Coagulation (the basics) Coagulation (the basics) and recombinant Factor and recombinant Factor VIIa VIIa Mechanism of Action Mechanism of Action Jerrold H. Levy, MD Jerrold H. Levy, MD Emory University School of Emory University School of Medicine Medicine and Emory Healthcare and Emory Healthcare Atlanta, Georgia Atlanta, Georgia
Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,
Dec 17, 2015
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Coagulation (the basics) and Coagulation (the basics) and recombinant Factor VIIa recombinant Factor VIIa
Mechanism of ActionMechanism of Action
Jerrold H. Levy, MDJerrold H. Levy, MDEmory University School of MedicineEmory University School of Medicine
and Emory Healthcareand Emory HealthcareAtlanta, GeorgiaAtlanta, Georgia
Normal HemostasisNormal Hemostasis• First step in hemostasis is First step in hemostasis is formation of a platelet aggregateformation of a platelet aggregate
• At the molecular level interaction of At the molecular level interaction of coagulation factors takes place on coagulation factors takes place on the surface of activated plateletsthe surface of activated platelets
• The The Tissue Factor–FVIIaTissue Factor–FVIIa complex complex is the physiological activator of is the physiological activator of normal hemostasisnormal hemostasis
HemostasisHemostasisSubendothelial matrixSubendothelial matrix
Nitric oxideNitric oxide
Endothelial cellEndothelial cell
Initiation of coagulationInitiation of coagulation
Contact Tissue Factor + VIITissue Factor + VII
XIIIXIIIaa
XIIIXIII
ThrombinThrombin
FibrinFibrin(strong)(strong)
FibrinogenFibrinogen FibrinFibrin(weak)(weak)
IXIX
XIXI
XIXIaa
IXIXaa
XXaa VVaa
XIIXIIaa
ProthrombinProthrombin
TF-VIITF-VIIaa
(Prothrombinase)(Prothrombinase)
PLPL
PLPL(Tenase)(Tenase)
VIIIVIIIaa
PLPL
XX
Intrinsic Pathway
HKHKaa
Extrinsic Pathway
Common Pathway
TF Pathway
Coagulation PathwaysCoagulation Pathways
Protein C, Protein S, Antithrombin III
Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.
TF-Bearing CellTF-Bearing Cell
Activated PlateletActivated Platelet
PlateletPlatelet
TFTF
VIIIaVIIIa VaVa
VIIIaVIIIa VaVa
VaVa
VIIaVIIa
TFTF VIIaVIIa XaXa
XX IIIIIIaIIa
IXIXVV VaVa
IIII
VIII/vWFVIII/vWF
VIIIaVIIIa
IIII
IXaIXa
XXIXIX
XX
IXaIXa
IXaIXaVIIaVIIaXaXa
IIaIIa
IIaIIa
XaXa
Normal Hemostasis: Pivotal role of TF/VIIaNormal Hemostasis: Pivotal role of TF/VIIa
Adhesion
GpIIb/IIIa
Platelet Activation PathwaysPlatelet Activation Pathways
GpIIb/IIIaGpIIb/IIIa Aggregation
ADP
Adrenaline Platelet GpIb
Exposed Collagen
Endothelium
vWF
COLLAGEN
GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation
AdhesionAdhesion
ADP
Adrenaline
THROMBINTHROMBIN
COAGULATION COAGULATION and recombinantand recombinant
Factor VIIa Factor VIIa (NovoSeven(NovoSeven) )
Mechanism of Mechanism of ActionAction
TissueTissueFactorFactor Factor Factor
VIIaVIIa
• The first step in all coagulation: The Tissue Factor- The first step in all coagulation: The Tissue Factor- Factor VIIa Factor VIIa complex formationcomplex formation
Bleeding through a cut in a vessel wallBleeding through a cut in a vessel wall
TissueFactor- TissueFactor- Factor VIIa Factor VIIa ComplexComplex
• The first step in all coagulation: The Tissue Factor- The first step in all coagulation: The Tissue Factor- Factor VIIaFactor VIIa complex formation complex formation
• This catalysis the coagulation cascade in normalThis catalysis the coagulation cascade in normal persons persons and in patients with bleeding disordersand in patients with bleeding disorders
Bleeding through a cut in a vessel wallBleeding through a cut in a vessel wall
Platelets
rFactorVIIarFactorVIIa
Recombinant Factor VIIa (rFVIIa)Recombinant Factor VIIa (rFVIIa) in high concentration in high concentration binds to platelets; thisbinds to platelets; this complex catalysis further coagulation. complex catalysis further coagulation. The local coagulation activation is greatly enhancedThe local coagulation activation is greatly enhanced
TissueFactor- TissueFactor- Factor VIIa Factor VIIa ComplexComplex
Recombinant Factor VIIa Platelet BindingRecombinant Factor VIIa Platelet Binding
rFVIIarFVIIa
Platelets
High peak levels of recombinant Factor VIIaHigh peak levels of recombinant Factor VIIa(rFVIIa) induces formation of a strong fibrin network.(rFVIIa) induces formation of a strong fibrin network.This network cross-binds and forms a solid This network cross-binds and forms a solid
hemostatic plughemostatic plug
TissueFactor-TissueFactor- rFVIIarFVIIa ComplexComplex
Further formation of a hemostatic plugFurther formation of a hemostatic plug
HEMOSTASIS: HEMOSTASIS: ROLE OF FACTOR ROLE OF FACTOR
VII and TISSUE VII and TISSUE FACTORFACTOR
TF-Bearing CellTF-Bearing Cell
VaVaTFTFVIIaVIIa XaXaXX IIII
IIa (Thrombin)IIa (Thrombin)
Normal HemostasisNormal Hemostasis
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIII
IIaIIaVIII/vWFVIII/vWF
VIIIaVIIIa
Normal HemostasisNormal Hemostasis
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
Normal HemostasisNormal Hemostasis
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
Activated PlateletActivated Platelet
Normal HemostasisNormal Hemostasis
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTF VIIaVIIaIXIX
IXaIXa
Activated PlateletActivated Platelet
Normal HemostasisNormal Hemostasis
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTF VIIaVIIaIXIX
IXaIXa
Activated PlateletActivated Platelet
VIIIaVIIIa VaVaIXaIXaXaXa
IIaIIa
IIII
Normal HemostasisNormal Hemostasis
XX
Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.
