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CONTROL OF HEMOSTASIS

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CONTROL OF HEMOSTASIS

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    1. CONTROL OF HEMOSTASIS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

    2. SIMPLIFIED CLINICIAN’S VIEW OF HEMOSTASIS Platelet/coagulation factor activation Lots of exciting biochemistry CLOT Most clinicians who are not hematologists, blood bankers, or in related fields view hemostasis in a simplified manner. Hemostasis involved important interactions from multiple pathways to facilitate clot formation.Most clinicians who are not hematologists, blood bankers, or in related fields view hemostasis in a simplified manner. Hemostasis involved important interactions from multiple pathways to facilitate clot formation.

    3. COMPONENTS OF HEMOSTASIS Vasculature Coagulation proteins Platelets Three major pathways are involved in all hemostasis, and they include the vasculature, coagulation proteins, and platelets. Patients bleed due to abnormalities of one or any combination of these three factors.Three major pathways are involved in all hemostasis, and they include the vasculature, coagulation proteins, and platelets. Patients bleed due to abnormalities of one or any combination of these three factors.

    4. Hemostasis Hemostasis refers to the prevention of blood loss, and is accomplished by vasoconstriction and coagulation by cellular and coagulation factors. Undue bleeding is controlled and the fluidity of the blood is maintained by counterbalances within the coagulation and fibrinolytic systems. Blood vessel injury or disruption, platelet defects, abnormalities of the normally circulating anticoagulants and fibrinolytic mechanisms may upset the balance between fibrinolysis and coagulation. Blood normally circulates through endothelium-lined vessels without coagulation or platelet activation occurring and without appreciable hemorrhage. Injury to the endothelial cells triggers the hemostatic process, which typically begins with the attachment of platelets (“Adhesion”) to the damaged endothelium or exposed subendothelial proteins such as collagen and von Willebrand factor (vWf). The platelets then change form (“Activate”) and release factors that stimulate the clotting process. They also bind together (“Aggregate”). At the same time, plasma proteins may react with elements in the subendothelium, activating the “contact” phase of coagulation. Exposed fibroblasts and macrophages present tissue factor, a membrane protein, to the blood at the injured site, thereby triggering the “Extrinsic “phase of blood coagulation. Under normal conditions, hemostasis protects the individual from massive bleeding secondary to trauma. In abnormal states, life-threatening bleeding can occur or thrombosis can occlude the vascular tree. Hemostasis is influenced by a number of different factors including: (a) vascular extracellular matrix and alterations in endothelial reactivity, (b) platelets, (c) coagulation proteins, (d) inhibitors of coagulation, and (e) fibrinolysis. Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease, 5th ed. Philadelphia: W.B. Saunders, 1994 pp 99-106. 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 1B-1:1-5.Hemostasis refers to the prevention of blood loss, and is accomplished by vasoconstriction and coagulation by cellular and coagulation factors. Undue bleeding is controlled and the fluidity of the blood is maintained by counterbalances within the coagulation and fibrinolytic systems. Blood vessel injury or disruption, platelet defects, abnormalities of the normally circulating anticoagulants and fibrinolytic mechanisms may upset the balance between fibrinolysis and coagulation. Blood normally circulates through endothelium-lined vessels without coagulation or platelet activation occurring and without appreciable hemorrhage. Injury to the endothelial cells triggers the hemostatic process, which typically begins with the attachment of platelets (“Adhesion”) to the damaged endothelium or exposed subendothelial proteins such as collagen and von Willebrand factor (vWf). The platelets then change form (“Activate”) and release factors that stimulate the clotting process. They also bind together (“Aggregate”). At the same time, plasma proteins may react with elements in the subendothelium, activating the “contact” phase of coagulation. Exposed fibroblasts and macrophages present tissue factor, a membrane protein, to the blood at the injured site, thereby triggering the “Extrinsic “phase of blood coagulation. Under normal conditions, hemostasis protects the individual from massive bleeding secondary to trauma. In abnormal states, life-threatening bleeding can occur or thrombosis can occlude the vascular tree. Hemostasis is influenced by a number of different factors including: (a) vascular extracellular matrix and alterations in endothelial reactivity, (b) platelets, (c) coagulation proteins, (d) inhibitors of coagulation, and (e) fibrinolysis. Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease, 5th ed. Philadelphia: W.B. Saunders, 1994 pp 99-106. 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 1B-1:1-5.

    5. COAGULATION PATHWAYS

    6. Coagulation Pathways 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.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.

    7. Normal Hemostasis: Pivotal role of TF/VIIa 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.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.

    8. PLATELET ACTIVATION PATHWAYS

    9. Platelet Activation Pathways (1) 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. 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.

