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Achieving Perioperative Hemostasis

Achieving Perioperative Hemostasis. Jay Kambam, MD, FACA Chief, Cardiac Anesthesia James A. Haley VA Medical Center Tampa, FL & Adjunct Professor of Anesthesiology USF, Tampa, FL & Vanderbilt University Medical Center Nashville, TN. NO DISCLOSURES. May 15, 2012.

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Achieving Perioperative Hemostasis

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  1. Achieving Perioperative Hemostasis Jay Kambam, MD, FACA Chief, Cardiac Anesthesia James A. Haley VA Medical Center Tampa, FL & Adjunct Professor of Anesthesiology USF, Tampa, FL & Vanderbilt University Medical Center Nashville, TN NO DISCLOSURES May 15, 2012

  2. PERIOPERATIVE HEMOSTASIS • Normal hemostasis is a complex interaction between vessel wall, platelet function, plasmatic coagulation, and fibrinolysis. • Causes of perioperative coagulopathy and bleeding are multifactorial • Because of PCI and Stents, multiple antiplatelet drugs and thrombin inhibitors are increasingly being used • Understanding the details of perioperative hemostasis and pharmacodynamics of drugs involving hemostasis is essential Jay kambam

  3. Hemostasis • Blood must be fluid • Must coagulate (clot) at appropriate time • Rapid • Localized • Reversible (fibrinolysis) Thrombosis…inappropriate coagulation (Examples: DVT, Stent Thrombosis) Jay kambam

  4. HEMOSTASIS:3 Major systems involved • Vessel wall vasoconstriction Endothelin • Platelets First Hemostasis Plug Adhesion, Activation, Aggregation (AAA) • Coagulation cascade Second Hemostasis Plug Coagulation factors Plasmin FSP Jay kambam

  5. Hemostasis Vessel Injury Collagen, vWF Endothelin PLATELET ADHESION VASOCONSTRICTION INITIAL RELEASE REACTION ADP SEROTONIN PLATELET AGGREGATION PHOSPHOLIPIDS INCREASED RELEASE REACTION ADP COAGULATION SECOND HEMOSTATIC PLUG FIRST HEMOSTATIC PLUG (FIBRIN PLUG) (PLATELET PLUG) FSP Platelet-fibrin clot Jay kambam

  6. VESSEL WALL - ENDOTHELIUM

  7. VESSEL WALL - ENDOTHELIUM Vessel injury or FB/Stent, low flow Thrombogenic Antithrombogenic (Favors fluid blood) (Favorsclotting) Anticoagulants Procoagulants Jay kambam

  8. VESSEL WALL Endothelin, Collagen, tPAI, vWF, Factors, PL Prostacyclin, NO, ADPase, tPA, Heparin, Thrombomodulin Jay kambam

  9. Antithrombotic Properties of Endothelium • Anti-platelet properties • Covers highly thrombogenic basement membrane • Uninjured endothelium does not bind platelets • PGI2 (prostacyclin) and NO from uninjured endothelium inhibit platelet binding (anti-Txa2) • ADPase counters the platelet aggregating effects of ADP Jay kambam

  10. Antithrombotic Properties of the Endothelium Anticoagulant & Fibrinolytic properties • Heparin like molecules: activate anti-thrombin III • Thrombomodulin(glycoprotein) - Antithrombin • Binds to thrombin • Decreases ability to produce fibrin • Increases ability to activate Protein C, which inactivates factors Va and VIIIa • Endothelial cells produce tPA which activates fibrinolysis via plasminogen to plasmin Jay kambam

  11. Prothrombotic Properties of Endothelium • Synthesis of von Willebrandfactor (vWF) • Release of collagen & tissue factor (FIII) • Production of plasminogen activator inhibitors (tPAI) • Membrane phospholipids bind and facilitate activation of clotting factors via Ca++ bridges

  12. VASOCONSTRICTION Serotonin causes vasoconstriction Jay kambam

  13. First Hemostasis Plug PLATELETS

  14. Dense Granule Alpha Granule Jay kambam

  15. Contents of platelet secretary granules and their physiological activities Secretary Granules Physiological activities 1.Alpha Granules Coagulation factors I & VCofactors for coagulation cascade Platelet specific proteins Platelet F4 PF4 potentiates ADP induced aggregation & antiheparin activity Low affinity PF4 LA-PF4 possesses antiheparinactvty Glycoproteins Adhesion and cell to cell interaction 2.Dense Granules ADP and ATPADP stimulates aggregation & secretion CalciumPromotes coagulation SerotoninVasoconstriction Jay kambam

  16. Adhesion, Activation, Aggregation (AAA) Jay kambam

  17. PLATELET FUNCTION AGGREGATION • GPIIb/IIIa- fibrinogen interaction • Key step for hemostasis, part of final common pathway • Therapeutic target of inhibitors Jay kambam

  18. Platelet Activation Pathways Collagen Thrombin PAR-4 ADP Epinephrine P2Y12 Arachidonic acid TxA2 GP1b vWF GP IIb/IIIa Fibrinogen Jay kambam

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  20. Second Hemostasis Plug PLASMATIC COAGULATION

  21. Hemostasis Vessel Injury Collagen, vWF Endothelin PLATELET ADHESION VASOCONSTRICTION INITIAL RELEASE REACTION ADP SEROTONIN PLATELET AGGREGATION PHOSPHOLIPIDS INCREASED RELEASE REACTION ADP COAGULATION SECOND HEMOSTATIC PLUG FIRST HEMOSTATIC PLUG (FIBRIN PLUG) (PLATELET PLUG) FSP Platelet-fibrin clot Jay kambam

