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Achieving Perioperative Hemostasis Jay Kambam, MD, FACA Chief, Cardiac Anesthesia James A. Haley VA Medical Center Tampa, FL & Adjunct Professor of Anesthesiology.

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Presentation on theme: "Achieving Perioperative Hemostasis Jay Kambam, MD, FACA Chief, Cardiac Anesthesia James A. Haley VA Medical Center Tampa, FL & Adjunct Professor of Anesthesiology."— Presentation transcript:

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2 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 May 15, 2012 NO DISCLOSURES

3 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

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

5 HEMOSTASIS: 3 Major systems involved Jay kambam

6 Vessel Injury Platelet-fibrin clot FSP Jay kambam Endothelin Collagen, vWF

7 VESSEL WALL - ENDOTHELIUM

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

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

10 Antithrombotic Properties of Endothelium Jay kambam

11  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

12 Prothrombotic Properties of Endothelium  Synthesis of von Willebrand factor (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

13 Jay kambam VASOCONSTRICTION Serotonin causes vasoconstriction

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15 Alpha Granule Dense Granule Jay kambam

16 Contents of platelet secretary granules and their physiological activities Jay kambam

17 Adhesion, Activation, Aggregation (AAA) Jay kambam

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

19 Platelet Activation Pathways Arachidonic acid TxA 2 GP IIb/IIIa Epinephrine Collagen Thrombin ADP P2Y12 PAR-4 GP1b vWF Fibrinogen Jay kambam

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22 Vessel Injury Platelet-fibrin clot FSP Jay kambam Endothelin Collagen, vWF

23 Jay kambam

24 Fibrinogen I Fibrin Thrombin IIa Prothrombin II VIIa TF IIIa IXa VIIIa XIa XIIa XIIIa Soft clot Fibrin Hard clot V VIII Jay kambam

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26 FINAL STEPS - COAGULATION Jay kambam

27 Platelet-Fibrin clot Jay kambam

28 Minimum Fibrinogen Levels Jay kambam

29 CRYOPRECIPITATE Jay kambam

30 Transfusion-associated Circulatory Overload (TACO) Jay kambam

31 FIBRINOLYSIS

32 FibrinFibrin Split Products (FSP) Plasmin Plasminogen tPA (Tissue Plasminogen Activator) Fibrinolysis Jay kambam

33 FIBRINOLYSIS Jay kambam

34 Antifibrinolytics

35 Lysine Analog Jay kambam

36 € Aminocaproic acid & Tranexamic acid Jay kambam

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39 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

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

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42 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

43 Antiplatelet agents 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( P2Y 12 ). Jay kambam

44 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

45 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

46 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

47 Gp IIb/IIIa ANTAGONISTS Platelet Gp IIb/IIIa receptors play a pivotal role in platelet-mediated thrombus formation, binding to fibrinogen,vWF & Collagen IIb/IIIa antagonists 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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49 Platelet Activation Pathways Arachidonic acid TxA 2 GP IIb/IIIa Epinephrine Collagen Thrombin ADP P2Y12 PAR-4 GP1b vWF Fibrinogen Jay kambam

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

51 Glycoprotein IIb/IIIa inhibitors Tirofiban (Aggrastat) Nonpeptide K D 15 nmol/L Indication: acute coronary syndrome Jay kambam

52 Glycoprotein IIb/IIIa inhibitors Eptifibatide (Integrelin) Cyclic peptide K D 120 nmol/L Acute coronary syndrome Jay kambam

53 Glycoprotein IIb/IIIa inhibitors Abciximab (ReoPro) Human/murine chimeric monoclonal antibody Fab K D 5 nmol/L Indication: PCI Jay kambam