    10. As ADP, thrombin, and thromboxane as previously mentioned are some of the agonists that bind to a specific receptor site on the platelet and initiates intracellular signals that amplify platelet activation, recruit other platelets, and activate the fibrinogen binding site, namely the Gp IIb/IIIa complex which, once activated, undergoes a conformational change that allows fibrinogen to bind to the activated sites. The multivalent fibrinogen molecule attaches to the Gp IIb/IIIa complex on one platelet and links to other platelets that have been activated by ADP from the circulation or released from other activated platelets. Numerous platelets are bound together and form a platelet plug that serves as the nidus for further steps in the process of thrombus formation that result in the thrombin-mediated conversion of fibrinogen to fibrin and incorporation of red cells to form a thrombus that may become occlusive. At many of the steps in the cascade of reactions leading to platelet aggregation, there are potential opportunities to intervene and prevent platelet aggregation. Aspirin acts by inhibiting the enzyme cyclooxygenase, preventing the production of prostaglandin and thromboxane A2 from arachidonic acid.1 Thromboxane A2 and its proaggregatory inhibitor act to activate the Gp IIb/IIIa binding site on the platelet allowing fibrinogen binding. Prostaglandins and thromboxane A2 are released from the platelet and exert effects on other systems. Thus the effect of clopidogrel is specific, affecting the binding site for ADP, and does not involve production or inhibition of other active compounds.2 1. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-1294. 2. Herbert JM. Clopidogrel and antiplatelet therapy. Exp Opin Invest Drugs 1994;3:449-455.As ADP, thrombin, and thromboxane as previously mentioned are some of the agonists that bind to a specific receptor site on the platelet and initiates intracellular signals that amplify platelet activation, recruit other platelets, and activate the fibrinogen binding site, namely the Gp IIb/IIIa complex which, once activated, undergoes a conformational change that allows fibrinogen to bind to the activated sites. The multivalent fibrinogen molecule attaches to the Gp IIb/IIIa complex on one platelet and links to other platelets that have been activated by ADP from the circulation or released from other activated platelets. Numerous platelets are bound together and form a platelet plug that serves as the nidus for further steps in the process of thrombus formation that result in the thrombin-mediated conversion of fibrinogen to fibrin and incorporation of red cells to form a thrombus that may become occlusive. At many of the steps in the cascade of reactions leading to platelet aggregation, there are potential opportunities to intervene and prevent platelet aggregation. Aspirin acts by inhibiting the enzyme cyclooxygenase, preventing the production of prostaglandin and thromboxane A2 from arachidonic acid.1 Thromboxane A2 and its proaggregatory inhibitor act to activate the Gp IIb/IIIa binding site on the platelet allowing fibrinogen binding. Prostaglandins and thromboxane A2 are released from the platelet and exert effects on other systems. Thus the effect of clopidogrel is specific, affecting the binding site for ADP, and does not involve production or inhibition of other active compounds.2 1. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-1294. 2. Herbert JM. Clopidogrel and antiplatelet therapy. Exp Opin Invest Drugs 1994;3:449-455.

    11. CLOT FORMATION This scanning electron photomicrograph shows the actual clot formation. The fibrin "mesh" of cross-linked fibrin monomers can be seen as a white stringlike substance trapping red blood cells in a fresh clot.The red cells are not sticking together; they are being held together by fibrin. Much the same process occurs early in clot development, when platelet aggregates are held together by fibrinogen, which stabilizes the first hemostatic plug. Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of hemostasis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 6,13,14.This scanning electron photomicrograph shows the actual clot formation. The fibrin "mesh" of cross-linked fibrin monomers can be seen as a white stringlike substance trapping red blood cells in a fresh clot.The red cells are not sticking together; they are being held together by fibrin. Much the same process occurs early in clot development, when platelet aggregates are held together by fibrinogen, which stabilizes the first hemostatic plug. Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of hemostasis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 6,13,14.

    12. Fibrinolysis The presence of fibrin triggers the activation of plasminogen to plasmin, most likely through t-PA (tissue plasminogen activator). However, several activators may play a role. The activators, which function as enzymes, have been grouped into so-called intrinsic, extrinsic (HMWK = high molecular weight kininogen), and exogenous systems. Plasminogen is the target substrate of the activation systems and after cleavage becomes the active enzyme plasmin. Plasmin then splits fibrin and fibrinogen into fragments, which interfere with thrombin activity, platelet function, and fibrin polymerization, leading to clot dissolution. Streptokinase, unlike other activators, does not function as an enzyme during plasminogen activation-rather it forms a complex with plasminogen that exposes an active site capable of cleaving free plasminogen to plasmin. Tissue-type plasminogen activator (t-PA) is one of the two physiologic plasminogen activators present in human blood. It is a serine protease whose principal site of synthesis is the endothelial cell. Other cells of the hemopoietic system that produce t-PA are monocytes, megakaryocytes, and mesothelial cells. Bachman F. The plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1592, 1597-1600. Harker L, Mann K. Thrombosis and fibrinolysis. In: Verstraete M, Fuster V, Topol EJ. Cardiovascular thrombosis, 2nd ed. Philadelphia: Lippincott-Raven, 1998 pp 16-19.The presence of fibrin triggers the activation of plasminogen to plasmin, most likely through t-PA (tissue plasminogen activator). However, several activators may play a role. The activators, which function as enzymes, have been grouped into so-called intrinsic, extrinsic (HMWK = high molecular weight kininogen), and exogenous systems. Plasminogen is the target substrate of the activation systems and after cleavage becomes the active enzyme plasmin. Plasmin then splits fibrin and fibrinogen into fragments, which interfere with thrombin activity, platelet function, and fibrin polymerization, leading to clot dissolution. Streptokinase, unlike other activators, does not function as an enzyme during plasminogen activation-rather it forms a complex with plasminogen that exposes an active site capable of cleaving free plasminogen to plasmin. Tissue-type plasminogen activator (t-PA) is one of the two physiologic plasminogen activators present in human blood. It is a serine protease whose principal site of synthesis is the endothelial cell. Other cells of the hemopoietic system that produce t-PA are monocytes, megakaryocytes, and mesothelial cells. Bachman F. The plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1592, 1597-1600. Harker L, Mann K. Thrombosis and fibrinolysis. In: Verstraete M, Fuster V, Topol EJ. Cardiovascular thrombosis, 2nd ed. Philadelphia: Lippincott-Raven, 1998 pp 16-19.