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  23. Intrinsic pathway (PTT) XIIa Extrinsic Pathway (PT) XIa TF IIIa Prothrombin II IXa VIIa VIII VIIIa Xa V Va Soft clot Thrombin IIa Fibrinogen I Fibrin Hard clot XIIIa Fibrin Jay kambam

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  25. FINAL STEPS - COAGULATION Jay kambam

  26. Platelet-Fibrin clot Jay kambam

  27. Minimum Fibrinogen Levels Jay kambam

  28. CRYOPRECIPITATE Jay kambam

  29. Transfusion-associated Circulatory Overload (TACO) Jay kambam

  30. FIBRINOLYSIS

  31. Fibrinolysis Plasminogen tPA(Tissue Plasminogen Activator) Plasmin Fibrin Split Products (FSP) Fibrin Jay kambam

  32. FIBRINOLYSIS Jay kambam

  33. Antifibrinolytics

  34. Lysine Analog Jay kambam

  35. €Aminocaproic acid & Tranexamic acid Jay kambam

  36. Anticoagulant and Antiplatelet Drugs

  37. Anticoagulant and Antiplatelet DrugsMechanism of action • PlateletsPrimary Hemostasis Plug Antiplatelet Drugs: TxA2 inhibitors: ASA Thienopyridines(P2Y12/ ADP receptor Inhibitors ): Clopidogrel(plavix), Prasugrel(apagrel), Ticlopidine(Ticlid) GP IIb/IIIa Antagonists: Tirofiban (Aggrastat), Eptifibatide (Integrelin), Abciximab (ReoPro) • Coagulation cascadeSecondary Hemostasis Plug Anticoagulants : Indirect Thrombin Inhibitors: Coumadin, Heparin Direct Thrombin Inhibitors: Lepirudin(Angiomax), Argatroban, Bivalirudin(Refludan),Dabigatran(Pradaxa) Jay kambam

  38. ANTIPLATELET DRUGS - Mechanisms • Aspirin - Thromboxane A2 Inhibitors • Clopidogrel(Plavix) • Prasugrel(apagrel)Thienopyridines • Ticlopidine(Ticlid) • Aggrastat(tirofiban) • ReoPro(abciximab) GP IIb/IIIa Antagonists • Integrilin(eptifibatide) P2Y12/ADP Receptor Inhibitors Jay kambam

  39. Antiplatelet Drugs: Inhibition of activation &/or aggregation Jay kambam

  40. Jay kambam

  41. ASPIRIN • Inhibition of Thromboxane A2 production • Orally administered • Rapidly absorbed from GIT • Peak levels observed in about 30 minutes • Irreversible COX type 1 inhibitor • Chew and do! Jay kambam

  42. Thienopyridines:TICLOPIDINE, CLOPIDOGREL & PRASUGREL • Antiplateletagents are used to treat, prevent arterial thrombosis. • Thienopyridine derivatives, inactive in vitro, requiring metabolism to achieve in vivo activity. • Inhibit binding of ADP to platelet receptor(P2Y12). Jay kambam

  43. CLOPIDOGREL Prodrug (Thienopyridine) Administered only orally No direct antiplatelet activity Metabolized in the liver Active metabolite inhibits platelet aggregation Peak concentration of active metabolite is seen in 1 -2 hrs Metabolite binds to platelet P2Y12 receptor and irreversibly inhibits ADP-induced platelet aggregation Jay kambam

  44. PRASUGREL • Prodrug (Thienopyridine) • Ten to 100 times more potent than clopidogrel • Administered only orally • No direct antiplatelet activity • Metabolized in the liver more rapidly (levels 2 times higher) • Faster activity • Active metabolite inhibits platelet aggregation • Peak concentration of active metabolite is seen in 0.5 hr • Metabolite binds to platelet P2Y12 receptor and irreversibly inhibits ADP-induced platelet aggregation Jay kambam

  45. PLATELET INHIBITORS • Aspirin - Thromboxane A2 Inhibitors • Clopidogrel(Plavix) • Prasugrel(apagrel)Thienopyridines • Ticlopidine(Ticlid) • Aggrastat(tirofiban) • ReoPro(abciximab) GP IIb/IIIa Antagonists • Integrilin(eptifibatide) P2Y12/ADP Receptor Inhibitors Jay kambam

  46. GpIIb/IIIa ANTAGONISTS • Platelet GpIIb/IIIa receptors play a pivotal role in platelet-mediated thrombus formation, binding to fibrinogen,vWF & Collagen • IIb/IIIaantagonists differ in receptor affinity, reversibility, and specificity • GpIIb/GpIIIa antagonists more completely inhibit platelet aggregation than do ASA and Theinopyridines Jay kambam

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  48. Platelet Activation Pathways Collagen Thrombin PAR-4 ADP Epinephrine P2Y12 Arachidonic acid TxA2 GP1b vWF GP IIb/IIIa Fibrinogen Jay kambam

  49. GP IIb/IIIa Antagonists: Tirofiban (Aggrastat) Eptifibatide (Integrelin) Abciximab (ReoPro) GP IIb/IIIa antagonist Inhibition of platelet aggregation GP IIb/IIIa receptors occupied by antagonists Agonist Fibrinogen ADP, thrombin, collagen, epi Inactive platelet GP IIb/IIIareceptors in unreceptive state Active Platelet Aggregating platelets Jay kambam

  50. Glycoprotein IIb/IIIa inhibitors Tirofiban(Aggrastat) • Nonpeptide • KD 15 nmol/L • Indication: acute coronary syndrome Jay kambam

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