Download - Normal Hemostasis
Normal Hemostasis Normal Hemostasis
Galila Zaher Galila Zaher
Consultant HematologistConsultant Hematologist
KAUHKAUH
Function of HaemostasisFunction of Haemostasis
Prevention of blood loss from intact Prevention of blood loss from intact vessels vessels
Arrest of bleeding from damaged vesselsArrest of bleeding from damaged vessels
Blood vessel reaction to injuryBlood vessel reaction to injury
Platelet plug formation at site of Platelet plug formation at site of damage damage
BLOOD CLOTTINGBLOOD CLOTTING
Plasma protein clotting factorsPlasma protein clotting factors
Vascular endotheliumVascular endothelium Platelets
COAGULOPATHIESCOAGULOPATHIES
Bleeding Bleeding Thrombosis Thrombosis
Clotting factors Natural Clotting factors Natural anticoagulantanticoagulant
plateletsplatelets
Normal HemostasisNormal Hemostasis
1.1. Vessel wallVessel wall2.2. PlateletPlatelet3.3. Blood Blood
coagulationcoagulation4.4. Fibrinolytic Fibrinolytic
systemsystem5.5. InhibitorsInhibitors
1.1. Local Local vasoconstriction vasoconstriction (noradrenaline & (noradrenaline & serotonin)serotonin)
2.2. Platelet release Platelet release thromboxane Athromboxane A22 (a (a vasoconstrictor) vasoconstrictor)
3.3. Prostacyclin is Prostacyclin is released counters released counters effects of effects of thromboxane Athromboxane A22
Hemostasis
Normal HemostasisNormal Hemostasis
1.1. Vessel wallVessel wall2.2. PlateletPlatelet3.3. Blood coagulationBlood coagulation4.4. Fibrinolytic systemFibrinolytic system5.5. InhibitorsInhibitors
AdhesionAdhesion
Shape changeShape change
AggregationAggregation
Release ReactionRelease Reaction
Adhesion
GpIIb/IIIa
Platelet Activation
GpIIb/IIIaGpIIb/IIIa Aggregation
ADP
Adrenaline Platelet GpIb
Exposed Collagen
Endothelium
vWF
COLLAGEN
GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation
AdhesionAdhesion
ADP
Adrenaline
THROMBINTHROMBIN
Clot formationClot formation
Platelet Platelet activation activation
Primary Primary hemostasishemostasis
CountCount&function&function
IImmediatemmediate
Fibrin Fibrin generationgeneration
Secondary Secondary hemostasishemostasis
Plasma clotting Plasma clotting factors factors
DelayedDelayed
VWFVWF
The largest multimers of vWF greater The largest multimers of vWF greater adhesive & prothrombotic potential adhesive & prothrombotic potential more sites to interact with:more sites to interact with:
Substrates in extra-cellular matrices and Substrates in extra-cellular matrices and
Platelet receptors.Platelet receptors.
F.VIII:C
F. VIIIC:Ag
vWF:Ag
vWF B:Co
vWF R:Co
Functions of vWFFunctions of vWF
Platelet Adhesion (to extracellular Platelet Adhesion (to extracellular matrices):GP Ib-IX-V complexmatrices):GP Ib-IX-V complex
Platelet Adhesion to each Platelet Adhesion to each other other (Aggregation):Mediated (Aggregation):Mediated by vWF & fibrinogen binding by vWF & fibrinogen binding to:to:GPIb-IX-V & GP IIb-IIIaGPIb-IX-V & GP IIb-IIIa
Clotting factor productionClotting factor production
Liver: source of plasma clotting factors Liver: source of plasma clotting factors except VWF except VWF Factor VIII: produced by liver & Factor VIII: produced by liver & endotheliumendotheliumVWF: endothelial cells & megakaryocytesVWF: endothelial cells & megakaryocytesVitamin K dependent clotting factors are: Vitamin K dependent clotting factors are:
II, VII, IX, XII, VII, IX, X
FactorsFactors NamesNames
IIIIIIIIIIIIIVIVVVVIIVIIVIIIVIIIIXIXXXXIXIXIIXIIXIIIXIII
FibrinogenFibrinogenProthrombinProthrombinThromboplastinThromboplastinCalciumCalciumLabile factorLabile factorStable factorStable factorAntihemophilic factorAntihemophilic factorAntihemophilic factor BAntihemophilic factor BStuart-Power factorStuart-Power factorPlasma thromboplastin antecedent (PTA)Plasma thromboplastin antecedent (PTA)Hagman factorHagman factorFibrin stablizing factorsFibrin stablizing factors
COAGULATION PATHWAYSCOAGULATION PATHWAYS
Intrinsic & extrinsic pathways Intrinsic & extrinsic pathways ““conclude” in the common pathwayconclude” in the common pathway
Intrinsic pathway clotting factorsIntrinsic pathway clotting factorsExtrinsic pathway clotting factorsExtrinsic pathway clotting factorsCommon pathway clotting factorsCommon pathway clotting factors
Intrinsic PathwayIntrinsic Pathway All clotting All clotting