    13. FIBRINOLYSIS

    14. Fibrinolysis Fibrinolysis pathway: Fibrinolysis plays an important role in the dissolution of thrombi and in maintaining the patency of vascular system. The fibrinolytic system removes thrombi by proteolytically degrading fibrin in soluble fragments. In this process plasmin is formed from plasminogen by the action of plasminogen activator. Plasmin cleaves fibrin to produce progressively smaller degradation products. KEY: t-PA = tissue plasminogen activator PG = plasminogen PL = plasmin FDP = fibrin degradation products Harker LA, Mann KG. Thrombosis and fibrinolysis. In: Fuster V, Verstraete M, Topol, eds. Cardiovascular thrombosis: thrombocardiology and thromboneurology, 2nd Ed. Lippincott-Raven 1998, pp 3-21. Fibrinolysis pathway: Fibrinolysis plays an important role in the dissolution of thrombi and in maintaining the patency of vascular system. The fibrinolytic system removes thrombi by proteolytically degrading fibrin in soluble fragments. In this process plasmin is formed from plasminogen by the action of plasminogen activator. Plasmin cleaves fibrin to produce progressively smaller degradation products. KEY: t-PA = tissue plasminogen activator PG = plasminogen PL = plasmin FDP = fibrin degradation products Harker LA, Mann KG. Thrombosis and fibrinolysis. In: Fuster V, Verstraete M, Topol, eds. Cardiovascular thrombosis: thrombocardiology and thromboneurology, 2nd Ed. Lippincott-Raven 1998, pp 3-21.

    15. CONDITIONS PRODUCING COAGULOPATHY

    16. Coagulopathy can prevent normal hemostatic mechanisms from functioning, including hemophilia where there are extremely low levels of factors VIII or IX. Also, inherited or acquired platelet disorders can occur following the use of antiplatelet agents including Plavix, ReoPro, Aggrastat, and Integrelin. The coagulopathy that occurs in patients with liver disease is of major concern because the key role the liver plays in producing the vitamin K dependent factors II, VII, IX and X. The coagulopathy of liver disease is quite complex and often very difficult to treat. Disseminated intravascular coagulation (DIC) is responsible for bleeding problems associated with complex bleeding disorders. Anticoagulation treatment with warfarin derivatives (coumadin and coumarin) produces a marked inhibition of II, VII, IX and X disorders. Coagulopathy can prevent normal hemostatic mechanisms from functioning, including hemophilia where there are extremely low levels of factors VIII or IX. Also, inherited or acquired platelet disorders can occur following the use of antiplatelet agents including Plavix, ReoPro, Aggrastat, and Integrelin. The coagulopathy that occurs in patients with liver disease is of major concern because the key role the liver plays in producing the vitamin K dependent factors II, VII, IX and X. The coagulopathy of liver disease is quite complex and often very difficult to treat. Disseminated intravascular coagulation (DIC) is responsible for bleeding problems associated with complex bleeding disorders. Anticoagulation treatment with warfarin derivatives (coumadin and coumarin) produces a marked inhibition of II, VII, IX and X disorders.

    17. The coagulopathy associated with liver disease is complex and involves many different factors, including decreased synthesis or dysfunction vitamin K dependent factors, fibrinolysis, platelet sequestration due to portal hypertension or other abnormalities, decreased synthesis of physiologic anticoagulants including antithrombin III, protein C and protein S.The coagulopathy associated with liver disease is complex and involves many different factors, including decreased synthesis or dysfunction vitamin K dependent factors, fibrinolysis, platelet sequestration due to portal hypertension or other abnormalities, decreased synthesis of physiologic anticoagulants including antithrombin III, protein C and protein S.

