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Anticoagulant, Antiagregant Therapy Dr Inna Tzoran Thrombosis and Hemostasis Unit Rambam Madical Center Overview Indications Heparin/heparin like drugs and their complications Warfarin New anticoagulant drugs Indications of Anticoagulant Therapy Treatment and Prevention of Deep Venous Thrombosis Pulmonary Emboli Prevention of stroke in patients with atrial fibrillation, artificial heart valves, cardiac thrombus. Ischaemic heart disease During procedures such as cardiac catheterisation Standard Heparin Heterogenous mixture of polysaccharide chains MW 3k to 30k Active in vitro and in vivo Administration - parenteral- Do not inject IM - only IV or deep s.c. Half-life 1 - 2 hrs - monitor APTT Adverse effect - haemorrhage - antidote - protamine sulphate Enhances Antithrombin Activity Heparin mechanism of action Heparin Antithrombin III Thrombin Monitoring Heparin Activated Partial Thromboplastin Time (APTT)Normal range: 25-40 seconds Therapeutic Range: 55-70 secondsTiming4-6 hours after commencing infusion4-6 hours after changing dosing regimen Low Molecular Weight Heparin Changed management of venous thromboembolism Standard (Unfractionated) heparin 3k to 30k LMWH contains polysaccharide chains MW 5k Enriched with short chains with higher anti-Xa:IIa ratio Complications of Heparin HaemorrhageHeparin-induced thrombocytopaenia (HIT)Osteoporosis (long-term only) Vitamin K Synthesis of Functional Coagulation Factors VII IX X II Vitamin K-Dependent Clotting Factors Warfarin Synthesis of Non Functional Coagulation Factors Antagonism of Vitamin K Warfarin Mechanism of Action Vitamin K VII IX X II Enhances Antithrombin Activity Warfarin Warfarin: Major Adverse Effect—Haemorrhage Factors that may influence bleeding risk: Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of management Warfarin-induced Skin Necrosis Prothrombin Time (PT) Historically, a most reliable and “relied upon” clinical testHowever:Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurredProblem addressed by use of INR (International Normalised Ratio) Changing over from Heparin to Warfarin May begin concomitantly with heparin therapy Heparin should be continued until target INR for two days When INR reaches desired therapeutic range, discontinue heparin Warfarin: Dosing & Monitoring Start lowInitiate 5 mg dailyEducate patientStabiliseTitrate to appropriate INR Monitor INR frequently (daily then weekly)Adjust as necessaryMonitor INR regularly (every 1–2 weeks) and adjust Relative Contraindications to Warfarin Therapy Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy Uncontrolled alcohol/drug abuse Unsupervised dementia/psychosis Reversing action of warfarin Plasma Rapid but short-lasting Vitamin K Not rapid, but lasts 1-2 weeks. Do not use if wishing to restart warfarin within next week. New Anticoagulation Drugs Direct Thrombin InhibitorsPO: DabigatranIV: hirudin, bivalirudin, and argatrobanSynthetic pentasaccharideAcivated Protein CTissue Factor Pathway Inhibitor (TFPI)Factor Xa inhibitor PO: rivaroxaban, apixaban, edoxaban Synthetic Pentasaccharide Two doses available. Twice daily treatment. No monitoring needed. Recent studies showed it as good as or even superior to warfarin in atrial fibrillation and VTE treatment. Once/ twice daily No dose monitoring needed. As good as warfarin in efficacy and superior on safety in AF and VTE treatment Enhances Antithrombin Activity Dabigatran Rivaroxaban Apixaban Edoxaban Antiagregants Indications Ischemic heart disease primary and secondary prevention CVA PVD Atrial fibrilation to avoid CVA Aspirin COX-2 inhibitor side effects: gastritis, gastric ulcer Allergy Thrombocytopenia AD receptor inhibitor Side effects: Bleeding Thrombocytopenia allergy New antiplatelet agents AD receptor inhibitor: Prasugrel Ticagrelor Elinogrel