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

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

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

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 Normal Hemostasis is a complex interaction between vessel wall, platelets, plasmatic coagulation, and fibrinolysis. Fibrinogen is in the key position of coagulation cascade and fibrinolytic pathway. It is essential that one should have a clear understanding of the New CV drugs of armamentarium in the managemnt of perioperative hemostasis. Jay kambam

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

VESSEL WALL - ENDOTHELIUM

VESSEL WALL - ENDOTHELIUM
Vessel injury or FB/Stent, low flow Thrombogenic Antithrombogenic (Favors fluid blood) (Favors clotting) Endothelium is a highly sophisticated organ that possesses both thrombogenic and antithrombogenic properties. Anticoagulants Procoagulants Jay kambam

VESSEL WALL Endothelin, Collagen, tPAI, vWF, Factors, PL
Prostacyclin, NO, ADPase, tPA, Heparin, Thrombomodulin Endothelin Reflex vasoconstriction Collagen Basement Membrane = Very thrombogenic in the absence of endothelium UNINJURED ENDOTHELIUM: Nonthrmbogenic INJURED ENDOTHELIUM: Thrombotic Jay kambam

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

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 Thrombin facilitates fibrinogen to fibrin Va and VIIIa = Key steps in coagulation Jay kambam

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 TPAI = bocks plasminogen conversion to plasmin Collagen: 1st Hemo Plug FIII, PL: 2nd Hemo plug

VASOCONSTRICTION Serotonin causes vasoconstriction
Endothelin - Reflex vasoconstriction Collagen release --- vWF --- Platelets attraction UNINJURED ENDOTHELIUM: Nonthrmbogenic INJURED ENDOTHELIUM: Thrombotic Serotonin causes vasoconstriction Jay kambam

First Hemostasis Plug PLATELETS

Dense Granule Alpha Granule
Fig: Structure of Platelet. Contents of platelet secretary granules and their physiological activities Dense Granule Alpha Granule Jay kambam

Contents of platelet secretary granules and their physiological activities
Secretary Granules Physiological activities 1.Alpha Granules Coagulation factors I & V Cofactors for coagulation cascade Platelet specific proteins Platelet F PF4 potentiates ADP induced aggregation & antiheparin activity Low affinity PF4 LA-PF4 possesses antiheparin actvty Glycoproteins Adhesion and cell to cell interaction 2.Dense Granules ADP and ATP ADP stimulates aggregation & secretion Calcium Promotes coagulation Serotonin Vasoconstriction Contents of platelet secretary granules and their physiological activities: Secretary granules and contents Physiological activities Alpha Granules Coagulation factors I & V cofactors for coag cascade Platelet specific proteins Platelet F PF4 potentiates ADP induced aggregation & antihep activity low affinity PF4 (BTG) LA-PF4 possesses antihep actvty Cationic proteins permeability factor increases endothelial permblty chemical factor attracts leukocytes Glycoproteins cell adhesion and cell to cell interaction Jay kambam

Adhesion, Activation, Aggregation (AAA)
Platelet Steps: 1 – 5 + collagen & vWF Collagen, ADP, TXA2, and vWF -- Thrombogenic Plasma vWF binds to collagen and uncoils Adhesion of platelets to vWF and collagen Tethering and rolling of platelets Platelets become activated and aggregated Rlease of TxA2, ADP, and vWF recruit and activate additional platelets Activation of GPIIb/IIIa receptors enabling the interplatelet connection with fibrinogen Activated platelets provide a highly efficient surface for activated coagulation factors enabling the thrombin burst Adhesion, Activation, Aggregation (AAA) Jay kambam

PLATELET FUNCTION AGGREGATION
GPIIb/IIIa - fibrinogen interaction Key step for hemostasis, part of final common pathway Therapeutic target of inhibitors ASA – Tx A inhibitor Theinopyridines – ADP inhibition GIIb/IIIa inhibition Jay kambam

Platelet Activation Pathways
Collagen Thrombin PAR-4 ADP Epinephrine Arachidonic acid P2Y12 TxA2 Surgery: Collagen, epinephrine, thrombin, and ADP from platelets GP1b vWF Fibrinogen GP1b vWF GP IIb/IIIa Fibrinogen Jay kambam

