Emergency warfarin reversal a
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warfarin reversal in emergency
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Emergency warfarin reversal a
- 2. Coagulation Pathways Contact Tissue Factor + VII XIIIa XIII Thrombin Fibrin (strong) Fibrinogen Fibrin (weak) IX XI XIa IXa X a Va XIIa Prothrombin TF-VII a (Prothrombinase) PL PL (Tenase) VIIIa PL X Intrinsic Pathway HKa Extrinsic Pathway Common Pathway TF Pathway Protein C, Protein S, Antithrombin III
- 3. Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z) Warfarin acts as a vitamin K antagonist Inactivation CYP2C9 Pharmacodynamic Epoxide Reductase -Carboxylase ( GGCX ) Warfarin
- 4. New Target Protein for Warfarin -Carboxylase ( GGCX ) Clotting Factors (FII, FVII, FIX, FX, Protein C/S/Z) Rost et al. & Li, et al., Nature (2004) 5 kb - chr 16 Epoxide Reductase ( VKORC1 )
- 6. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Peak anticoagulant effect may be delayed by 72 to 96 hours Factor II 72h Factor VII 6h Factor IX 24h Factor X 36h
- 9. Hit the right INR in 15 minutes
- 16. Peri- operative use of Factor VIIa (Recombinant).
- 17. Coagulation Pathways Contact Tissue Factor + VII XIIIa XIII Thrombin Fibrin (strong) Fibrinogen Fibrin (weak) IX XI XIa IXa X a Va XIIa Prothrombin TF-VII a (Prothrombinase) PL PL (Tenase) VIIIa PL X Intrinsic Pathway HKa Extrinsic Pathway Common Pathway TF Pathway Protein C, Protein S, Antithrombin III
- 18. Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61. TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa Xa X II IIa IX V Va II VIII/vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa
- 19. Platelet Activation Pathways Adhesion GpIIb/IIIa ADP Adrenaline Platelet GpIb COLLAGEN THROMBIN GpIIb/IIIa GpIIb/IIIa Aggregation Exposed Collagen Endothelium vWF GpIIb/IIIa GpIIb/IIIa Aggregation GpIIb/IIIa GpIIb/IIIa Aggregation Adhesion Adhesion ADP Adrenaline
- 23. Platelets rFactorVIIa Recombinant Factor VIIa (rFVIIa) in high concentration binds to platelets; this complex catalysis further coagulation. The local coagulation activation is greatly enhanced TissueFactor- Factor VIIa Complex Recombinant Factor VIIa Platelet Binding
- 24. 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 TissueFactor- rFVIIa Complex Further formation of a hemostatic plug
- 26. X II IIa (Thrombin) TF-Bearing Cell Va TF VIIa Xa
- 27. X II IIa VIII/vWF VIIIa TF-Bearing Cell Va TF VIIa Xa
- 28. X II IIa VIII/vWF VIIIa V Va Platelet TF-Bearing Cell Va TF VIIa Xa
- 29. X II IIa VIII/vWF VIIIa V Va Platelet Activated Platelet TF-Bearing Cell Va TF VIIa Xa
- 30. X II IIa VIII/vWF VIIIa V Va Platelet TF VIIa IX IXa Activated Platelet TF-Bearing Cell Va TF VIIa Xa
- 31. Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61. Activated Platelet Platelet TF VIIIa Va VIIa X II TF-Bearing Cell Va TF VIIa Xa IIa IX V Va II VIII/vWF VIIIa IXa X IXa IIa Xa
- 33. X II IIa TF-Bearing Cell Va TF Xa
- 34. X II IIa VIII/vWF VIIIa V Va Platelet Activated Platelet TF-Bearing Cell Va TF Xa
- 35. X II IIa VIII/vWF VIIIa V Va Platelet TF IX IXa Activated Platelet TF-Bearing Cell Va TF Xa
- 36. X II IIa VIII/vWF VIIIa V Va Platelet TF IX IXa Activated Platelet X Xa VIIIa IXa TF-Bearing Cell Va TF VIIa Xa
- 37. Activated Platelet X Xa Recombinant Factor VIIa binding to activated platelets
- 38. Activated Platelet X Xa IIa II Recombinant Factor VIIa binding to activated platelets
- 44. Thanks.
