Haemostasis

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Haemostasis, coagulation system, fibrinolysis and
laboratory assessments These slides were
kindly provided by AstraZeneca
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What is haemostasis?
Platelet
Normal blood flow
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What is haemostasis?
Vessel injury and exposure of subendothelium
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Vasoconstriction
1. Vasoconstriction
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Primary haemostasis
Loose platelet plug
Collagen
1. Vasoconstriction
2. Primary haemostasis
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Primary haemostasis adhesion of platelets
1. Adhesion
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The role of platelets
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The role of platelets
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Primary haemostasis activation of platelets
Activated Platelet
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Primary haemostasis platelet aggregation
Activated Platelet
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Secondary haemostasis coagulation and formation
of fibrin
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Coagulation system
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Coagulation factors

• Factor I (Fibrinogen)
• Factor II (Prothrombin)
• Factor III (Tissue Factor)
• Factor IV (Ca)
• Factor V
• Factor VII
• Factor VIII
• Factor IX
• Factor X
• Factor XI
• Factor XII
• Factor XIII

Some new factors involved in coagulation
Protein C
Protein S
Thrombomodulin
Antithrombin
Tissue Factor Pathway Inhibitor
Carboxypeptidase U
Thrombin Activatable Fibrinolysis Inhibitor
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The coagulation theory 1905
Thromboplastin Ca
Prothrombin
Thrombin
Fibrinogen
Fibrin
Morawitz, Fuld and Spiro 1905
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The coagulation cascade today
TFPI / FXa / TF / FVIIa
TFPI / FXa
FXIIa
FX
Tissue factor
FXI
FXIa
FIXa / FVIIIa
FVIIa

FXa
FIXa
FIX

Protein S
FVIIIa
FVIII

APC
FV
FVa
FVa / FXa




Thrombomodulin


Heparin cofactor II
Tissue factor
Prothrombin
Thrombin
Protein C
FVIIa








Antithrombin
FXIII
FVII
FVIIa
Fibrin
Fibrinogen
Thrombin/AT
CPU
pro-CPU
FXIIIa
t-PA/PAI
PAI
Liver
Cross-linked fibrin
t-PA
Plasminogen
Plasmin
FDP
Antiplasmin
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Initiation phase of coagulation
Tissue factorFVIIa
Tissue factor pathway inhibitor (TFPI)
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Amplification phase of coagulation
Clot stabilisation
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Amplification and initiation phase of coagulation
- summary
Amplification
Initiation
Factor XIa
Tissue factor

Factor VIIa / Tissue factor
Factor IXa/VIIIa
Factor VIII
Factor Xa/Va
Factor V
Factor X
Factor Xa
Prothrombin
Thrombin
Feedback activation
Fibrinogen
Fibrin
Thrombus formation
Platelet aggregation
Platelets
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The protein C system and termination of
coagulation
Tenase complex
FIXa FVIIIa
FX
FXa
Prothrombinase complex
FXaFVa
Prothrombin
Thrombin
Fibrin
Fibrinogen
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Fibrinolysis
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Thrombin has a central role in blood coagulation

• Thrombin
• Cleaves fibrinogen to fibrin
• Induces platelet aggregation
• Stimulates its own generation
• Downregulates its own formation

• The coagulation system is a complex interaction
  of several enzymes, cofactors and inhibitors in
  which thrombin is the conductor of the
  orchestra as it is involved in coagulation,
  anticoagulation and fibrinolysis

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Model of the thrombin molecule
Fibrinogen binding site
Active site
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Fibrinogen binding to thrombin
Fibrinogen binding site
Active site
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Fibrinogen binding to thrombin
Fibrinogen binding site
Fibrinopeptides
D

Active site
Fibrin
D
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Fibrin polymerisation
Thrombin
D
D
E
D
D
D
D
E
E
D
D
E
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Laboratory tests of haemostasis
Test Purpose Normal range
Platelet count No of platelets in the
blood 150-300 x 109/l blood Bleeding
time Functional platelet aggregation lt12
min Activated partial Activity of all coagulation
factors 35-45 sthromboplastin time in the
amplification loop (aPTT) Prothrombin time
(PT) Activity of vitamin K-dependent 10-20
s coagulation factors International
normalised Calculated from PT as the ratio
1.0ratio (INR) between PT in patient plasma and
reference sample Thrombin time (TT) Activity of
thrombin 10-30 s Ecarin clotting time Effect of
direct 20-40 s(ECT) thrombin
inhibitors Fibrin degradation Fibrinolytic
system lt10 mg/l plasmaproducts
(FDPs) D-dimers Fibrinolytic system lt0.5 mg/l
plasma
Depends on the amount of thrombin added to the
sample Depends on the amount of ecarin added
to the sample May also be expressed as
fibrinogen equivalent units (FEU)
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Activated partial thromboplastin time (aPTT)
Amplification
Initiation
Factor XIa
Tissue factor

• 1. Contact activation
• 2. Add Ca and
• start the clock

Factor VIIa / Tissue factor
Factor IXa
Factor Xa
Factor X
Factor Xa
Prothrombin
Thrombin
Fibrinogen
Fibrin
Thrombus formation
Normal range 30 to 40 s
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Prothrombin time (PT)

• Add tissue factor
• Add Ca
• and start the clock

Amplification
Initiation
Factor XIa
Tissue factor

Factor VIIa / Tissue factor
Factor IXa
Factor Xa
Factor X
Factor Xa
Prothrombin
Thrombin
Fibrinogen
Fibrin
Thrombus formation
Normal range 12 to 20 s
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Thrombin time (TT)
Amplification
Initiation
Factor XIa
Tissue factor

Factor VIIa / Tissue factor
Factor IXa
Factor Xa
Factor X
Factor Xa
Prothrombin
Thrombin
1. Add a known amount of thrombin
Fibrinogen
Fibrin
Thrombus formation
Normal range 15 to 25 s
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Ecarin clotting time (ECT)
Amplification
Initiation
Factor XIa
Tissue factor
Factor VIIa / Tissue factor
Factor IXa
Factor Xa
Factor X
Factor Xa
Prothrombin
Meizothrombin
1. Add a known amount of Ecarin
Fibrinogen
Fibrin
Thrombus formation
Normal range 15 to 25 s