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Anticoagulants.ppt
This document discusses the physiology of coagulation and various anticoagulant and thrombolytic agents. It covers the intrinsic and extrinsic pathways of coagulation and the mechanisms of several common anticoagulants including heparin, low molecular weight heparins, warfarin, and direct thrombin and factor Xa inhibitors. It also addresses considerations for reversing anticoagulation with protamine or newer antidotes and managing patients on anticoagulants who require surgery or procedures.
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Anticoagulants.ppt
- 1.
- 2. Physiology ofCoagulation Anticoagulants ◦ Heparin/Protamine ◦ Low Molecular Weight Heparins ◦ Coumadin ◦ Thrombin Inhibitors ◦ Factor X Inhibitors ◦ Thrombolytic Agents ◦ Antiplatelet Agents Anesthetic Considerations The Patient on Warfarin? ◦ Neuraxial Anesthesia and Anticoagulants
- 3. Primary hemostasis ◦Constriction of blood vessels ◦ Platelet plug Secondary hemostasis ◦ Extrinsic pathway ◦ Intrinsic pathway ◦ Common final pathway
- 4. Vasoconstriction Plateletaggregation – primary hemostasis – weak plug Coagulation and fibrin formation – secondary hemostasis Fibrin clot Clot retraction Invasion by fibroblasts scar formation
- 10. First isolatedin 1922 Heparin requires a cofactor, antithrombin III to inhibit coagulation Heparin + ATIII inhibit ◦ IX, X, XIa, XIIa ◦ Indirectly suppresses thrombin induced activation V, VIII by binding thrombin ◦ t½ 1-2 h (altered renal, liver disease); onset immediate IV; SQ results in 1 to 2 hr delay. ◦ Not absorbed through GI tract.
- 11. Rx DVT,unstable angina: aPTT 1.5-2.5 x control Angioplasty, stinting: ACT 350 sec CPB (cardiac surgery): ACT 480 sec Substantial variability in patient response ◦ Heparin resistance due to ATIII deficiency ◦ Patients at risk: cardiac surgery, use of nitroglycerin infusion, nephrotic syndrome, cirrhosis, prolonged heparin infusion, DIC ◦ 4 fold variation in heparin sensitivity; 3 fold variation in rate in which it is metabolized.
- 12. Monitored withtest of intrinsic pathway: aPPT aPTT 1.5-2.5 control correlated with heparin levels of 0.2-0.7 U ml. Interventional cardiology seek ACT value 200- 400seconds or heparin concentration 1-3 U ml. Cardiac surgical procedures ACT > 400-500 seconds consistent with level of 3-8 U ml.
- 13. Follow IVadministration, peak effect 1 min; Following SQ onset 1 to 2 hours. Distribution limited by large molecular size to vascular space and endothelial system Eliminated by kidneys or by metabolism in reticuloendothelial system and liver. t½ dose dependent ◦ Low doses, 100-150 u/kg, 1 h ◦ CPB dose 350-400 u/kg 2 h; may persist 4-6 h without neutralization ◦ Average time 1-2 hr but increased with liver/renal disease or dose> 100u Kg. ◦ ACT used to monitor effect and reversal during CPB.
- 14. Boluses decreasesystemic vascular resistance ◦ Usually small, 10-20% ◦ May be greater and require vasopressors Rarely anaphylaxis During CPB ACT values for heparin anticoagulation can be misleading due to: 1 Hypothermia 2 Hemodilution Heparin induced thrombocytopenia (HIT)
- 15. Develops in5-28% patients Marked by a fall in platelet count after exposure to heparin Results from heparin’s proaggregatory effect on platelets Two subtypes
- 16. Type I ◦Rapid onset: 2-5 d ◦ Characterized by mild decrease in platelet count without thrombosis or immune response Type II ◦ Considerably more severe ◦ Occurs after more than 5 d administration (avg 9 d) ◦ Immune mediated ◦ Antibody binding between heparin-platelet complex ◦ Causes platelet activation, complement activation, white clot ◦ High morbidity Incidence thrombosis 20% Mortality after thrombosis 40%
- 18. Hirudin, thrombininhibitor derived from leech; Bivalirudin is synthetic peptide based on hirudin Not associated with immune thrombocytopenia Binds thrombin and does not depend on ATIII for anticoagulant activity Adm IV infusion; rapid onset, peak 4 h; t½ 4.5 h; activity persists 24 h; monitoring requires measurement and anti-Xa activity Monitor with ACT; DC 4-6 hr before surgery Indicated for patients at risk of HIT, unstable angina having PTCA.