Jay kambam

Second Hemostasis Plug
PLASMATIC COAGULATION

Factor Trivial Name(s) Pathway: Intrinsic/Extrinsic
Fibrinogen Both II Prothrombin III Tissue Factor Extrinsic IV Calcium V Proaccelerin, labile factor, accelerator (Ac-) globulin VI (same as Va) Accelerin VII Proconvertin, serum prothrombin conversion accelerator (SPCA), cothromboplastin VIII Antihemophiliac factor A, antihemophilic globulin (AHG) Intrinsic IX Christmas Factor, antihemophilic factor B,plasma thromboplastin component (PTC) X Stuart-Prower Factor XI Plasma thromboplastin antecedent (PTA) XII Hageman Factor XIII Protransglutaminase, fibrin stabilizing factor (FSF), fibrinoligase Jay kambam

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

Steps: 1 - 5 Jay kambam

FINAL STEPS - COAGULATION
Jay kambam

Platelet-Fibrin clot Jay kambam

Minimum Fibrinogen Levels
Fibrinogen concentrate Jay kambam

CRYOPRECIPITATE Jay kambam

Transfusion-associated Circulatory Overload (TACO)
Jay kambam

FIBRINOLYSIS plasminogen activators: r-tPA (Alteplase, Reteplase, Tenecteplase) • UPA (Urokinase, Saruplase) • Streptokinase# • Anistreplase • Monteplase

Fibrinolysis Plasminogen tPA (Tissue Plasminogen Activator) Plasmin
Also called as fibrin degredation products Plasmin Fibrin Fibrin Split Products (FSP) Jay kambam

FIBRINOLYSIS Jay kambam

Antifibrinolytics plasminogen activators: r-tPA (Alteplase, Reteplase, Tenecteplase) • UPA (Urokinase, Saruplase) • Streptokinase# • Anistreplase • Monteplase

Lysine Analog Lysine Analog: Tranaxemic acid, Amicar Jay kambam

€Aminocaproic acid & Tranexamic acid
Jay kambam

Anticoagulant and Antiplatelet Drugs

Anticoagulant and Antiplatelet Drugs Mechanism of action
Platelets Primary 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 cascade Secondary Hemostasis Plug Anticoagulants : Indirect Thrombin Inhibitors: Coumadin, Heparin Direct Thrombin Inhibitors: Lepirudin (Angiomax), Argatroban, Bivalirudin (Refludan), Dabigatran (Pradaxa) Jay kambam

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 Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors. Compared to clopidogrel, "prasugrel(trade name apagrel) inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI".[2] Clopidogrel, unlike prasugrel, was issued a black box warning from the FDA on March 12, 2010, as the estimated 2-14% of the US population that have low levels of the CYP 2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.[3][4] Prasugrel has not been shown to carry those same limitations. Jay kambam

Antiplatelet Drugs: Inhibition of
activation &/or aggregation TXA2 inhibitors ADP receptor inhibitors Jay kambam

GpIIb-IIIa inhibitors
Jay kambam

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

Thienopyridines: TICLOPIDINE, CLOPIDOGREL & PRASUGREL
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(P2Y12). Jay kambam

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

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

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 Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors. Compared to clopidogrel, "prasugrel(trade name apagrel) inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI".[2] Clopidogrel, unlike prasugrel, was issued a black box warning from the FDA on March 12, 2010, as the estimated 2-14% of the US population that have low levels of the CYP 2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.[3][4] Prasugrel has not been shown to carry those same limitations. Jay kambam

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

Jay kambam

Platelet Activation Pathways
Collagen Thrombin PAR-4 ADP Epinephrine Arachidonic acid P2Y12 TxA2 Surgery: Collagen, epinephrine, thrombin, and ADP from platelets GP1b vWF Fibrinogen GP1b vWF GP IIb/IIIa Fibrinogen Jay kambam

GP IIb/IIIa antagonist
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/IIIa receptors in unreceptive state Active Platelet Glycoprotein IIb/IIIa inhibitors are frequently used during percutaneous coronary interventions (angioplasty with or without intracoronary stent placement). They work by preventing platelet aggregation and thrombus formation. They do so by inhibition of the GpIIb/IIIa receptor on the surface of the platelets. They may also be used to treat acute coronary syndromes, without percutaneous coronary intervention, depending on TIMI risk. They should be given intravenously. The oral form is associated with increased mortality and hence should not be given. In integrin nomenclature glycoprotein IIb/IIIa is called αIIbβ3. Aggregating platelets Jay kambam