Editor's Notes
- Coagulation may be initiated by vascular injury, however, multiple coagulation pathways are involved in the actual formation of clot. Vasoconstriction occurs immediately following vascular injury and is followed by platelet adhesion to collagen in the vessel wall exposed by injury. Subsequently platelet aggregation results in a platelet plug which is later strengthened by fibrin. Fibrin production may begin with the conversion of factor X to factor Xa. Factor X can be activated by means of two reaction sequences. One requires tissue factor (TF) which is exposed to the blood as a result of vascular injury. Because TF is not in the blood, it is an extrinsic element in coagulation, hence the name "extrinsic" pathway for this sequence. The catalytic action of TF is the central precipitating event in the clotting cascade. TF acts in concert with factor VIla and phospholipid (PL) to convert factor IX to IXa and factor X to Xa. The "intrinsic" pathway is initiated by the "contact" activation of factor XI by the XIIa/activated high molecular weight kininogen (HKa) complex. Factor XIa also converts factor IX to IXa and factor IXa in turn converts factor X to Xa, in concert with factors VIIIa and phospholipid (the “tenase complex”). However factor Xa is formed, it is the active catalytic ingredient of the "Prothrombinase” complex, which includes factor Va and PL and converts prothrombin to thrombin. Thrombin cleaves fibrinopeptides (FPA, FPB) from fibrinogen, allowing the resultant fibrin monomers to polymerize, and converts factor XIII to XIIIa which crosslinks the fibrin clot. Thrombin accelerates the clotting cascade by its potential to activate factors V and VIII, but continued proteolytic action also activates protein C which degrades Va and VIIIa. Adapted from: Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of hemostasis.Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 p 9.1154-1155. Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1154-1155. Goodnight S. Physiology of coagulation and the role of vitamin K. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing oral anticoagulation therapy, Gaithersburg: Aspen Publishers, 1997 pp 1-7.
- And encoded for the gene now named VKORC1. In this work by Rost et al that should the overt warfarin resistance was due to non-synonymous mutation in VKORC1 - that is patients needing doses at 25-50 mg/d had clear predisposing mutations. Interestingly, NO nonsynomymous mutations were found in control chromosomes.
- Coagulation may be initiated by vascular injury, however, multiple coagulation pathways are involved in the actual formation of clot. Vasoconstriction occurs immediately following vascular injury and is followed by platelet adhesion to collagen in the vessel wall exposed by injury. Subsequently platelet aggregation results in a platelet plug which is later strengthened by fibrin. Fibrin production may begin with the conversion of factor X to factor Xa. Factor X can be activated by means of two reaction sequences. One requires tissue factor (TF) which is exposed to the blood as a result of vascular injury. Because TF is not in the blood, it is an extrinsic element in coagulation, hence the name "extrinsic" pathway for this sequence. The catalytic action of TF is the central precipitating event in the clotting cascade. TF acts in concert with factor VIla and phospholipid (PL) to convert factor IX to IXa and factor X to Xa. The "intrinsic" pathway is initiated by the "contact" activation of factor XI by the XIIa/activated high molecular weight kininogen (HKa) complex. Factor XIa also converts factor IX to IXa and factor IXa in turn converts factor X to Xa, in concert with factors VIIIa and phospholipid (the “tenase complex”). However factor Xa is formed, it is the active catalytic ingredient of the "Prothrombinase” complex, which includes factor Va and PL and converts prothrombin to thrombin. Thrombin cleaves fibrinopeptides (FPA, FPB) from fibrinogen, allowing the resultant fibrin monomers to polymerize, and converts factor XIII to XIIIa which crosslinks the fibrin clot. Thrombin accelerates the clotting cascade by its potential to activate factors V and VIII, but continued proteolytic action also activates protein C which degrades Va and VIIIa. Adapted from: Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of hemostasis.Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 p 9.1154-1155. Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1154-1155. Goodnight S. Physiology of coagulation and the role of vitamin K. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing oral anticoagulation therapy, Gaithersburg: Aspen Publishers, 1997 pp 1-7.
