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