- 19. Commercially preparedfrom fish sperm Initially combined with insulin to prolong its effect (NPH) Mechanism ◦ Produces strong ionic bond with heparin devoid of anticoagulant effects ◦ 1 mg protamine neutralizes 100 U of heparin ◦ Neutralize 5000 U administer 50 mg protamine ◦ Neutralization of heparin occurs in 5 mi
- 20. Protamine clearedby RES in 10-20 minutes. Clearance quicker than heparin. Heparin rebound is bleeding 30 min to 9 hrs after protamine administration. May be related to extravascular release of heparin from protein binding sites. RX: Clinical monitoring and small doses( 25 mg hr X 6 hr postop) protamine as indicated.
- 21. Always administerslowly ◦ Rate administration more important route ◦ Limit syringe boluses less 1 mg/kg or 20 mg/minute
- 22. Systemic hypotension10 min after administration indicates protamine Normal, low pulmonary pressure indicate rapid administration or anaphylactoid reaction Rx ◦ Rapid fluid administration ◦ Anaphylaxis: IVs, epinephrine, bronchodilators, steroids
- 23. Hypotension withrapid administration Noncardiogenic pulmonary edema Anaphylactoid reactions ◦ True allergy is uncommon ◦ Patient at risk Prior reaction to protamine – Allergy to fish – Exposure to NPH insulin – Allergy to any drug – Men who have had vasectomy? 1 Develop antibodies to sperm antigens including protamine. 2 Vasectomized men not at > risk from protamine. 3 22-33% have antiprotamine antibodies.
- 24. Increase PVR,RV failure, decreased CO, systemic hypotension Heparin-protamine complexes form thromboxane by pulmonary macrophages leading to vasoconstriction
- 25. Marked byhigh pulmonary pressures ◦ Inotropes pulmonary dilating properties ◦ Isuprel, milrinone Hemodynamic collapse: Return CPB
- 26. Always administerslowly Peripheral sites offer no advantage over central for diluted, slowly administered drug Only patients with prior history adverse response to protamine warrant special consideration Prior problem ◦ 1 mg/100 ml over 10 min ◦ Full dose if no response develops ◦ Skin test, little predictive value, frequently false positive
- 27. Excessive dose(600-800mg) has antiplatelet activity with increased bleeding. Administer 1-1.2 mg protamine for 100 U heparin or 0.5 mg for every 100U in last 4 hours. Cardiac Surgery 1 0.5-1 mg for every 100 U entire procedure. 2 1 mg protamine for every 100 U initially and during CPB. Monitor clinically and with Hepcon system.
- 28. Interfere productionVit K factors: II, VII, IX, X Factors II, X most important antithrombotic activity Onset 8-12 h; peak 36-72 h; normal hemostasis 1-3 d Lab tests ◦ PT and INR (International Normalized Ratio) most sensitive ◦ PT + INR: reflect primarily factor VII, X ◦ INR > 1.2: factor VII less 55% Factor activity level of 40% needed for normal hemostasis Recovery factor VII rapid; II, X slower Emergent situations: vit K, FFP, 4 factor PPC Variability in drug response
- 29. PCC tradename: Beriplex, Octaplex;Kcentra, Cofact. Contains FII,VII,IX,X plus protein C and S; also contains heparin. FDA approved April 30, 2013. Indicated to reverse coumadin in patients with: 1 INR>8; 2 prolonged prothrombin time, 3 raised d-dimer. 4 emergency operation in patient on coumadin. 5 deficiency of one of II,VII,IX,X factors.
- 30. Contraindicated withDIC: 1 Adding factors provides fuel for the fire (myth) 2 If factors are low, Kcentra may restore normal coagulation. Kcentra made of pooled plasma; requires lower volume than FFP to reverse coumadin. May be associated with thromboembolic events.
- 31. Fractions ofheparin, MW 2000-6000 Better bioavailability, longer duration: dosing qd or BID with transatlantic differences in dosing Given subcu Examples: Enoxaparin (Lovenox), Dalteparin(Fragmin), Binds ATIII to inhibit X; smaller effect on thrombin Effect prolonged in patients with renal failure t½ 4.5 h; activity persists 24 h; monitoring requires measurement anti-Xa activity Only partially antagonized by protamine; reverses only IIa activity
- 32. Pharmacological propertiesdiffer from UFH: 1Lack of monitoring of anticoagulant effect. 2 Prolonged half-life 3 Irreversibility with protamine. After SQ administration elimination T1/2 is 3-6 hrs. Anti-Xa levels peak at 3-5 hrs but significant anti-Xa activity still present 12 hours after injection.
