Haemostasis and NovoSeven ® The updated cell-based model of haemostasis and NovoSeven ® (rFVIIa) mode of action

Haemostasis and NovoSeven®

The updated cell-based model of haemostasis andNovoSeven® (rFVIIa) mode of action

Haemostasis and NovoSeven® – mode of action; Feb 2006

►

4. NovoSeven® mode of action

3. Secondary haemostasis

2. Primary haemostasis

1. The haemostatic system

Chapter


Primary haemostasis:• Vasoconstriction (immediate)• Platelet adhesion (within seconds)• Platelet aggregation and contraction (within minutes)

Secondary haemostasis:• Activation of coagulation factors (within seconds)• Formation of fibrin (within minutes)

Fibrinolysis:• Activation of fibrinolysis (within minutes)• Lysis of the plug (within hours)

The haemostatic system – The three phases


The haemostatic system – Blood vessel and endothelium

Haemostasis requires and involves various physiological components:

The blood vessel wall• Endothelial cells

• Subendothelial tissue

• Smooth muscle cells

The components of blood• Platelets (thrombocytes)

• Coagulation (clotting) factors

• Fibrinolytic/ anticoagulant proteins


►

4. NovoSeven® mode of action




Chapter


Primary haemostasis –Vasoconstriction

The first response to endothelial injury is the constriction of the damaged vessel which reduces the blood flow at the site of injury1


Primary haemostasis –Formation of a platelet plug

The exposure of subendothelial components such as collagen promotes platelet adhesion1,2

The adherence of platelets to the sub-endothelium leads to platelet activation and the formation of platelet aggregates (platelet plug)2


►4. NovoSeven® mode of action




Chapter


Secondary haemostasis involves a series of interactions between coagulation factors which occur on the surface of tissue-factor-bearing cells and activated platelets1,2

This results in the generation of a thrombin burst and the formation of a haemostatic plug at the site of vascular injury1,2

Based on the “cell-based model”, coagulation occurs in three overlapping phases – initiation, amplification and propagation1,2

Secondary haemostasis


Secondary haemostasis –Initiation phase

Upon vessel wall injury, tissue factor (TF) is exposed to circulating endogenous factor VII/VIIa – leading to the TF/VIIa complex which initiates coagulation1,2

At the surface of TF-bearing cells the TF/VIIa complex activates:1,2

• Factor IX to IXa • Factor X to Xa

Factor Xa binds to factor Va on the cell surface1,2

Adapted from Hoffman M et al., 2001.1


Secondary haemostasis – Amplification phase


The factor Xa/Va complex activates small amounts of prothrombin to thrombin at the surface of subendothelial cells1,2

This limited amount of thrombin activates factors V, VIII and platelets3

The activated plateletbinds factors Va, VIIIaand IXa1


Secondary haemostasis – Propagation phase

Thrombin-activated platelets change shape and expose negatively charged phospholipids to which the factor VIIIa/IXa complex binds

• This results in factor X activation on the surface of activated

platelets1,2 The factor Xa/Va complex activates

large amounts of prothrombin resulting in a “thrombin burst” which:

• Converts fibrinogen to fibrin1,2 • Activates fibrin-stabilising

factor XIII2 The amount and rate of thrombin

generation determines the strength of the haemostatic plug3



The thrombin burst is particularly important because it:

Converts fibrinogen into fibrin monomers, which polymerise and form the mesh-work basis of the haemostatic plug1,2

Activates more platelets and other factors, thereby further amplifying the system1,2

Activates thrombin-activatable fibrinolysis inhibitor (TAFI) which protects the plug from fibrinolysis3

Activates factor XIII, which helps stabilising the haemostatic plug4

Secondary haemostasis – Thrombin burst


Overview of secondary haemostasis1-3

Upon vessel wall injury, tissue factor (TF) is exposedto circulating endogenousfactor VII/VIIa – leading tothe TF/VIIa complex, which

initiates coagulation A limited amount of

thrombin activates factors

V, VIII and platelets Activation of factor X leads

to the formation of the prothrombinase complex Xa/Va which subsequently generates

large amounts of thrombin This “thrombin burst”

induces the generation of a haemostatic plug that

prevents further blood loss Adapted from Hoffman M et al., 2001.1


► 4. NovoSeven® mode of action




Chapter


At pharmacological doses NovoSeven® (rFVIIa) directly activates factor X on the surfaces of activated platelets1-3

Once activated factor Xa in combination with factor Va generates large amounts of thrombin4

This “thrombin burst” leads to the formation of a stable haemostatic plug at the site of vascular injury1

NovoSeven® (rFVIIa) mode of action


NovoSeven® (rFVIIa) controls bleeding at the site of vascular injury only1

rFVIIa works locally at the site of vascular injury, where tissue factor (TF) is exposed and activated platelets are found1

Binding of factor VIIa or rFVIIa to TF initiates the coagulation generating small amounts of thrombin2

At pharmacological doses rFVIIa directly activates factor X on the surface of activated platelets resulting in a “thrombin burst”3,4

The thrombin burst leads to the formation of a stable haemostatic plug which controls the bleeding3


Documents

Haemostasis and NovoSeven ® The updated cell-based model of haemostasis and NovoSeven ® (rFVIIa) mode of action