    18. HEMOSTASIS: ROLE OF FACTOR VII and TISSUE FACTOR

    19. FVIIa Mechanism of Action FVIIa Mechanism of Action This slide depicts a schematic model of the activation pathway of FVIIa in the absence of platelet surface FVIIIa and FIXa complex. Here FX activation by FVIIa/TF leads to platelet activation and cofactor activation. At high doses, FVIIa binds weakly to the surface of activated platelets, and on the platelet surface it can convert FX to FXa. This FXa remains associated with the platelet surface, where it can bind to FVa and generate sufficient thrombin for hemostasis. Because high-dose rFVIIa only activates factor X on activated platelets and not on resting platelets, the reaction is localized to the site of injury. Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.FVIIa Mechanism of Action This slide depicts a schematic model of the activation pathway of FVIIa in the absence of platelet surface FVIIIa and FIXa complex. Here FX activation by FVIIa/TF leads to platelet activation and cofactor activation. At high doses, FVIIa binds weakly to the surface of activated platelets, and on the platelet surface it can convert FX to FXa. This FXa remains associated with the platelet surface, where it can bind to FVa and generate sufficient thrombin for hemostasis. Because high-dose rFVIIa only activates factor X on activated platelets and not on resting platelets, the reaction is localized to the site of injury. Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.

    20. 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. 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.

    21. CONTACT ACTIVATION AND CARDIOPULMONARY BYPASS Cardiac surgery and cardiopulmonary bypass represent one of the most common methods by which contact activation and coagulopathy can be produced.Cardiac surgery and cardiopulmonary bypass represent one of the most common methods by which contact activation and coagulopathy can be produced.

    22. The contact of blood with the artificial surface of the bypass circuit activates inflammatory pathways. Proteolytic enzymes control these amplifying cascades, the vast majority of which are serine proteases. During bypass heparin is routinely given to inhibit the intrinsic pathway by activating the naturally occurring serine protease inhibitor, AT-III. A serine protease inhibitor such as aprotinin in a dose dependant fashion, inhibits the other cascades involving fibrinolysis, kinins and complement, thus impacting on the development and amplification of the systemic inflammatory response associated with CPB.The contact of blood with the artificial surface of the bypass circuit activates inflammatory pathways. Proteolytic enzymes control these amplifying cascades, the vast majority of which are serine proteases. During bypass heparin is routinely given to inhibit the intrinsic pathway by activating the naturally occurring serine protease inhibitor, AT-III. A serine protease inhibitor such as aprotinin in a dose dependant fashion, inhibits the other cascades involving fibrinolysis, kinins and complement, thus impacting on the development and amplification of the systemic inflammatory response associated with CPB.

    23. Contact Activation - The Role of Kallikrein The contact factor pathway is initiated when plasma factor XII (FXII) binds to the negatively charged surface of the bypass circuit. It is autoactivated to form FXIIa. Prekallikrein (PKK) circulates complexed with high molecular weight kininogen (HK) and HK is necessary to achieve surface bindingwhich brings PKK into close orientation with FXIIa. PKK is cleaved to kallikrein and kallikrein in turn, converts surface bound FXII to FXIIa. This reciprocal activation is a positive feedback loop and leads to very rapid mutual activation of FXII and kallikrein. Factor XI also binds to the negative charged surface via its HK moiety When sufficient FXIIa is formed as a result of reciprocal activation, FXIIa activates surface bound FXI to FXIa and the subsequent generation of thrombin HK is cleaved to liberate bradykinin. The contact factor pathway is initiated when plasma factor XII (FXII) binds to the negatively charged surface of the bypass circuit. It is autoactivated to form FXIIa. Prekallikrein (PKK) circulates complexed with high molecular weight kininogen (HK) and HK is necessary to achieve surface bindingwhich brings PKK into close orientation with FXIIa. PKK is cleaved to kallikrein and kallikrein in turn, converts surface bound FXII to FXIIa. This reciprocal activation is a positive feedback loop and leads to very rapid mutual activation of FXII and kallikrein. Factor XI also binds to the negative charged surface via its HK moiety When sufficient FXIIa is formed as a result of reciprocal activation, FXIIa activates surface bound FXI to FXIa and the subsequent generation of thrombin HK is cleaved to liberate bradykinin.

    24. Kallikrein plays a seminal role in the incitement and amplification of the inflammatory response. The foreign surface of the CPB circuit activates trace amounts of bound factor XII that in the presence of prekallikrein and surface-bound high-molecular-weight kininogen (HMW-kininogen) result in kallikrein production. Kallikrein greatly accelerates factor XII activation, and a positive feedback loop thus amplifies the intrinsic coagulation cascade. The potent action of kallikrein to liberate bradykinin from HMW-kininogen is an important reaction in relation to the whole-body inflammatory response to CPB. Bradykinin enhances vascular permeability, produces hypotension, contracts smooth muscle, causes pain, and releases tissue-type plasminogen activator (t-PA). Increases in vascular permeability can result in both diffuse and specific-organ edema. Kallikrein also converts plasminogen to plasmin, activates the complement system, liberates renin from prorenin, and primes neutrophils for chemotactic activity. Activation of both the kallikrein-kinin system and the complement cascade has been demonstrated in patients undergoing open heart surgery with CPB. Kallikrein plays a seminal role in the incitement and amplification of the inflammatory response. The foreign surface of the CPB circuit activates trace amounts of bound factor XII that in the presence of prekallikrein and surface-bound high-molecular-weight kininogen (HMW-kininogen) result in kallikrein production. Kallikrein greatly accelerates factor XII activation, and a positive feedback loop thus amplifies the intrinsic coagulation cascade. The potent action of kallikrein to liberate bradykinin from HMW-kininogen is an important reaction in relation to the whole-body inflammatory response to CPB. Bradykinin enhances vascular permeability, produces hypotension, contracts smooth muscle, causes pain, and releases tissue-type plasminogen activator (t-PA). Increases in vascular permeability can result in both diffuse and specific-organ edema. Kallikrein also converts plasminogen to plasmin, activates the complement system, liberates renin from prorenin, and primes neutrophils for chemotactic activity. Activation of both the kallikrein-kinin system and the complement cascade has been demonstrated in patients undergoing open heart surgery with CPB.