Activated PlateletActivated Platelet
PlateletPlatelet
TFTF
VIIIaVIIIa VaVa
VIIaVIIa
XX IIII
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa IIaIIa
IXIXVV VaVa
IIII
VIII/vWFVIII/vWF
VIIIaVIIIa
IXaIXa XX
IXaIXa IIaIIaXaXa
Normal HemostasisNormal Hemostasis
FACTOR VIIa Mechanism of Action
• Increases the tissue factor (TF) Increases the tissue factor (TF) occupancyoccupancy
• In pharmacological doses binds to In pharmacological doses binds to activated plateletsactivated platelets
• Activates Factor X independent of Activates Factor X independent of tissue factortissue factor
Proceedings of the National Academy of Sciences 97(10):5255-60, 2000. Circulation. 103(21):2555-9, 2001. Blood Coagulation & Fibrinolysis. 11 Suppl 1:S107-11, 2000.
Proceedings of the National Academy of Sciences. 96(16):8925-30, 1999.Haemostasis. 30 Suppl 2:41-7, 2000. Thrombosis Research. 98(4):311-21, 2000.
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
Recombinant Factor VIIaRecombinant Factor VIIa ( (77))Mechanism of ActionMechanism of Action
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
Activated PlateletActivated Platelet
Recombinant Factor VIIa Recombinant Factor VIIa ((77) ) Mechanism of ActionMechanism of Action
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTFIXIX
IXaIXa
Activated PlateletActivated Platelet
Recombinant Factor VIIa Recombinant Factor VIIa ((77) ) Mechanism of ActionMechanism of Action
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTFIXIX
IXaIXa
Activated PlateletActivated Platelet
Recombinant Factor VIIa Recombinant Factor VIIa ((77) ) Mechanism of ActionMechanism of Action
XX
XaXaVIIIaVIIIaIXaIXa
Recombinant Factor VIIa Recombinant Factor VIIa ((77) ) Mechanism of ActionMechanism of Action
Activated PlateletActivated Platelet
XXXaXa
Recombinant Factor VIIaRecombinant Factor VIIa binding to activated plateletsbinding to activated platelets
Recombinant Factor VIIa Recombinant Factor VIIa ((77) Mechanism ) Mechanism of Actionof Action
Activated PlateletActivated Platelet
XXXaXa IIaIIaIIII
Recombinant Factor VIIaRecombinant Factor VIIa binding to activated plateletsbinding to activated platelets
[FVIIa] (nM)[FVIIa] (nM)
Relative Relative FluorescenceFluorescence
Monroe et al. Monroe et al. BrBr J HaematolJ Haematol 1997;99:542. 1997;99:542.
2.02.0
1.51.5
1.01.0
0.00.0
0.50.5
00 150150 300300 450450 600600
ActivatedUnactivatedActivated,without Ca+2
FVIIa Binding to PlateletsFVIIa Binding to Platelets
Monroe et al. Monroe et al. Blood Coagul Fibrinolysis Blood Coagul Fibrinolysis 1998;9(suppl 1):S15.1998;9(suppl 1):S15.
Time (min)Time (min)
[FXa] (nM)[FXa] (nM)
50 nM VIIa50 nM VIIa20 nM VIIa20 nM VIIa10 nM VIIa10 nM VIIa 5 nM VIIa5 nM VIIa 2 nM VIIa2 nM VIIa NoneNone
00
66
55
44
33
22
11
001010 2020 3030 4040
FVIIa Activates FX on Platelets in the Absence FVIIa Activates FX on Platelets in the Absence of TFof TF
Recombinant Factor VIIaRecombinant Factor VIIa Mechanism of action: ConclusionMechanism of action: Conclusion
•Recombinant Factor VIIaRecombinant Factor VIIa increases increases the Tissue Factor occupancythe Tissue Factor occupancy
•Recombinant Factor VIIaRecombinant Factor VIIa in in pharmacological doses binds to pharmacological doses binds to activated plateletsactivated platelets
•Recombinant Factor VIIaRecombinant Factor VIIa provides provides Factor X activation independent of Factor X activation independent of Tissue FactorTissue Factor
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