Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action

1
Coagulation (the basics) and recombinant Factor
VIIa Mechanism of Action

• Jerrold H. Levy, MD
• Emory University School of Medicine
• and Emory Healthcare
• Atlanta, Georgia

2
Normal Hemostasis

• First step in hemostasis is formation of a
  platelet aggregate
• At the molecular level interaction of coagulation
  factors takes place on the surface of activated
  platelets
• The Tissue FactorFVIIa complex is the
  physiological activator of normal hemostasis

3
Hemostasis
Endothelial cell
Subendothelial matrix
Nitric oxide
4
Initiation of coagulation
5
Coagulation Pathways
Intrinsic Pathway
Extrinsic Pathway
IX
Tissue Factor VII
TF Pathway
Contact
X
TF-VIIa
XI
Common Pathway
PL
XIIa
HKa
Prothrombin
XIa
PL
(Tenase)
IXa
PL
VIIIa
Xa
XIII
Va
(Prothrombinase)
Thrombin
Protein C, Protein S, Antithrombin III
XIIIa
Fibrinogen
Fibrin (strong)
Fibrin (weak)
6
Normal Hemostasis Pivotal role of TF/VIIa
II
X
VIII/vWF
VIIa
TF
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
IIa
Xa
VIIIa
IXa
Va
Activated Platelet
VIIa
IXa
Va
IIa
Xa
VIIIa
II
IX
X
Hoffman et al. Blood Coagul Fibrinolysis
19989(suppl 1)S61.
7
Platelet Activation Pathways
COLLAGEN
THROMBIN

ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adhesion
8
COAGULATION and recombinant Factor VIIa
(NovoSeven) Mechanism of Action
9
Bleeding through a cut in a vessel wall
Tissue Factor
Factor VIIa

• The first step in all coagulation The Tissue
  Factor-
• Factor VIIa complex formation

10
Bleeding through a cut in a vessel wall
TissueFactor- Factor VIIa Complex

• The first step in all coagulation The Tissue
  Factor-
• Factor VIIa complex formation
• This catalysis the coagulation cascade in normal
• persons and in patients with bleeding disorders

11
Recombinant Factor VIIa Platelet Binding
TissueFactor- Factor VIIa Complex
rFactorVIIa
Platelets
Recombinant Factor VIIa (rFVIIa) in high
concentration binds to platelets this complex
catalysis further coagulation. The local
coagulation activation is greatly enhanced
12
Further formation of a hemostatic plug
TissueFactor- rFVIIa Complex
rFVIIa
Platelets

• High peak levels of recombinant Factor VIIa
• (rFVIIa) induces formation of a strong fibrin
  network.
• This network cross-binds and forms a solid
• hemostatic plug

13
HEMOSTASIS ROLE OF FACTOR VII and TISSUE FACTOR
14
Normal Hemostasis
X
II
IIa (Thrombin)
15
Normal Hemostasis
II
X
VIII/vWF
IIa
VIIIa
16
Normal Hemostasis
II
X
VIII/vWF
IIa
VIIIa
V
Va
Platelet
17
Normal Hemostasis
II
X
VIII/vWF
IIa
VIIIa
V
Va
Platelet
Activated Platelet
18
Normal Hemostasis
II
X
VIII/vWF
IIa
VIIIa
TF
V
Va
VIIa
IX
Platelet
IXa
Activated Platelet
19
Normal Hemostasis
II
X
VIII/vWF
IIa
VIIIa
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
Xa
IIa
VIIIa
IXa
Va
Activated Platelet
20
Normal Hemostasis
II
X
VIII/vWF
TF
VIIa
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
IIa
Xa
VIIIa
IXa
Va
Activated Platelet
Hoffman et al. Blood Coagul Fibrinolysis
19989(suppl 1)S61.
21
FACTOR VIIa Mechanism of Action

• Increases the tissue factor (TF) occupancy
• In pharmacological doses binds to activated
  platelets
• Activates Factor X independent of tissue factor
• Proceedings of the National Academy of Sciences
  97(10)5255-60, 2000. Circulation.
  103(21)2555-9, 2001. Blood Coagulation
  Fibrinolysis. 11 Suppl 1S107-11, 2000.
• Proceedings of the National Academy of Sciences.
  96(16)8925-30, 1999.
• Haemostasis. 30 Suppl 241-7, 2000. Thrombosis
  Research. 98(4)311-21, 2000.

22
Recombinant Factor VIIa (7)Mechanism of Action
II
X
IIa
23
Recombinant Factor VIIa (7) Mechanism of Action
II
X
VIII/vWF
IIa
VIIIa
V
Va
Platelet
Activated Platelet
24
Recombinant Factor VIIa (7) Mechanism of Action
II
X
VIII/vWF
IIa
VIIIa
TF
V
Va
IX
Platelet
IXa
Activated Platelet
25
Recombinant Factor VIIa (7) Mechanism of Action
II
X
VIII/vWF
IIa
VIIIa
TF
V
Va
IX
Platelet
IXa
X
VIIIa
IXa
Xa
Activated Platelet
26
Recombinant Factor VIIa (7) Mechanism of Action
Recombinant Factor VIIa binding to activated
platelets
Activated Platelet
Xa
X
27
Recombinant Factor VIIa (7) Mechanism of Action
Recombinant Factor VIIa binding to activated
platelets
Activated Platelet
IIa
Xa
X
II
28
FVIIa Binding to Platelets
2.0
Activated Unactivated Activated, without Ca2
1.5
Relative Fluorescence
1.0
0.5
0.0
0
150
300
450
600
FVIIa (nM)
Monroe et al. Br J Haematol 199799542.
29
FVIIa Activates FX on Platelets in the Absence of
TF
FXa (nM)
Time (min)
Monroe et al. Blood Coagul Fibrinolysis
19989(suppl 1)S15.
30
Recombinant Factor VIIa Mechanism of action
Conclusion

• Recombinant Factor VIIa increases the Tissue
  Factor occupancy
• Recombinant Factor VIIa in pharmacological doses
  binds to activated platelets
• Recombinant Factor VIIa provides Factor X
  activation independent of Tissue Factor