed by activated Factor XIIIa, a transglutaminase:
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D
E
D D
E
D
D
E
D D
E
D D
E
FXIII
D
E
D D
E
D
FXIIIaLiaisons covalentes
Fibrine stable insolubleFibrine stable insoluble
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Clot Dissolving Pathway
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Dissolving of Blood Clots:
Fibrinolysis
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