Emergency warfarin reversal a
-
Upload
wahid-altaf-sheeba-hakak -
Category
Health & Medicine
-
view
1.015 -
download
0
description
Transcript of 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
TF-Bearing CellTF-Bearing Cell
VaVaTFTFVIIaVIIa XaXaXX IIII
IIa (Thrombin)IIa (Thrombin)
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIII
IIaIIaVIII/vWFVIII/vWF
VIIIaVIIIa
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
Activated PlateletActivated Platelet
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTF VIIaVIIaIXIX
IXaIXa
Activated PlateletActivated Platelet
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
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.
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
Activated PlateletActivated Platelet
TF-Bearing CellTF-Bearing Cell
VaVaTFTF XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTFIXIX
IXaIXa
Activated PlateletActivated Platelet
TF-Bearing CellTF-Bearing Cell
VaVaTFTF VIIaVIIa XaXa
XX IIIIIIaIIa
VIII/vWFVIII/vWF
VIIIaVIIIa
VV VaVa
PlateletPlatelet
TFTFIXIX
IXaIXa
Activated PlateletActivated Platelet
XX
XaXaVIIIaVIIIaIXaIXa
Activated PlateletActivated Platelet
XXXaXa
Recombinant Factor VIIaRecombinant Factor VIIa binding to activated plateletsbinding to activated platelets
Activated PlateletActivated Platelet
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.