    25. ANTICOAGULANTS/ ANTITHROMBINS

    26. ANTITHROMBINS/ ANTICOAGULANTS Argatroban Bivalirudin (Angiomax) Hirudin: r-lepirudin, (Refludan) Low molecular weight heparin (LMWH)/Xa inhibitors Warfarin Levy JH: Novel IV antithrombins. Am Heart J 2001:141:1043 Multiple antithrombins/anticoagulants are currently available or under investigation. Recombinant hirudin (lepirudin [Refludan®]), bivalirudin (Angiomaxx®), and argatroban (Novastan®) are . The direct thrombin inhibitors that inhibit fibrin-bound thrombin, which is resistant to the ATIII-dependent inhibitors. Unfractionated heparin (UFH) is the only anticoagulant that can be acutely reversed by the use of protamine. Low-molecular-weight heparins (LMWHs) inactivate Factor Xa without prolonging contact activation (Factor XII) mediated hemostatic tests. During extracorporeal circulation, ATIII levels are significantly reduced and their responses to heparin are not linear, which suggests that ATIII may represent a potential therapeutic strategy in patients with heparin resistance. It is important to consider monitoring anticoagulation when novel IV antithrombins are administered. Clinical studies have used hemostatic tests originally designed for monitoring heparin, including the activated clotting time (ACT) and the activated partial thromboplastin time (aPTT), but these tests are not reliable measures of IV antithrombin activity. LMWH is best measured by anti-factor Xa activity, and its role in cardiovascular medicine is rapidly growing. Reference: Levy JH: Novel intravenous antithrombins. Am Heart J. 2001 Jun;141(6):1043-7. Multiple antithrombins/anticoagulants are currently available or under investigation. Recombinant hirudin (lepirudin [Refludan®]), bivalirudin (Angiomaxx®), and argatroban (Novastan®) are . The direct thrombin inhibitors that inhibit fibrin-bound thrombin, which is resistant to the ATIII-dependent inhibitors. Unfractionated heparin (UFH) is the only anticoagulant that can be acutely reversed by the use of protamine. Low-molecular-weight heparins (LMWHs) inactivate Factor Xa without prolonging contact activation (Factor XII) mediated hemostatic tests. During extracorporeal circulation, ATIII levels are significantly reduced and their responses to heparin are not linear, which suggests that ATIII may represent a potential therapeutic strategy in patients with heparin resistance. It is important to consider monitoring anticoagulation when novel IV antithrombins are administered. Clinical studies have used hemostatic tests originally designed for monitoring heparin, including the activated clotting time (ACT) and the activated partial thromboplastin time (aPTT), but these tests are not reliable measures of IV antithrombin activity. LMWH is best measured by anti-factor Xa activity, and its role in cardiovascular medicine is rapidly growing. Reference: Levy JH: Novel intravenous antithrombins.Am Heart J. 2001 Jun;141(6):1043-7.

    27. LMWH Anti-Xa activity greater than AT activity, purified from UFH, MWt 4500-6000 Long duration of action, not reversible with protamine Included enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep)

    28. Thrombin Inactivation: Heparin Heparin molecules vary according to a number of different factors including molecular weight, length, constituents, sulfation and charge. All of these factors contribute to functional heterogeneity between heparin molecules. The molecular weight and net charge (degree of sulfation) of heparin molecules are the factors that largely determine protein binding and heparin pharmacokinetics. Both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) exert their anticoagulant activity by activating ATIII(antithrombin). This interaction with ATIII is mediated by a unique pentasaccharide sequence which is randomly distributed along the heparin chains. This binding sequence of the pentasaccharide to ATIII causes a conformational change in the ATIII that accelerates its interaction with thrombin and Xa (activated factor X) by about 1000 times. After this sequence has been completed, UFH or LMWH dissociates from ATIII and is available to activate further ATIII molecules. The main difference between UFH and LMWH is their relative inhibitory activity against Xa and thrombin. Any pentasaccharide-containing heparin chain can inhibit the action of Xa by binding to ATIII and causing a conformational change. However, to inactivate thrombin, heparin must bind to both ATIII and thrombin forming a ternary complex. This ternary complex can only be formed by pentasaccharide-containing heparin chains composed of at least 18 saccharide units. Most of the UFH chains are at least 18 saccharide units long; however, fewer than half of the LMWH chains have sufficient length to bind both ATIII and thrombin. Heparin molecules vary according to a number of different factors including molecular weight, length, constituents, sulfation and charge. All of these factors contribute to functional heterogeneity between heparin molecules. The molecular weight and net charge (degree of sulfation) of heparin molecules are the factors that largely determine protein binding and heparin pharmacokinetics. Both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) exert their anticoagulant activity by activating ATIII(antithrombin). This interaction with ATIII is mediated by a unique pentasaccharide sequence which is randomly distributed along the heparin chains. This binding sequence of the pentasaccharide to ATIII causes a conformational change in the ATIII that accelerates its interaction with thrombin and Xa (activated factor X) by about 1000 times. After this sequence has been completed, UFH or LMWH dissociates from ATIII and is available to activate further ATIII molecules. The main difference between UFH and LMWH is their relative inhibitory activity against Xa and thrombin. Any pentasaccharide-containing heparin chain can inhibit the action of Xa by binding to ATIII and causing a conformational change. However, to inactivate thrombin, heparin must bind to both ATIII and thrombin forming a ternary complex. This ternary complex can only be formed by pentasaccharide-containing heparin chains composed of at least 18 saccharide units. Most of the UFH chains are at least 18 saccharide units long; however, fewer than half of the LMWH chains have sufficient length to bind both ATIII and thrombin.