- 33. Danapanoid orOrgaran Fondaparinax or Arixtra Rivanoxaban or Xarelto Apixban or Eliquis
- 34. Is approvednow in US, Canada,and Europe First available oral direct factor Xa inhibitor. Maximum inhibition occurs 4 hr after administration; onset within 30 min Effect lasts 8-12 Hr; Factor Xa activity does not return to normal for 24 hr. Dependent on renal elimination; avoid with CrCl<30ml/min.
- 35. Predictable pharmacokinetics Low potential for interaction with diet or alcohol No routine monitoring required Contraindicated in severe liver disease; hepatic metabolism. Contraindicated in severe hepatic disease (metabolism) and severe renal disease (elimination).
- 36. Reversibility aftercessation 24 hr depending on plasma concentration and elimination half life. No antidote available Brighton T Australian Prescriber Vol 33 (2): 38-41; 2010
- 37. Used forprevention thromboembolism. Direct factor Xa inhibitor FDA approved December 2012. Highly protein bound, reaches peak plasma concentration 2-3 hr, limited drug interactions. Given at 2.5 mg BID orally. Half-life in healthy subjects 8-15 hr.
- 38. Acts byantithrombin III inhibition of Xa. Administered SQ or IV q day. Rapidly and completely absorbed; peak steady state 3 hr; 94% bound to ATIII. Eliminated unchanged in urine in 72 hr with normal renal function. DC before surgery 2 days, longer with renal disease
- 39. This drugreversed anticoagulant activity of apixaban and rivaroxaban in healthy older patients within minutes of bolus and infusion. 1 Apixaban: 400 mg bolus; infusion 4, mg/min 2 hrs 2 Rivaroxaban: 800 mg bolus; 8 mg/min for 2 hrs. Andexanet is a specific, rapidly acting antidote being developed for urgent reversal factor Xa inhibitors. Siegal D M et al N Eng J Med 2015; 373:2413-24
- 40. Bivalirudin orAngiomax Desirudin or Revasc Argatroban or Acova Dibigatian or Pradaxa Lepirudin or Refludan (No longer on market)
- 41. IV, syntheticdirect thrombin inhibitor. Indicated for prophylaxis or Rx thrombus in patients at risk for HIT undergoing PCI. Half life 40 to 50 minutes; return to baseline 4 hours. Argatroban eliminated via liver; most other replacements for heparin in patients at risk for HIT eliminated by kidney. Monitored by aPTT or ACT. Stop 4-6 hours before surgery.
- 42. Analog ofhirudin approved for use in patients with HIT. Irreversibly inhibits thrombin. HIT patients receiving this drug develop antibodies requiring close monitoring a PTT to avoid bleeding complications. Drug prolonged in patients with renal dysfunction. Stop 24 hours before surgery
- 43. Analog ofhirudin administered SC. Direct thrombin inhibitor Approved for prevention DVT after total hip or knee replacement surgery. Being studied in patients with acute coronary syndrome or PTCA. Anaphylaxis reported but risk low. Primarily eliminated by kidney. Monitor by aPTT Hold 24 hours before surgery.
- 44. Direct oralcompetitive reversible thrombin inhibitor; inhibitor factor Xa Onset anticoagulation: 30 min Duration 24-36 hr Reversibility after cessation: 24-36 hr depending on plasma concentration, elimination half-life. No routine monitoring required but PTT and thrombin times can be used. Stop before surgery 48 hours normal renal function; 72-96 hours abnormal renal function.
- 45. Predictable pharmacokinetics. Low potential for interaction with diet or alcohol. Proton pump inhibitors inhibit absorption. No hepatic metabolism so safe with liver disease. Severe renal disease: > drug exposure, elimination half-life.
- 46. Metabolized byesterase-catalyzed hydrolysis. Renal, GI clearance. Dose: 1 Cr Cl. 30 ml/min 150 mg PO BID 2 Cr Cl < 15mL/min 75 mg PO BID Antidote now available.
