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Reversal of antithrombotic agent
This document discusses the reversal of various antithrombotic agents, including antiplatelet drugs, anticoagulants, and thrombolytics. It provides information on the mechanisms of action, dosing, monitoring, and reversal strategies for aspirin, clopidogrel, unfractionated heparin, low molecular weight heparin, fondaparinux, warfarin, dabigatran, rivaroxaban, and thrombolytics. For elective procedures, most agents should be stopped 24-72 hours beforehand. For emergencies, the document outlines specific reversal agents like protamine, idarucizumab, factor concentrates, and transfusions when needed to rapidly reverse the
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Reversal of antithrombotic agent
- 1. Reversal Of AntithromboticAgents DR ANKIT GAJJAR MD,IDCCM,IFCCM,EDIC Consultant Intensivist at INS Hospital, Surat
- 2. Antithrombotic Agents • Antiplatelet drugs…. Aspirin, Clopidogrel • Anti coagulants Parenteral UFH LMWH…. Enoxaparin, Dalteparin Fondaparinux Oral Warfarin NOAC • Thrombolysis
- 3. Vascular Injury Exposure ofcollagen and vWF Tissue factor exposure Platelet adhesion and release Activation of coagulation Platelet recruitment and activation Thrombin generation Fibrin formationPlatelet aggregation Platelet – fibrin thrombus
- 4. • Drugs usedin thrombosis • Anticoagulants: drugs which prevent clotting by inhibiting clotting factors (coagulation process) (used in prevention and treatment of thrombosis). • Antiplatelets: drugs which prevent and inhibit platelet activation and aggression (used as prophylactic therapy in high risk patients). • Thrombolytics or Fibrinolytics: act by dissolving existing or already formed thrombi or emboli and used in the acute treatment of thrombosis. •
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- 6. The role ofplatelets
- 7. The role ofplatelets
- 8. The role ofplatelets
- 9. The role ofplatelets
- 10. Plaque Disruption Collagen vWF Plateletadhesion and secretion Aspirin Ticlopidine Clopidogrel Abciximab Eptifibatide Tirofiban Platelet aggregation Platelet recruitment and activation COX-1 ADP GPllb / llla activation X Mechanisms of action of antiplatelet drugs X TXA2
- 13. Antiplatelet Agents • Aspirin Irreversiblyinhibit COX 1 enzyme Rapid onset <1 hr Half life 15- 30 minutes 5-7 days for platelet recovery
- 14. Antiplatelet Agents • Clopidogrel •Irreversibly inhibit ADP receptor subtype P2Y12 receptor, required for platelet activation • Half life 8 hrs • 5 days for platelet recovery
- 15. Antiplatelet Agents • Mixingof Aspirin treated platelets ex-vivo, with 30-50 % untreated donor platelets, restored abnormal platelets aggregation response. So, infusion of 2-3 adult dose of donor platelets are effective in emergency reversal of aspirin in adults. Vilahur et al 2007 Li et al 2012 British journal of Haematology 2012, 160, 35-46
- 16. Antiplatelet Agents • Reversal Electivesurgery wait for 5-7 days For emergency surgery, replacement with platelet transfusion should be consider For conservative management, platelet transfusion is not recommended (risk/benefit ratio) Desmopressin (0.4 micrg/kg) can be consider spcifically in patient with Uremia No role of FFP and Protamine Dastur CK, Stroke and Vascular Neurology 2017
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- 22. UFH • Acts onintrinsic pathway • Inactivates IX, X, XI and XII and thrombin and inhibit conversion of fibrinogen to fibrin • Metabolized in liver and reticulo endothelial system • No Renal adjustment • Dose : 60-80 Unit/kg bolus f/b 12-18 Unit/kg/hr Px - 5000 Unit Bd / Tid • Monitoring by aPTT level • Does not affect Prothrombin Time
- 23. UFH • Shorter halflife 30-90 minutes • Reversal If stopped before 4 hours, no need of any reversal If infusion is going on, calculate last 2-2.5 hours of heparin and give protamine sulphate 1 mg/100 unit of heparin (maximum 50 mg) If dose unknown, give 50 mg of protamine 100 % reversal effect Mesure aPTT before OT No role of FFP or Vitamin K
- 24. LMWH • Enoxaparin andDalteparin • Inhibit factor X>II • Does not affect aPTT and PT level • Renal clearance, so dose adjustment in renal failure • Dose: Therapeutic - I mg/kg bid or 1.5 mg/kg od (1 mg/kg od in renal failure) Prophylactic – 40 mg sc od • No need of monitoring (factor Anti Xa level can be monitored in special case)