    29. Factor Xa Inactivation: LMWH/Heparin The majority of LMWH chains are unable to inactivate thrombin and rely predominately on their inactivation of Xa for their anticoagulant effect. However, in vivo, both UFH and LWMHs have been proven to be effective anticoagulants. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-698. Hirsh J, Warkentin TE, Raschke R, Granger CB, Ohman EM, Dalen JE. Heparin and low-molecular weight heparin. Chest 1998; 114::489s-510s. Clive K, Hirsh J. Heparin biochemistry, pharmacology, pharmacokinetics, and dose-response relationships. In: Ezekowitz MD, ed. Systemic cardiac embolism. New York:Marcel Dekker, 1994 pp 71-77.The majority of LMWH chains are unable to inactivate thrombin and rely predominately on their inactivation of Xa for their anticoagulant effect. However, in vivo, both UFH and LWMHs have been proven to be effective anticoagulants. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-698. Hirsh J, Warkentin TE, Raschke R, Granger CB, Ohman EM, Dalen JE. Heparin and low-molecular weight heparin. Chest 1998; 114::489s-510s. Clive K, Hirsh J. Heparin biochemistry, pharmacology, pharmacokinetics, and dose-response relationships. In: Ezekowitz MD, ed. Systemic cardiac embolism. New York:Marcel Dekker, 1994 pp 71-77.

    30. LMWH—Clinical Applications Prevention of DVT/PE In patients undergoing hip replacement, during & following hospitalization In patients undergoing knee replacement In patients undergoing abdominal surgery who are at risk of TE complications Treatment of DVT/PE Ischemic complications of unstable angina and non-Q wave MI Not all LMWH products have the same indications. Patients undergoing abdominal surgery who are at risk include: ? Those over 40 years ? Obesity ? General Anesthesia longer than 30 minutes ? Those with malignancy ? Those with history of DVT/PE Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Normiflo® (Ardeparin Sodium Injection, USP), Prescribing Information (undated), Wyeth-Ayerst Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc. Not all LMWH products have the same indications. Patients undergoing abdominal surgery who are at risk include: ? Those over 40 years ? Obesity ? General Anesthesia longer than 30 minutes ? Those with malignancy ? Those with history of DVT/PE Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Normiflo® (Ardeparin Sodium Injection, USP), Prescribing Information (undated), Wyeth-Ayerst Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc.

    31. Biological Consequences of Reduced Binding of LMWH to Proteins and Cells Compared with UFH, LMWHs have the following: 1. Reduced ability to catalyze inactivation of thrombin because the smaller fragments cannot bind to thrombin, but can still inactivate Xa. 2. Reduced nonspecific binding to plasma proteins which yields a more predictable dose response. 3. Reduced binding to macrophages and endothelial cells which tends to lead to an increased plasma half-life. 4. Reduced binding to platelets and PF4 which may lead to a lower incidence of HIT 5. Possibly reduced binding to osteoblasts resulting in less activation of osteoclasts and associated reduction in bone loss. Hirsh J, Warkentin TE, Raschke R, Granger CB, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin. Chest 1998;114:501s.Compared with UFH, LMWHs have the following: 1. Reduced ability to catalyze inactivation of thrombin because the smaller fragments cannot bind to thrombin, but can still inactivate Xa. 2. Reduced nonspecific binding to plasma proteins which yields a more predictable dose response. 3. Reduced binding to macrophages and endothelial cells which tends to lead to an increased plasma half-life. 4. Reduced binding to platelets and PF4 which may lead to a lower incidence of HIT 5. Possibly reduced binding to osteoblasts resulting in less activation of osteoclasts and associated reduction in bone loss. Hirsh J, Warkentin TE, Raschke R, Granger CB, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin. Chest 1998;114:501s.