- This slide illustrates the pivotal role of FVIIa/tissue factor activation in producing hemostasis. This slide represents a schematic model of normal hemostasis that requires activation of both FX and FIX. FVIIa/tissue factor (TF)-activated FXa and FIXa play distinct roles in coagulation. FXa cannot move to the platelet surface because of the presence of normal plasma inhibitors, but instead remains on the TF-bearing cell and activates a small amount of thrombin. This thrombin is not sufficient for fibrinogen cleavage but is critical for hemostasis since it can activate platelets, activate and release FVIII from von Willebrand factor (vWF), activate platelet and plasma FV, and activate FXI. FIXa moves to the platelet surface, where it forms a complex with FVIIIa and activates FX on the platelet surface. This platelet surface FXa is relatively protected from normal plasma inhibitors and can complex with platelet surface FVa, where it activates thrombin in quantities sufficient to provide for fibrinogen cleavage. Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.
- Multiple pathways are responsible for platelet activation. Platelets adhere to damaged blood vessels via cell surface adhesion molecules and their membrane receptors such as glycoprotein Ib/IX (GP Ib/IX), the ligand for von Willebrand factor (VWF), which in turn can activated platelets and cause conformational changes. Further, other activators including thrombin, adrenaline, ADP, and collagen can also activate platelets. When activation occurs, the glycoprotein IIb/IIIa membrane receptor (GP IIb/IIIa) is exposed. This receptor forms bridges using fibrinogen resulting in aggregation. Platelet activation also exposes a phospholipid surface (meeting place) upon which coagulation proteins carry out their reactions. The sequential activation of these coagulation factors ultimately leads to the formation of fibrin, which is a critical component in stabilizing the hemostatic plug. Thrombin when generated, plays a pivotal role in hemostasis, via both fibrin conversion and platelet activation.
- Current data suggest that high-dose FVIIa can enhance thrombin generation when normal levels of all of the coagulation factors are present. FVIIa on the platelet surface generates additional FX (and probably FIXa), so that thrombin generation is significantly increased. This observation may account for the efficacy of FVIIa in patients with thrombocytopenia. With high-dose FVIIa, each platelet can produce more thrombin than it would normally. So even if there are fewer platelets at the site of an injury, each platelet that does localize is more efficient at generating thrombin. The following slides illustrate the interactive steps involved in hemostatic activation associated with TF-FVIIa activation. Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.
- Normal Hemostasis Current data suggest that high-dose FVIIa can enhance thrombin generation when normal levels of all of the coagulation factors are present. FVIIa on the platelet surface generates additional FX (and probably FIXa), so that thrombin generation is significantly increased. This observation may account for the efficacy of FVIIa in patients with thrombocytopenia. With high-dose FVIIa, each platelet can produce more thrombin than it would normally. So even if there are fewer platelets at the site of an injury, each platelet that does localize is more efficient at generating thrombin. Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.
- References: Andersen H. Greenberg DL. Fujikawa K. Xu W. Chung DW. Davie EW. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proceedings of the National Academy of Sciences of the United States of America. 96(20):11189-93, 1999. Camerer E. Huang W. Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proceedings of the National Academy of Sciences of the United States of America. 97(10):5255-60, 2000. Friederich PW. Levi M. Bauer KA. Vlasuk GP. Rote WE. Breederveld D. Keller T. Spataro M. Barzegar S. Buller HR. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation. 103(21):2555-9, 2001. . Hedner U. NovoSeven as a universal haemostatic agent. Blood Coagulation & Fibrinolysis. 11 Suppl 1:S107-11, 2000. . Pike AC. Brzozowski AM. Roberts SM. Olsen OH. Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proceedings of the National Academy of Sciences of the United States of America. 96(16):8925-30, 1999. . Siegbahn A. Cellular consequences upon factor VIIa binding to tissue factor. Haemostasis. 30 Suppl 2:41-7, 2000. . Wiiger MT. Pringle S. Pettersen KS. Narahara N. Prydz H. Effects of binding of ligand (FVIIa) to induced tissue factor in human endothelial cells. Thrombosis Research. 98(4):311-21, 2000.