54 Anticoagulant and Antiplatelet Drugs Jay kambam

55 Anticoagulants: Direct & indirect antithrombin drugs Anticoagulants: Direct & indirect antithrombin drugs Jay kambam

56 ANTICOAGULANTS  Indirect Thrombin Inhibitor Drugs: Vitamin K antagonists, Coumadin (in vivo only) Ca ++ chelators (in vitro only) –EDTA, Citrate, Oxalate Heparin (in vivo and in vitro)  Direct Thrombin Inhibitor Drugs:  Bivalirudin (Refludan), Lepirudin (Angiomax), Argatroban (Acova)  Dabigatran (Pradaxa)*  Indirect Thrombin Inhibitor Drugs: Vitamin K antagonists, Coumadin (in vivo only) Ca ++ chelators (in vitro only) –EDTA, Citrate, Oxalate Heparin (in vivo and in vitro)  Direct Thrombin Inhibitor Drugs:  Bivalirudin (Refludan), Lepirudin (Angiomax), Argatroban (Acova)  Dabigatran (Pradaxa)* Jay kambam

57 Role of vitamin K  Some clotting factors require a post-translational modification (PTM) before they are active in clotting  These factors are II, VII, IX, X  This PTM involves the addition of a COO- to certain Glu residues in the clotting factors  This PTM results in the formation of several  -carboxy glutamates = Gla  This PTM requires vitamin K Role of vitamin K  Some clotting factors require a post-translational modification (PTM) before they are active in clotting  These factors are II, VII, IX, X  This PTM involves the addition of a COO- to certain Glu residues in the clotting factors  This PTM results in the formation of several  -carboxy glutamates = Gla  This PTM requires vitamin K Jay kambam

58 HEPARIN - SOURCES Lungs Liver Intestinal mucosa Mast cells of RES Bovine and Porcine Jay kambam

59 HEPARIN - STRUCTURE  One of the strongest acids  Heavily sulfated polyanionic mucopolysaccharide  Mol Wt: 6000-25000 Daltons  Similar to nucleic acids (Phosphates) Jay kambam

60 HEPARIN - PROPERTIES  Action begins immediately  Peaks in 2 - 5 min  Distribution volume - small (plasma, RES)**  Dose: Adult 3-4mg/kg; Child: 1-3mg/kg  Duration of action - 60-90 min in normothermic bypass; prolonged with hypothermia  Acute Side effects: vasodilatation ** ideal body weight Jay kambam

61 HEPARIN - MECHANISM OF ACTION Jay kambam

62 HEPARIN RESISTANCE Jay kambam

63 HEPARIN RESISTANCE Since the likely cause is ATIII deficiency: the treatment options are: –Give ATIII 50 units /kg –and or 2-4 units of FFP Jay kambam

64 Heparin Induced Thrombocytopenia (HIT Syndrome)  Immune-mediated allergic reaction to heparin/platelet factor 4 complex  Thrombocytopenia:  Platelet count <150,000 or a 30% to 50% drop from baseline during heparin exposure  Onset 5 to 14 days after initiating heparin but can be earlier or later  With or without thrombotic complications at presentation  Diagnosis is clinical  Any type of heparin or route of administration can lead to HIT Jay kambam

65 Temporal Patterns of Thrombocytopenia in HIT Day 1Day 5Day 14 Day 30 Delayed- Onset HIT (9-40+ days) Rapid-onset HIT (hours-days) Typical-Onset HIT Mean day 9 (5-14 days) Heparin (re) Exposure THROMBOCYTOPENIA (± THROMBOSIS) Jay kambam

66  HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH)  Up to 1% incidence with low molecular weight heparin (LMWH)  Mortality rate of 22% to 28% has been reported in patients with HIT associated with thrombosis not treated with alternative anticoagulation. Jay kambam

67 HEPARIN ALTERNATIVES Direct Thrombin Inhibitors Bivalirudin (Refludan) Lepirudin (Angiomax) Argatroban (Acova) The best choice depends on patient’s health status (hepatic or renal function) Dabigatran (Pradaxa)* Jay kambam

68 Diagnosis and Management Decisions for HIT Current or recent heparin exposure with thrombocytopenia Presence of thrombosis or other characteristic sequelae If HIT is suspected, discontinue all forms of heparin IMMEDIATELY: Initiate alternative anticoagulant, as indicated Jay kambam