    32. Heparin/LMWH—Adverse Effects Heparin Bleeding Thrombocytopenia Osteoporosis Hypersensitivity Bleeding still remains the most common side effect associated with heparin and LMWH. There has been reported a lower incidence of heparin-induced thrombocytopenia with LMWH. These findings may be due to the fact that LMWHs cause less activation of platelets and release of platelet factor 4 which yields fewer complexes. LMWH products should not be given to patients with HIT because there is a chance of cross-reactivity. When given for more than one month, unfractionated heparin can cause osteoporosis. The incidence of osteoporosis may be lower in patients given LMWH vs UFH. Weitz, Jeffrey I. Low-molecular-weight heparins. N Engl J Med.1997;337:688-698. Heparin (Heparin Sodium Injection, USP), Prescribing Information (1996), Eli Lilly & Co. Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc. Bleeding still remains the most common side effect associated with heparin and LMWH. There has been reported a lower incidence of heparin-induced thrombocytopenia with LMWH. These findings may be due to the fact that LMWHs cause less activation of platelets and release of platelet factor 4 which yields fewer complexes. LMWH products should not be given to patients with HIT because there is a chance of cross-reactivity. When given for more than one month, unfractionated heparin can cause osteoporosis. The incidence of osteoporosis may be lower in patients given LMWH vs UFH. Weitz, Jeffrey I. Low-molecular-weight heparins. N Engl J Med.1997;337:688-698. Heparin (Heparin Sodium Injection, USP), Prescribing Information (1996), Eli Lilly & Co. Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc.

    33. LMWH—Special Precautions When neuroaxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with LMWHs for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. Risk of these events is increased by the use of indwelling epidural catheters or concomitant use of NSAIDs, platelet inhibitors, or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment. Class labeling for all LMWHs. Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc.Class labeling for all LMWHs. Lovenox® (Enoxaparin Sodium Injection, USP), Prescribing Information (1997), Rhone-Poulenc Rorer. Fragmin® (Dalteparin Sodium Injection, USP), Prescribing Information (1997), Pharmacia & UpJohn Company. Orgaran® (Danaparoid Sodium Injection, USP), Prescribing Information (1998), Organon, Inc.

    34. Warfarin—Mechanism of Action The model in this slide provides a simplified explanation for the antagonism of clotting factor biosynthesis by warfarin. The cyclic interconversion of vitamin K from its vitamin K epoxide (KO) back to its hydroquinone (KH2) form, which occurs under normal physiological and dietary conditions, is disrupted in the presence of pharmacologically effective doses of warfarin. This metabolic disruption of the cycle results in decreased availability of the active cofactor form of vitamin K, vitamin K hydroquinone (KH2). The result is decreased presence of g-carboxyglutamic acid in the vitamin K-dependent clotting factors. Warfarin inhibits the enzymatic conversion (by reductases) of KO to its active cofactor form, KH2. This inhibition decreases the amount of KH2 available to participate in the conversion of prothrombin to its biologically active form. In order for prothrombin to have normal biological activity, between 10-13 glutamic acid (glu) residues must be converted to g-carboxyglutamic acid (gla) residues. This reaction requires the addition of a second carboxyl group (-COOH) to glutamic acid residues. Bovill EG, Mann KG, Lawson JH, Sadowski, J. Biochemistry of vitamin K: implications of warfarin therapy. In: Ezekowitz MD, ed. Systemic cardiac embolism. New York:Marcel Dekker, 1994 pp 31-54. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1567-1581.The model in this slide provides a simplified explanation for the antagonism of clotting factor biosynthesis by warfarin. The cyclic interconversion of vitamin K from its vitamin K epoxide (KO) back to its hydroquinone (KH2) form, which occurs under normal physiological and dietary conditions, is disrupted in the presence of pharmacologically effective doses of warfarin. This metabolic disruption of the cycle results in decreased availability of the active cofactor form of vitamin K, vitamin K hydroquinone (KH2). The result is decreased presence of g-carboxyglutamic acid in the vitamin K-dependent clotting factors. Warfarin inhibits the enzymatic conversion (by reductases) of KO to its active cofactor form, KH2. This inhibition decreases the amount of KH2 available to participate in the conversion of prothrombin to its biologically active form. In order for prothrombin to have normal biological activity, between 10-13 glutamic acid (glu) residues must be converted to g-carboxyglutamic acid (gla) residues. This reaction requires the addition of a second carboxyl group (-COOH) to glutamic acid residues. Bovill EG, Mann KG, Lawson JH, Sadowski, J. Biochemistry of vitamin K: implications of warfarin therapy. In: Ezekowitz MD, ed. Systemic cardiac embolism. New York:Marcel Dekker, 1994 pp 31-54. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1567-1581.

    35. Warfarin—Indications Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic complications associated with AF and/or cardiac valve replacement Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI Current indications for the use of warfarin. Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company. Current indications for the use of warfarin. Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.

