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

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

3. The haemostatic system – The three phases
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)
Haemostasis and NovoSeven® – mode of action; Feb 2006

4. 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

5. 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

6. 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
Colman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16.
Haemostasis and NovoSeven® – mode of action; Feb 2006

7. 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
Colman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Haemostasis and NovoSeven® – mode of action; Feb 2006

8. 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

9. Secondary haemostasis
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
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Haemostasis and NovoSeven® – mode of action; Feb 2006

10. 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
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Adapted from Hoffman M et al.,
Haemostasis and NovoSeven® – mode of action; Feb 2006

11. 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 platelet binds factors Va, VIIIa and IXa1
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Monroe DM, et al. Blood Coagul Fibrinolysis 1996; 7: 459–464.
Adapted from Hoffman M et al.,
Haemostasis and NovoSeven® – mode of action; Feb 2006

12. 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
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Collet JP, et al. Arterioscler Thromb Vasc Biol 2000; 20(5): 1354–1361.
Adapted from Hoffman M et al.,
Haemostasis and NovoSeven® – mode of action; Feb 2006

13. Secondary haemostasis – Thrombin burst
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
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–20.
Bajzar L, Manuel R, Nesheim ME. J Biol Chem 1995; 270(24): 14477–14484.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Haemostasis and NovoSeven® – mode of action; Feb 2006

14. Overview of secondary haemostasis1-3
Upon vessel wall injury, tissue factor (TF) is exposed to circulating endogenous factor VII/VIIa – leading to the 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 
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–20.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
Adapted from Hoffman M et al.,
Haemostasis and NovoSeven® – mode of action; Feb 2006

15. 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

16. NovoSeven® (rFVIIa) mode of action
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
Monroe DM, et al. Br J Haematol 1997; 99: 542–547.
Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–S20.
Hoffman M, Monroe DM. Dis Mon 2003; 49(1): 14–21.
Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–8.
Haemostasis and NovoSeven® – mode of action; Feb 2006

17. 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 
Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.
Jurlander B, et al. Semin Thromb Hemost 2001; 27(4): 373–384.
Monroe DM, et al. Br J Haematol 1997; 99: 542–547.
Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–S20.
Adapted from Hoffman M et al.,
Haemostasis and NovoSeven® – mode of action; Feb 2006