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

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

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

Anticoagulant and Antiplatelet Drugs
Platelets Primary Hemostasis Plug Antiplatelet Drugs: TxA2 Inhibitors: ASA Thienopyridines: Clopidogrel, Prasugrel, Ticlopidine; GP IIb/IIIa Antagonists: Tirofiban (Aggrastat), Eptifbatide (Integrelin), Abciximab (ReoPro) Coagulation cascade Secondary Hemostasis Plug Anticoagulants: Indirect Thrombin Inhibitors: Coumadin, Heparin Direct Thrombin Inhibitors: Lepirudin, Argatroban, Bivalirudin, Dabigatran Jay kambam

Anticoagulants: Direct & indirect antithrombin drugs
Inhibits production of thrombin or directly inhibit thrombin action Jay kambam

Indirect Thrombin Inhibitor Drugs:
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)* Jay kambam

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 g-carboxy glutamates = Gla This PTM requires vitamin K Jay kambam

HEPARIN - SOURCES Lungs Liver Intestinal mucosa Mast cells of RES
Bovine and Porcine Heparin can be found in the lungs, liver, intestinal mucosa, and in the mast cells of the reticuloendothelial system. Jay kambam

HEPARIN - STRUCTURE One of the strongest acids
Heavily sulfated polyanionic mucopolysaccharide Mol Wt: Daltons Similar to nucleic acids (Phosphates) Heparin is one of the strongest acids in the body, primarily because of its heavily sulfated polyanionic mucopolysaccharide structure. The molecular weight of heparin ranges from 6-25,000 daltons. Heparin and nucleic acids are very similar in structure. In nucleic acids the acid groups are phosphates, and in heparin they are sulfates. Jay kambam

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 min in normothermic bypass; prolonged with hypothermia Acute Side effects: vasodilatation ** ideal body weight Following systemic administration, the anticoagulation action of heparin begins immediately and peaks in two to five minutes. The small volume of distribution strongly implies that heparin distributes exclusively into the plasma compartment. However, the recent animal data suggest that there is also uptake into the reticuloendothelial system. Most normothermic patients maintain adequate anticoagulation during cardiopulmonary bypass for minutes after receiving 3-4 mg/kg of heparin. However, under hypothermia, this action of heparin is markedly prolonged. Jay kambam

HEPARIN - MECHANISM OF ACTION
Heparin is not a direct anticoagulant Heparin activates antithrombin III Heparin + antithrombin III (Beta Globulin) Heparin-antithrombin III complex (HATC) HATC induces anticoagulation by inhibiting four coagulation activating factors (aII, aIX, aX, and aXI). HATC, in particular, inhibits thrombogenic actions of activated thrombin (aII) and factor X (aX) Heparin, a polyanionic mucopolysaccharide induces anticoagulation by inhibiting four coagulation activating factors (aII, aIX, aX, and aXI). Most notably heparin activates antithrombin III . In sufficient concentrations, heparin binds to a beta globulin, antithrombin III, and potentiates its attraction to several substrates participating in the coagulation cascade. In particular, the heparin-antithrombin III complex inhibits the thrombogenic actions of activated thrombin (aII) and factor X (aX) . Jay kambam

HEPARIN RESISTANCE Heparin resistance is usually defined as failure to achieve a target ACT (>450 seconds) after administration of heparin up to 6 mg or 600 units/Kg body weight. Possible causes: a . ATIII deficiency (congenital or acquired) b. Arteriosclerotic disease c. Septicemia d. Pregnancy e. Birth control pills f. Liver disease g. Prolonged anticoagulant therapy h.Thrombocytosis i. Nephrotic Syndrome Jay kambam

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

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

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

Incidence of HIT 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. HIT is among the most serious immunopathologic reactions to drugs, occurring in up to 5% of patients treated with UFH. Up to 1% incidence of HIT is reported with the use of low molecular weight heparin (LMWH). Thromboses secondary to HIT are a serious and not uncommon sequelae. It is important to remember that not all patients who develop HIT antibodies develop clinical HIT. Gruel Y, Pouplard C, Nguyen P, et al. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121: Kelton JG. The clinical management of heparin-induced thrombocytopenia. Semin Hematol. 1999;36(suppl 1):17-21. Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol. 1997;56:12-16. Rice L, Attisha W, Drexler A, et al. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002;136(3): Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med. 1999;106: Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101: Warkentin TE. Heparin-induced thrombocytopenia. Part 1: The diagnostic clues. J Crit Illness. 2002;17(5): Warkentin TE, Sheppard J, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96(5): Warkentin TE, Roberts R, Hirsh J, et al. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002;136(3) Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med. 2003;163: Jay kambam

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)* * = not approved for HIT Jay kambam