- 25. LMWH • Reversal For electivesurgery, stop before 24 hours For immediate reversal, - last dose < 8 hours – 1 mg protamine / 1 mg enoxaparin (additional 0.5 mg protamine / 1 mg enoxaparin can be used) - last dose 8-12 hours – 0.5 mg protamine / 1 mg enoxaparin 60 % reversal No use of FFP or Vitamin K
- 26. Fondaparinux • Indirect FactorXa inhibitor • Does not affect aPTT and PT • No need of monitoring • Renal clearance (C/I if CrCl < 30 ml/min) • Dose : Prophylactic : 2.5 mg sc od Therapeutic : < 50 kg 5 mg sc od 50-100 kg 7.5 mg sc od > 100 kg 10 mg sc od
- 27. Fondaparinux • Reversal Elective surgerystop before 24 hours No agent for immediate reversal Factor VIIa can be try
- 28. Warfarin • Inhibit VitaminK dependent factor II, VII, IX and X • Mesure PT for dose adjustment • Half life 36 hrs. • 5 days for INR to become normal • Target INR 2-3
- 29. Warfarin • For immediatereversal of INR • Inj vit K 10 mg iv with PCC or FFP • PCC – 4 factor or 3 factor PCC 1500-2000 IU Cost and availability Rapid and specific reversal • FFP – 15 – 20 ml/kg (6-8 units of FFP) Shorter duration of action large volume infusion and more complication Slow reversal than PCC Target INR <1.5
- 30. Warfarin • Factor VIIacan be used • No role of protamine sulphate
- 31. Warfarin • Supratherapeutic INRwithout bleeding • INR 5-9 – omit 1-2 dose+- 1.25 -5 mg PO vitamin K • INR >9 ( no bleed )- omit 1-2 dose +/- 2.5 - 5 mg PO vitamin K • Surgery Reversal INR > 1.5-2.5 hrs. • Sx <24 hrs – 0.5 -1 mg IV vit.K x1 +/- 5-8 ml/kg FFP • Sx 24-96 hrs- 0.5 -1 mg PO vitamin K INR > 2.5 – 5 • Sx <24 hrs – 1-2.5 IV Vitamin K +/- 5-8ml /kg FFP • Sx 24-96 hrs – 1-2.5 mg PO vitamin K
- 32. Warfarin • For electivesurgery • Stop warfarin before 5 days • Switch over to UFH / LMWH • Stop UFH / LMWH before surgery
- 33. Dabigatran • NOAC • Directthrombin inhibitor (Argatroban, bivalirudin) • Dose : 150 mg PO bd if CrCl 15-30 ml/min – 75 mg PO bd • No need of monitoring for therapeutic effect but Thrombin time will be elevated • No use of FFP or Protamine • Indication : Stroke prevention in non valvular AF
- 34. Dabigatran • Reversal • Forelective surgery, stop before 24 hours • For emergency reversal, Idarucizumab (Praxbind®) Infuse two 2.5 gram/50 mL vials undiluted over 5-10 minutes each - Second vial should be infused within 15 minutes of first vial • Activated Charcoal – within 1 hr. of Dabigatran • Dialysis – Last resort, removes 60% of dabigatran(mainly in renal failure) • 4 factor PCC (50 unit/kg) if Praxibind is not available • Factor VIIa can be tried • A normal aPTT and TT rules out clinically relavent Dabigatran effect.
- 35. Factor Xa inhibitors •Rivaroxaban, Apixaban, Edoxaban • Elective surgery – stop before 24 hours • Emergency reversal • If presenting within 2 hours of intake – activated charcoal • 4 factor PCC – 50 units / kg • Laboratory testing not helpful • Not dialysable
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- 37. Thrombolytic agents • Cryoprecipitate10 units • If fibrinogen <150 mg/dl post cryoprecipitate, consider additional cryoprecipitate • 6-8 unit of platelet concentrate • If cryoprecipitate not available, FFP can be given • If not available, than tranexamic acid 15-20 ml/kg
- 38. Protamine Sulphate • Protamineis basic in nature and combine with acidic heparin • Calculate dose • Maximum dose 50 mg (1 ampoule) • Severe Allergic reaction • Administration Dilute in 5 ml of sterile water Inject over 10 minutes
- 39. TAKE HOME MESSAGE DRUGElective Emergency Not indicated Monitoring Aspirin Clopidogrel Stop before 5-7 days Platelet concentrate Desmopressin (Uremia) FFP Vitamin K Protamine None UFH Stop before 4-6 hours Protamine Sulphate (100%) FFP Vitamin K aPTT LMWH Stop before 24 hours Protamine Sulphate (60 %) FFP Vitamin K Anti Xa level Fondaperinux Stop before 24 hours FVIIa FFP Vitamin K Protamine Anti Xa level Warfarin Stop before 5-7 days Vitamin K 4 PCC 50 Unit/kg FFP 15-20 ml/kg Protamine PT
- 40. Drug Elective EmergencyNot indicated Monitoring Dabigatran Stop before 24 hours Activated Charcoal Praxbind 5 gm 4 factor PCC Dialysis FFP Vitamin K Protamine TT aPTT Rivaroxaban Stop before 24 hours Activated Charcoal 4 factor PCC FFP Vitamin K Protamine Dialysis None Thrombolytics --- 10 Cryoprecipitate 6-8 RDP FFP ---- Fibrinogen
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