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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
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Page 1: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 2: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 3: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

HemostasisHemostasisSubendothelial matrixSubendothelial matrix

Nitric oxideNitric oxide

Endothelial cellEndothelial cell

Page 4: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

Initiation of coagulationInitiation of coagulation

Page 5: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 6: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 7: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 8: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

COAGULATION COAGULATION and recombinantand recombinant

Factor VIIa Factor VIIa (NovoSeven(NovoSeven) )

Mechanism of Mechanism of ActionAction

Page 9: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 10: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 11: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 12: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 13: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

HEMOSTASIS: HEMOSTASIS: ROLE OF FACTOR ROLE OF FACTOR

VII and TISSUE VII and TISSUE FACTORFACTOR

Page 14: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

TF-Bearing CellTF-Bearing Cell

VaVaTFTFVIIaVIIa XaXaXX IIII

IIa (Thrombin)IIa (Thrombin)

Normal HemostasisNormal Hemostasis

Page 15: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

TF-Bearing CellTF-Bearing Cell

VaVaTFTF VIIaVIIa XaXa

XX IIII

IIaIIaVIII/vWFVIII/vWF

VIIIaVIIIa

Normal HemostasisNormal Hemostasis

Page 16: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

TF-Bearing CellTF-Bearing Cell

VaVaTFTF VIIaVIIa XaXa

XX IIIIIIaIIa VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

Normal HemostasisNormal Hemostasis

Page 17: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

TF-Bearing CellTF-Bearing Cell

VaVaTFTF VIIaVIIa XaXa

XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

Activated PlateletActivated Platelet

Normal HemostasisNormal Hemostasis

Page 18: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 19: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 20: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 21: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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.

Page 22: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

TF-Bearing CellTF-Bearing Cell

VaVaTFTF XaXa

XX IIIIIIaIIa

Recombinant Factor VIIaRecombinant Factor VIIa ( (77))Mechanism of ActionMechanism of Action

Page 23: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 24: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 25: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 26: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 27: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 28: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

[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

Page 29: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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

Page 30: Coagulation (the basics) and recombinant Factor VIIa Mechanism of Action Jerrold H. Levy, MD Emory University School of Medicine and Emory Healthcare Atlanta,

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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