Haemostasis and NovoSeven®
The updated cell-based model of haemostasis andNovoSeven® (rFVIIa) mode of action
Haemostasis and NovoSeven® – mode of action; Feb 2006
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4. NovoSeven® mode of action
3. Secondary haemostasis
2. Primary haemostasis
1. The haemostatic system
Chapter
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
►
4. NovoSeven® mode of action
3. Secondary haemostasis
2. Primary haemostasis
1. The haemostatic system
Chapter
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
►4. NovoSeven® mode of action
3. Secondary haemostasis
2. Primary haemostasis
1. The haemostatic system
Chapter
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
Secondary haemostasis – Amplification phase
Adapted from Hoffman M et al., 2001.1
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Adapted from Hoffman M et al., 2001.1
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
► 4. NovoSeven® mode of action
3. Secondary haemostasis
2. Primary haemostasis
1. The haemostatic system
Chapter
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Haemostasis and NovoSeven® – mode of action; Feb 2006
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
Adapted from Hoffman M et al., 2001.1