    36. Elimination Half-Lives of Vitamin K-Dependent Proteins An anticoagulation effect generally occurs within 24 hours after drug administration. Peak effect may be delayed 72–96 hrs. The effect may be more pronounced as effect of daily maintenance doses overlap. These coagulation proteins are depleted at rates of their elimination half-lives. The anticoagulation effect is delayed until newly produced dysfunctional vitamin-K dependent clotting factors replace the existing normal ones as they are cleared from circulation. Anticoagulants have no direct effect on established thrombus. The goal of therapy is to reduce extension of the formed clot and secondary complications. Wittkowsky A. Warfarin pharmacology. In: Ansell J., Oertel L.& Wittkowsky A, eds. Managing oral anticoagulation therapy. Gaithersburg: Aspen, 1997 pp 4B-1:1-3. Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company. An anticoagulation effect generally occurs within 24 hours after drug administration. Peak effect may be delayed 72–96 hrs. The effect may be more pronounced as effect of daily maintenance doses overlap. These coagulation proteins are depleted at rates of their elimination half-lives. The anticoagulation effect is delayed until newly produced dysfunctional vitamin-K dependent clotting factors replace the existing normal ones as they are cleared from circulation. Anticoagulants have no direct effect on established thrombus. The goal of therapy is to reduce extension of the formed clot and secondary complications. Wittkowsky A. Warfarin pharmacology. In: Ansell J., Oertel L.& Wittkowsky A, eds. Managing oral anticoagulation therapy. Gaithersburg: Aspen, 1997 pp 4B-1:1-3. Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.

    37. Warfarin—Contraindications Risk of hemorrhage is greater than benefits of therapy Pregnancy Hemorrhagic tendencies or blood dyscrasias Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye Bleeding tendencies with active ulceration or overt bleeding Senility, alcoholism, psychosis or other lack of patient cooperation Spinal puncture and procedures with potential for uncontrollable bleeding Inadequate laboratory facilities The contraindications to warfarin are: ? Where the risk of hemorrhage is greater than the potential clinical benefits of therapy ? Pregnancy ? Hemorrhagic tendencies or blood dyscrasias ? Traumatic surgery resulting in large open surfaces, recent or contemplated surgery of the central nervous system or eye ? Bleeding tendencies associated with active ulceration or overt bleeding of (1) gastro-intestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; or bacterial endocarditis ? Unsupervised patients with senility, alcoholism, psychosis or other lack of patient cooperation ? Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding ? Inadequate laboratory facilities Also included are: ? Threatened abortion, eclampsia and preeclampsia ? Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.The contraindications to warfarin are: ? Where the risk of hemorrhage is greater than the potential clinical benefits of therapy ? Pregnancy ? Hemorrhagic tendencies or blood dyscrasias ? Traumatic surgery resulting in large open surfaces, recent or contemplated surgery of the central nervous system or eye ? Bleeding tendencies associated with active ulceration or overt bleeding of (1) gastro-intestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; or bacterial endocarditis ? Unsupervised patients with senility, alcoholism, psychosis or other lack of patient cooperation ? Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding ? Inadequate laboratory facilities Also included are: ? Threatened abortion, eclampsia and preeclampsia ? Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.

    38. Warfarin—Adverse Effects Fatal or non-fatal hemorrhage from any tissue or organ Necrosis of skin and other tissues Other adverse reactions reported less frequently include: Systemic cholesterol microembolization Alopecia Purple toes syndrome, urticaria, dermatitis including bullous eruptions The adverse effects associated with warfarin are: ? Fatal or non-fatal hemorrhage from any tissue or organ ? Necrosis of skin and other tissues ? Other adverse reactions reported less frequently include: ? Body as a whole—pain, edema, asthenia, hypersensitivity/allergic reactions, fever, headache, malaise ? Central and peripheral nervous system—dizziness, paresthesia ? Gastrointestinal—nausea, diarrhea, abdominal pain, vomiting ? Liver and biliary—elevated liver enzymes, hepatitis, jaundice, cholestatic hepatic injury ? Platelet, bleeding, and clotting—systemic cholesterol microembolization ? Skin and appendages—alopecia, rash pruritus, purple toes syndrome, urticaria, dermatitis including bullous eruptions ? Vascular, extracardiac—vasculitis Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.The adverse effects associated with warfarin are: ? Fatal or non-fatal hemorrhage from any tissue or organ ? Necrosis of skin and other tissues ? Other adverse reactions reported less frequently include: ? Body as a whole—pain, edema, asthenia, hypersensitivity/allergic reactions, fever, headache, malaise ? Central and peripheral nervous system—dizziness, paresthesia ? Gastrointestinal—nausea, diarrhea, abdominal pain, vomiting ? Liver and biliary—elevated liver enzymes, hepatitis, jaundice, cholestatic hepatic injury ? Platelet, bleeding, and clotting—systemic cholesterol microembolization ? Skin and appendages—alopecia, rash pruritus, purple toes syndrome, urticaria, dermatitis including bullous eruptions ? Vascular, extracardiac—vasculitis Coumadin® (Warfarin Sodium Tablets, USP) Crystalline, Prescribing Information (1998), DuPont Pharmaceuticals Company.

    39. LOVE=HEMOSTASIS Everybody talks about it, nobody understands it. JH Levy 2000 In summary, hemostasis and hemostatic mechanisms are complex physiologic responses that are important for clinicians to understand when managing critical ill patients.In summary, hemostasis and hemostatic mechanisms are complex physiologic responses that are important for clinicians to understand when managing critical ill patients.

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