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 The presence of thrombi concurrent with thrombocytopenia strongly suggests the presence of HIT. HIT is considered a “clinicopathologic” syndrome in that definitive diagnosis requires both clinical features and laboratory confirmation of the presence of heparin/PF4 antibodies. However, because of its prothrombotic nature, when clinical features suggest HIT, heparin administration should be discontinued immediately. An alternative anticoagulant should be used. Greinacher et al. Thrombosis Research In Press. While the immediate cessation of all forms of heparin therapy in cases of strongly suspected HIT is recommend, discontinuation of heparin alone is not adequate for treatment for HIT. Indeed, the highest risk for new, progressive, or recurrent thrombosis is during the first few days after stopping heparin. Accordingly, alternative, non-heparin, rapidly acting anticoagulant therapy should be initiated [as indicated] promptly once a clinical diagnosis of HIT has been made. When treatment was delayed pending laboratory confirmation of the diagnosis within a clinical trial setting, the incidence of new thrombosis was approximately 10-fold higher than during the period of treatment with direct thrombin inhibitor (DTI). Jay kambam Hirsh J, Heddle N, Kelton J. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med. 2004;164; Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med. 1999;106: Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost. 1999;82: Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol. 1998;35(suppl 5): 9-16. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101:

Dabigatran (Pradaxa) Direct thrombin inhibitor-oral 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

Dabigatran Discontinuation before surgery
Jay kambam

Anticoagulant and Antiplatelet Drugs Mechanism of action
Platelets Primary 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 cascade Secondary Hemostasis Plug Anticoagulants : Indirect Thrombin Inhibitors: Coumadin, Heparin Direct Thrombin Inhibitors: Lepirudin (Angiomax), Argatroban, Bivalirudin (Refludan), Dabigatran (Pradaxa) Jay kambam

Perioperative Hemostasis Optimize coagulation & reduce fibrinolysis
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

Stupid Monkey drinking my coffee
@Kilimanjaro, Kenya

HISTORICAL ACHIEVEMENTS
Heparin and protamine are the two most important drugs that made extracorporeal circulation possible during cardiac surgery. It is interesting to note that the actions of both these drugs were discovered accidentally. Friedrick Miescher in 1868 identified a nitrogenous base that was coupled to the acidic nuclear material of rhine salmon sperm; this coupled material is now called as protamine. Kossel in 1896 isolated protamines from various kinds of fish and suggested naming each protamine according to the species of fish from which it was isolated, for example, salmine from salmon; scombrine from mackerel; and clupeine from herring. In 1916, a medical student, Jay Mclean, accidentally discovered heparin's anticoagulant property while volunteering his own tissue extracts toward the advancement of science. Hagedorn in the 1930's demonstrated that protamine can delay the absorption of subcutaneously administered insulin and thus prolong its action. This important achievement of Hagedorn stimulated several investigators to look at the effect of protamine in prolonging the absorption of other compounds. Heparin was one of the compounds examined at that time. It is said that while Best in Toronto was testing long-acting insulin in depancreatized dogs, Jaques was working on heparin’s chemistry in the adjacent room. One evening in the 1930's when Jaques and his colleague McCutcheon mixed protamine with heparin, a precipitate that resembled a plastic appeared (the so called heparin-protamine complex). At about the same time in , Chargoff and Olson discovered heparin's antidote, again quite by surprise, when they were trying to develop a long acting heparin by adding protamine to heparin. Anaphylactic reactions to protamine were first reported by Walther in 1939. In 1973, Jacques and colleagues developed the heparin-protamine titration test.

Platelet Alterations During & After CPB
2. Changes Affecting Platelet Aggregation: a) Decreased ability of Platelet Aggregation to Agonists b) Platelets are Activated by CPB ( % Spent) c) Platelets bind to Monocytes and Neutrophils CPB is associated with activation of -platelets resulting in decreased number of platelets and depletion of its contents affecting platelet aggregation.

Platelet Alterations During & After CPB
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 CPB is associated with preactivation of platelets leading to Depletion of plasmin inhibitors (stored in platelets) which are critical to protecting the clot from lysis by plasmin

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

Heparin Manufacturing Process
Combine 5000 lbs intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 900 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 1000F for three days, then bring to boil. Filter solids and assay for heparin content.

Heparin source comparison
BOVINE LUNG PORCINE MUCOSAL Cost Less More Mol Wt (Daltons) , ,000 Chemical structure Shorter chains Longer chains Platelet aggregation Thrombin inhibition Less More Factor aX inhibition More Less Post op bleeding More Less Protamine requirement Less More Delayed thrombocytopenia

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

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

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

Achieving Perioperative Hemostasis

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