factors are factors are within the within the blood vesselsblood vessels
Clotting slowerClotting slower Activated Activated
partial partial thromboplastin thromboplastin test (aPTT)test (aPTT)
Extrinsic PathwayExtrinsic Pathway Initiating factor is Initiating factor is
outside blood outside blood vessels - tissue vessels - tissue factorfactor
Clotting faster Clotting faster Prothrombin test Prothrombin test
(PT)(PT)
Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin Thrombin
Fibrinogen Fribrin monomer
Fibrin polymerXIII
Intrinsic Pathway Extrinsic Pathway
Factors affectedBy Heparin
Vit. K dependent FactorsAffected by Oral Anticoagulants
The “Cascade”, “Waterfall” The “Cascade”, “Waterfall” model:model:
The “Cascade”, “Waterfall” The “Cascade”, “Waterfall” model:model:
Macfarlane (1964), Davie & Macfarlane (1964), Davie & Ratnoff (1964)}Ratnoff (1964)}Drawbacks of the ‘cascade model’:Drawbacks of the ‘cascade model’:
i.i. Model inadequate to explain Model inadequate to explain pathways leading to hemostasis pathways leading to hemostasis in in vivo vivo
ii.ii. Deficiency of FXII, HMK,PK does not Deficiency of FXII, HMK,PK does not cause bleedingcause bleeding
iii.iii. Activation of FX by the extrinsic Activation of FX by the extrinsic pathway does not compensate for the pathway does not compensate for the lack of FVIII or FIX in hemophiliacslack of FVIII or FIX in hemophiliacs
Platelet
Thrombin
VIIIa XIa
IXa TFVIIa
XaProthrombin
Fibroblast
Initiation
Amplification
Activated platelets
XIaIXaXaProthrombin
Thrombin
Propagation
• TF–independent mechanism of rFVIIa TF–independent mechanism of rFVIIa enhanced hemostasisenhanced hemostasis
Alternative (Cell-based) ModelAlternative (Cell-based) Model
The initiation phase:The initiation phase:
Commences on TF-bearing cells (fibroblasts)Commences on TF-bearing cells (fibroblasts) FXa, IXa & thrombinFXa, IXa & thrombin
Initiation of the coagulation process Initiation of the coagulation process
The amplification phase: The amplification phase:
Coagulation moves from TF-bearing cells to Coagulation moves from TF-bearing cells to
activated platelets, activated platelets,
The propagation phase:The propagation phase:
The active proteases combine with cofactors The active proteases combine with cofactors on on
platelet surface to generate thrombin; platelet surface to generate thrombin; End-result is fibrin polymerizationEnd-result is fibrin polymerization
1.1. Vessel wallVessel wall2.2. PlateletPlatelet3.3. Blood coagulationBlood coagulation4.4. Fibrinolytic systemFibrinolytic system5.5. InhibitorsInhibitors
1.1. Fibrin is Fibrin is digested by digested by enzymes from enzymes from plasma and plasma and from cells. from cells.
2.2. Endothelium Endothelium replaces the replaces the fibrinfibrin
FibrinolysisFibrinolysis
• PlasminogenPlasminogen
TPATPA
ThrombinThrombin
XIIaXIIa• PlasminPlasmin
Activation of fibrinolysis
plasminogenplasminogen
thrombin
plasmin
damaged cellsdamaged cells
t-PAPAI
cross-linked fibrinfibrinogen
FDP(X,Y,D,E)
X-FDP(D-Dimer, cross-linked oligomers, DD/E ...)
antiplasmin
extrinsic pathway extrinsic pathway
inflammation
traumamental/physical stress
Generation Of Fibrin and D-DimerGeneration Of Fibrin and D-Dimer
DE
D
E
DDEE
F XIIIa
fibrin
fibrin polymer DDE
DE
D
E
DDE
cross-linkedfibrin (clot)
fibrinogenE
DDE
thrombinFpA, FpB
D-dimer cross-linkage
ED
ED
ED
ED
E
DE
DE
E
DDE
E
D
E
D
E
EDD
E
COAGLATION INHIBITORSCOAGLATION INHIBITORS
Antithrombin (FXIa, IXa, Xa & IIa)Antithrombin (FXIa, IXa, Xa & IIa)
Protein C/S complex (F Va & F Protein C/S complex (F Va & F VIIIa)VIIIa)
Tissue factor pathway inhibitor -Tissue factor pathway inhibitor -(TFPI)(TFPI)
VIIIaVIIIa
PcPc
PsPs
PAI-1PAI-1
Lysis of fibrinLysis of fibrin
ATIIIATIII
XaXa
VaVa
XIIaXIIaXIIXII
VIIaVIIa VIIVII
XIaXIa
IXIX IXaIXa
XIXI
X XX X
IIaIIaIIII
FibrinFibrinFibrinogenFibrinogen
Factor IXa -FVIIIa
Factor Xa+FVa
Factor XIa Factor IIa(thrombin)
Fibrinogen Fibrin
TFPI
AntiThrombin IIIProtein C
Tissue factor + Factor VIIa
The “Cascade”, “Waterfall” The “Cascade”, “Waterfall” model:model:
Intrinsic pathway XII ---> XIIa
XI---------XIa
IX --------> IXa + VIII APC PC +PSCa +PL
X----------------------> Xa [Common pathway]
V+Ca+PL
Prothrombin -------------> thrombin AT
vfibrinogen--------------> fibrin
Extrinsic pathwayVII + TF ----->VIIa/TF