HAEMOSTASIS AND THROMBOSIS

HAEMOSTASIS AND THROMBOSISRegulation of coagulation

• Disturbed coagulation may lead to bleeding, thromboembolismand/or impaired wound healing!
• Formation of fibrin-platelet-thrombus
• Wound closure / cessation of bleeding
• Tissue regeneration / wound healing

Regulation

by
inhibitors
and
endothelial
cells
• Vessel wall injury
• Vasoconstriction,local bloodpressure drop
• Activationofplatelets
• Activation ofplasmaticcoagulation
• Activationoffibrinolysis


What is haemostasis?

Coagulation

Fibrinolysis
Fibrin clot formationsecondary haemostasis
Fibrinolysistertiary haemostasis
Vasoconstrictionof the damaged vessel
Platelet plug formationprimary haemostasis
Maintains blood in a fluid state in circulationand providesdefence mechanism against bleeding when injury occurs

What is the function of thrombin?

Activates platelets
Activates FVIII and FV
Activates FXIII necessary for the formation of fully stabilized fibrin clots/plugs
Activates FXI (feed-back loop leading to more thrombin formation via FIX)
Activates TAFI (thrombin activatable fibrinolysis inhibitor)

Necessary for haemostasis

Summary
Initiation
TF complexes with FVIIa, which activates FX to FXa
FXa generates small amount of thrombin on surface of TF-bearingcells with FVa as co-enzyme
FVIIa also activates FIX to FIXa
Amplification
Thrombin activates platelets
Thrombin cleaves FVIII from vWF and FVIII is activated to FVIIIa
Thrombin activates FXI and FV
Propagation
FIXa-FVIIIa complex generates FXa on the surface of activated platelets
This FXa generates a huge thrombin burst
Thrombin converts fibrinogen to fibrin


Platelet Function
Adherence Only
Aggregation &
Release

Direction of Blood Flow

Platelet Adherence

vWF

vWF
Gp Ib

vWF

Gp Ib

vWF

von Willebrand Disease

Bernard-Soulier Syndrome

Platelet Release Function

DenseGranule
Alpha-granule

Lysosome

ADP

ß-thromboglobulin

Platelet factor 4

Platelet-derived Growth Factor

Fibrinogen

Factor V

Hermansky-Pudlak
syndrome

Wiskott-Aldrich syndrome

Gray platelet syndrome

Chédiak-

Higashi anomaly
Hydrolase

Platelet Aggregation

IIIa

IIb

IIIa

IIb


IIIa

IIb
ADP
ADP

Fibrinogen

E
D
D

D

Dense Granule

Gp Ib

vWF

Release Defects

Thrombasthenia

Afibrinogenemia

Antithrombotic Properties of the Endothelium
• Anti-platelet properties
• Healthy endothelium does not bind platelets
• Produce PGI-2 (prostacyclin) and NO (Nitric Oxide), which inhibit platelet binding
• Produce ADP-ase which counters the platelet aggregating effects of ADP

Antithrombotic Properties of the Endothelium (cont.) Anticoagulant propertiesProduce Heparin-like proteoglycans which activate anti-thrombin Produce Thrombomodulin which make a complex with thrombin (TM.T complex ) and activates protein C ,Produce tPA which activates fibrinolysis by activating plasminogen to plasmin

Prothrombotic Properties of the Endothelium

Synthesis of von Willebrand factor
Release of tissue factor
Production of plasminogen activator inhibitors (PAI)
Membrane phospholipids bind and facilitate activation of clotting factors via Ca++ bridges

Procoagulant

Anticoagulant


Procoagulant
Anticoagulant

Virchow’s Triad

Pathogenesis of a Thrombus
Endothelial injury
Abnormal blood flow
Hypercoagulability
Genetic
acquired

Fibrinogen

Fibrin
Thrombin
Prothrombin
Xa
Va


VIIa
TF

Extrinsic Pathway

IXa

VIIIa

XIa

XIIa

Intrinsic pathway
XIIIa
Soft clot

Fibrin

Hard clot
V

VIII

Folate and Homocysteine Metabolic Pathways