Emergency warfarin reversal a

EMERGENCY WARFARIN REVERSAL

Dr Wahid Altaf.Kerry General Hospital.

Contact Tissue Factor + VIITissue Factor + VII

XIIIaXIIIa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)FibrinogenFibrinogen FibrinFibrin

(weak)(weak)

IXIX

XIXI

XIaXIa

IXaIXa

XXaa VaVa

XIIaXIIa

ProthrombinProthrombin

TF-TF-VIIVIIaa

(Prothrombinase)(Prothrombinase)

PLPL

PLPL

(Tena(Tenase)se)

VIIIaVIIIa

PLPL

XX

Intrinsic Pathway

HKaHKa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation Pathways

Protein C, Protein S,

Antithrombin III

Vitamin K-dependent clotting factorsVitamin K-dependent clotting factors(FII, FVII, FIX, FX, Protein C/S/Z)(FII, FVII, FIX, FX, Protein C/S/Z)

EpoxideReductase

-Carboxylase(GGCX)

Warfarin acts as a vitamin K antagonist

Warfarin

Inactivation

CYP2C9

Pharmacodynamic

New Target Protein for Warfarin

EpoxideReductase

-Carboxylase(GGCX)

Clotting Factors(FII, FVII, FIX, FX, Protein C/S/Z)

Rost et al. & Li, et al., Nature (2004)

(VKORC1)

5 kb - chr 165 kb - chr 16

Inactive factors II, VII, IX, and X

Proteins S and C

Active factors II, VII, IX, and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K, which is essential for activation of Prevents the reduction of vitamin K, which is essential for activation of certain factorscertain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS

Factor IIFactor II 72h72h

Factor VIIFactor VII 6h6h

Factor IXFactor IX 24h24h

Factor XFactor X 36h36h

Peak anticoagulant effect may be delayed by 72 to 96 hoursPeak anticoagulant effect may be delayed by 72 to 96 hours

Hit the right INR in 15 minutes

Prothrombin concentrate complex……Cofact

Cofact :

A vial of Cofact 250 IU contains 250 IU Factor IX; 140 – 350 IU Factor II; 70 - 200 IU Factor VII and 140 - 350 IU Factor X.

- A vial of Cofact 500 IU contains 500 IU Factor IX; 280 - 700 IU Factor II; 140 - 400 IU Factor VII and 280 - 700 IU Factor X.

Recommended dosages of Cofact in ml to achieve a Target INR ≤ 1.5

Initial INR 7.5 5.9 4.8 4.2 3.6 3.3 3.0 2.8 2.6 2.5 2.3 2.2Body Weight50 kg 60 60 60 50 50 50 40 40 30 30 30 3060 kg 80 70 70 60 60 60 50 50 40 40 40 3070 kg 90 80 80 70 70 70 60 60 50 40 40 4080 kg 100 100 90 90 90 80 80 70 60 50 50 4090 kg 100 100 100 90 90 90 80 80 70 60 50 40100 kg 100 100 100 100 100 90 90 80 70 70 60 50

Dosage of Fresh frozen plasmaThe dosage of Fresh Frozen Plasma is generally

12-15 mls/Kg1.

Volume of a unit of FFP is 220 mls.

Once thawed it should be transfused within 4 hours because of progressive loss of labile coagulation factors

The recommend infusion rate of plasma is a unit over 30 minutes to an uncompromised adult. 2

Risk of circulatory overload or anaphylactoid reactions are especially associated with rapid infusion rates.

Peri- operative use of Factor VIIa (Recombinant).

Contact Tissue Factor + VIITissue Factor + VII

XIIIaXIIIa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)FibrinogenFibrinogen FibrinFibrin

(weak)(weak)

IXIX

XIXI

XIaXIa

IXaIXa

XXaa VaVa

XIIaXIIa

ProthrombinProthrombin

TF-VIITF-VIIaa

(Prothrombinase)(Prothrombinase)

PLPL

PLPL

(Tena(Tenase)se)

VIIIaVIIIa

PLPL

XX

Intrinsic Pathway

HKaHKa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation 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

Adhesion

GpIIb/IIIa

Platelet 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

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 Factor VIIa VIIa

ComplexComplex

Recombinant Factor VIIa Platelet Recombinant Factor VIIa Platelet BindingBinding

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


VaVaTFTFVIIaVIIa XaXaXX IIII

IIa (Thrombin)IIa (Thrombin)


VaVaTFTF VIIaVIIa XaXa

XX IIII

IIaIIaVIII/vWFVIII/vWF

VIIIaVIIIa



XX IIIIIIaIIa VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet



XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet




XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

TFTF VIIaVIIaIXIX

IXaIXa


Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.


PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIaVIIa

XX IIII


VaVaTFTF VIIaVIIa XaXa IIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IXaIXa XX

IXaIXa IIaIIaXaXa

FACTOR VIIa Mechanism of Action

• Increases the tissue factor (TF) Increases the tissue factor (TF) occupancyoccupancy

• In pharmacological doses binds In pharmacological doses binds to activated plateletsto activated platelets

• Activates Factor X independent Activates Factor X independent of tissue factorof 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 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.


VaVaTFTF XaXa

XX IIIIIIaIIa


VaVaTFTF XaXa

XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet



VaVaTFTF XaXa

XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

TFTFIXIX

IXaIXa




XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

TFTFIXIX

IXaIXa


XX

XaXaVIIIaVIIIaIXaIXa


XXXaXa

Recombinant Factor VIIaRecombinant Factor VIIa binding to activated plateletsbinding to activated platelets


XXXaXa IIaIIaIIII

Recombinant Factor VIIaRecombinant Factor VIIa binding to activated plateletsbinding to activated platelets

Protocols for the use of factor VIIa (Recombinant)1. Haemophilia.

2. Warfarin toxicity.

3. Liver Disease.

4. Intracerebral Haemorrhage.

5. Paediatric Patients with coagulopathy.

6. Massive Bleeding.

Control of overt bleedingRECOMENDED INDICATIONS:

1.Blunt Trauma.

2.Coagulopathy.

3.Post partum haemorrhage.

4.Surgical Bleeding.

5.Perioperative bleeding after cardiac surgery.

Control of overt bleeding

NOT RECOMENDED INDICATIONS / NO EVIDENCE:

1. Penetrating trauma.

2. Elective Surgery.

Monitoring efficacy of factor VIIa

1. No specific method available.

2. Visual monitoring.

3. By assessment of transfusion requirements after dosing.

4.Sometimes PT used.

Contraindications for factor VIIa usage

1. Patients on multiple pressors for hypotension.

2. DIC patients.

3. Patients with Angina, Stroke and Deep venous thrombosis.

4.Patients hypersensitive to mouse, hamster or bovine proteins.

Thanks.

Emergency warfarin reversal a

Health & Medicine

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