- 47. Idarucizumab orPraxbind FDA approved in 2015 Humanized antibody fragment binds to pradaxa molecule reversing effect without interfering with coagulation cascade Approved for : 1 Emergency surgery/urgent procedures 2 Life threatening or uncontrolled bleeding. Following administration of 5 gm, complete reversal within minutes. In trials 1 thrombotic complication in 72 hours in a patient who did not have anticoagulants reinitiated. New England Journal Medicine RE-VERSE Ad Trial
- 48. Coumadin Pradaxa Dosage Varieswith INR 150 mg BID CrCl>30; 75 mg BID CrCl 15-30 Administration Tablet Capsule Onset 12-24 hr Within few hours Half-life 36 hours 12-17 hours Excretion Hepatic Renal Monitoring Yes; INR No Dietary Considerations No leafy green vegetables or food high in Vitamin K No Antidote Vitamin K Paxabind
- 49. Coumadin Pradaxa Drug InteractionsSeveral Avoid St John’s Wart, quinidine, rifampin Verapamil, amiodarone, clarithromycin Side Effects Bleeding, SOB, edema, allergic reactions Bleeding, GI disturbances, > risk MI, < risk intracranial bleed Cost .50 cents day, $15 month + INR cost $7 day, $210 month Procedural Points DC 5-6 days before Skip 2-8 doses depending renal function Age considerations > 75 increased risk cerebral bleed Caution in those <age 15 or over 75
- 50. If possible,DC Pradaxa 1-2 days (Cr Cl >50) or 3- 5 days (Cr Cl < 50) before invasive procedure. Consider longer time for patients having: 1 Major surgery 2 Spinal anesthesia 3 Epidural anesthesia
- 51. Assess ecarinclotting time (ECT) ECT better than PT, aPTT, thrombin time. If ECT not available, aPTT approximates Pradaxa activity. Brighton T Australian Prescriber Vol 33 (2) 38-41, 2010
- 53. Dabigatran Rivaroxban Apixaban MechanismDirect thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Time to peak effect(h) 1-3 2-4 1-3 Half like (h) 14-17 5-9 8-15 Dialyzable Yes No No Metabolism/excret ion 80% renally excreted 30% hepatic;35% renal excretion 15% hepatic; 25%renal excretion Coagulation tests affected aPTT PT PT Ecarin clotting time Antifactor X levels Antifactor X levels Thrombin time
- 54. Warfarin Dabigatran RivaroxabanApixban Oral activated charcoal No Yes likely likely Dialysis No Yes No No Vitamin K Yes No No No Fresh Frozen Plasma Yes Minimal Minimal Minimal Recombinant FVII Yes Possible Possible Possible 3-Factor Prothrombin Complex Concentrate(P CC) Likely Possible Possible Possible 4-Factor PCC yes Possible Possible possible
- 55. Drug Dose ClinicalStatus Indication Monitoring Hold Before Surgery Bivalirudin IV Available in US HIT; PTCA; ACT 4-6 hr Argatroban IV Available US and Europe HITPCT in HIT patients aPTT or ACT 4-6 hr Lepurdin IV Available in US and Europe HIT, prevention VTE aPTT 24 hr Desurdin SQ US and Europe Hip Surgery aPTT 24 hr Dabigatran Oral US and Europe Hip knee surgery; VTE,A fib Thrombin times, aPTT 48 hr normal renal function
- 56. Used forfull systemic anticoagulation. Activated protein C exerts antithrombotic effect factor Va/VIIIa. Also used in severe sepsis associated with organ dysfunction. DC 2 hr prior to invasive surgery or procedure with risk of bleeding. May reinstate 12 hours after invasive procedure if hemostasis achieved.