69 Dabigatran (Pradaxa)  Direct thrombin inhibitor-o ral anticoagulant, Half Life: 13-27hrs,  Does not require frequent blood tests for International normalized Ratio (INR) monitoring  Not highly protein bound, excreted 80% via kidneys & 20% via bile, partially through hemodialysis  There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event, unlike warfarin.  Dosage upto 150 mg twice daily?  The (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation  On February 14, 2011, the ACC & AHA added dabigatran to their guidelines for managment of non-valvular atrial fibrillation with a class I recommendation  aPTT (activated partial thromboplastin time), ECT (Ecarin clotting time), TT (Thrombin time) Jay kambam

70 Dabigatran Discontinuation before surgery Jay kambam

71 Vessel Injury Platelet-fibrin clot FSP Jay kambam Endothelin Collagen, vWF

72 Jay kambam

73  Normal hemostasis is a complex interaction between vessel wall, platelet function, plasmatic coagulation, and fibrinolysis.  Causes of perioperative coagulopathy and bleeding are multifactorial – Not addressed in this lecture  Fibrinogen is in the key position of coagulation cascade and fibrinolytic pathway.  Understanding the process of perioperative hemostasis and pharmacodynamics of drugs involving hemostasis is essential Jay kambam Perioperative Hemostasis Optimize coagulation & reduce fibrinolysis

74 Stupid Monkey drinking my coffee @Kilimanjaro, Kenya

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78 HISTORICAL ACHIEVEMENTS

79 2. Changes Affecting Platelet Aggregation: a) Decreased ability of Platelet Aggregation to Agonists b) Platelets are Activated by CPB (20- 30% Spent) c) Platelets bind to Monocytes and Neutrophils

80 3. Changes Affecting Clot resistance to Clot lysis by Plasmin: Preactivation of Platelets Leads to Depletion of Plasmin Inhibitors (stored in platelets) which are Critical to protecting the clot from lysis by the Plasmin

81 TICOLPIDINE/CLOPIDOGREL  In CAD stenting, ticlopidine reduces risk for subacute stent thrombosis  Clopidogrel reduces ischemic events with recent MI, stroke, or PVD  Clopidogrel + aspirin in stenting, is rapidly growing, given before stenting procedure  Bleeding variability for cardiac surgery relates to the duration of therapy

82 Heparin Manufacturing Process Combine 5000 lbs intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 90 0 F for 17 hrs. Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to adjust pH, and 235 gallons water. Bring to a boil then filter. Add 200 gallons hot water to filtrate and allow to stand overnight, then skim off the fat. Keep pancreatic extract at 100 0 F for three days, then bring to boil. Filter solids and assay for heparin content.

83 Heparin source comparison BOVINE LUNG PORCINE MUCOSAL CostLess More Mol Wt (Daltons) 5000-20,0006000-30,000 Chemical structure Shorter chainsLonger chains Platelet aggregation ++ + Thrombin inhibition Less More Factor aX inhibition More Less Post op bleeding More Less Protamine requirement Less More Delayed thrombocytopenia ++ +

84 Bivalirudin (Refludan) Half Life 25 min Reversal: None Metabolism: Renal > Hepatic Monitoring ACT, ECT (Ecarin Clotting Time ) Dosage 1.5 mg/kg bolus, then continuous infusion at 2.5 mg/kg /h Other: Titrate ACT > 500

85 Lepirudin (Angiomax) Half life: 30 min Reversal: None Metabolism: Hepatic > Renal Monitoring PTT, ACT Dosage 0.1 mg /kg bolus then 5-10 ug/kg/min Other: Incidence of Hypercoagulable state after DC the continuous infusion

86 Argatroban (Acova) Half life 80 min Reversal: None Metabolism: Renal Monitoring PTT, ECT (Ecarin Clotting Time) Dosage 0.25 mg/kg, then 0.5 mg /min infusion Other: Increase incidence of post-op bleeding. Incidence of anaphylaxis with the second exposure

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