- 57. Prototype: Aspirin+ NSAIDs Mechanism of action ◦ Inhibit thromboxane by blocking cyclooxygenase ◦ Thromboxane A2 stimulator of platelet aggregation ◦ ASA irreversibly inhibits the enzyme Toxicity ◦ GI bleeding ◦ CNS effect ◦ Enhance effects other anticoagulants
- 59. Glycoprotein IIB/IIIAreceptor inhibitor agents Aspirin preparations Platelet-ADP-receptor antagonist agents Platelet adhesion inhibitor agents
- 63. Drug Site of Action Routet½ Metabolism Antidote Stop Before Procedure Prolonged PT/PTT Aspirin COX 1-2 Oral 20 min Hepatic 0 7 d No/No Dipyrida- mole Adenosine Oral 40 min Hepatic 0 24 h No/No Clopido- grel ADP Oral 7 h Hepatic 0 5 d No/No Ticlopidine ADP Oral 4 d Hepatic 0 10 d No/No Abciximab GP IIb/ IIIa IV 30 min Renal 0 72 h No/No Eptifiba- tide GP IIb/IIIa IV 2.5 h Renal 0 24 h No/No Tirofiban GP IIb/ IIIa IV 2 h Renal Hemo- dialysis 24 h No/No
- 64. Drug Site of Action Routet½ Metabolis m Antidote Stop Before Procedure Prolonged PT/PTT Piroxicam COX 1-2 Oral 50 h Hepatic 0 10 d No/No Indometh- acin COX 1-2 Oral/ supp 5 h Hepatic 0 48 h No/No Ketorolac COX 1-2 Oral/ IV 5-7 h Hepatic 0 48 h No/No Ibuprofen COX 1-2 Oral 2 h Hepatic 0 24 h No/No Naproxen COX 1-2 Oral 13 h Hepatic 0 48 h No/No Diclofenac COX 1-2 Oral 2 h Hepatic 0 24 h No/No Rofecoxib Celecoxib COX 2 Oral 10-17 h Hepatic 0 0 No/No
- 65. First Generation ◦Streptokinase ◦ Urokinase ◦ Streptase, Kabinase ◦ Abbokinas Second Generation ◦ Alteplase ◦ Anistreplase ◦ Prourokinase ◦ Activase ◦ Eminase Third Generation ◦ Reteplase ◦ Tenecteplase ◦ Lanoteplase ◦ Staphylokinase ◦ Antibody-targeted PAS ◦ Vampire bat-PA ◦ Alfimeprase ◦ Retavase ◦ TNKase
- 66. Drugs ◦ Alteplase ◦Reteplase ◦ Anistreplase ◦ Urokinase ◦ Streptokinase Mechanism ◦ Catalyze activation plasminogen to plasmin ◦ Plasmin is fibrinolytic enzyme Clinical Uses ◦ Emergency Rx thrombosis ◦ Give less 3 h Toxicity: bleeding
- 69. Absolute ◦ Anyhistory of hemorrhagic cerebrovascular event ◦ Any other cerebrovascular events within 1yr ◦ Active internal bleeding ◦ Known intracranial neoplasm ◦ Suspected aortic dissection
- 70. Relative ◦ Bloodpressure over 180/110 mmHg ◦ Anticoagulants & INR over 2 ◦ Prolonged cardiopulmonary resuscitation ◦ Prior gastrointestinal hemorrhage ◦ Pregnancy ◦ Menstruation ◦ Recent trauma (within 2-4 weeks) ◦ Major surgery within 3 weeks
- 71. Which surgicalprocedures can be performed without stopping warfarin Optimal times to stop and restart warfarin Use of heparin as a bridge to surgery Jaffer AK et al: Cleveland Clinic J Med 70;2003
- 72. Usually, surgeryis safe if the INR is < 1.5 If INR is 2-3, almost always falls to < 1.5 within 115 h or 4.8 d after last dose Neurosurgical procedures, some noncardiac surgeries, nearly normal (INR < 1.2 desired) Check INR immediately before surgery
- 73. Fresh frozenplasma Vitamin K ◦ If surgery must be done within 24-96 h ◦ High doses (5-10 mg) can cause PO resistance to warfarin ◦ Rx 1-2.5 mg, if pt to be started on PO anticoagulation ◦ Median time for reversal with 1 mg is 27 h (R 0.7-147 h) Recombinant activated factor VII (rFVII2) ◦ $3,500 for dose ◦ Cannot monitor or predict hemostatic efficacy
- 74. The reasonthe patient is taking warfarin The patient’s risk factors for thromboembolism How long the patient remains off anticoagulation therapy The degree of anticoagulation reversal The type of surgical procedure (this factor mainly determines the risk of venous thrombosis)
- 76. American Society ofRegional Anesthesia(ASRA) Consensus Conference on Neuraxial Anesthesia and Anticoagulation
Editor's Notes
- #5 hemostasis means prevention of blood loss The more severely a vessel is traumatized, the greater the degree of vascular spasm. The spasm can last for many minutes or even hours, during which time the processes of platelet plugging and blood coagulation can take place. The platelet-plugging mechanism is extremely important for closing minute ruptures in very small blood vessels that occur many thousands of times daily Scar formation 1-2 weeks