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Anticoagulant Therapy Definition of Anticoagulation • Therapeutic interference ("blood-thinning") with the clotting mechanism of the blood to prevent or treat thrombosis and embolism. Overview • Indications • A basic case study • 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 and apheresis. A basic case study • • • • • 51 year old man Has severe osteoarthritis Required surgery on his right knee Underwent a total knee replacement 4 days after surgery complained of an increase in pain and swelling in the calf of the right leg • A doppler ultrasound demonstrated a thrombosis in the deep veins of the calf extending up to the popliteal vein. • Was started on 12 hourly injections of the low molecular weight heparin clexane given as subcutaneous injection • Simultaneously started on an oral tablet, warfarin, 5mg once per day. • Had daily blood tests to monitor the INR. • After 5 days, the INR had gone up to 2.2. The clexane was stopped and he was discharged from hospital to continue on warfarin 5mg daily. • He underwent INR testing every two weeks. • The warfarin was stopped after 3 months. He had no recurrence. Pertinent Questions from this case • • • • How do heparin drugs work? How does warfarin work? Why start both clexane and warfarin? What is an INR and how is heparin monitored? • What are the risks of both of these types of drugs? 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 seconds • Timing – 4-6 hours after commencing infusion – 4-6 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 Differences in Mechanism of Action • Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) • In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin • Less than half of the chains of LMWH are long enough Complications of Heparin • Haemorrhage • Heparin-induced thrombocytopaenia (HIT) • Osteoporosis (long-term only) Heparin-Induced Thrombocytopaenia • Most significant adverse effect of heparin after haemorrhage • Most common drug-induced thrombocytopenia • A large number of patients receive heparin in the hospital environment. Non-immune heparin-associated thrombocytopaenia (“HIT Type I”) • Benign • Up to 10% patients on heparin • Rapid decline in platelet count within first 2 days of heparin administration • Platelet count >100 000/ul • Returns to normal within 5 days despite continued heparin use (or within 2 days if heparin is stopped). Heparin-induced thrombocytopaenia: “HIT type 2” • Potentially catastrophic thrombosis (Heparininduced thrombocytopenia and thrombosis) • 8% of patients on heparin develop antibody without becoming thrombocytopenic • 1-5% patients on heparin develop thrombocytopaenia • Of those with thrombocytopaenia, 30% develop venous and/or arterial thrombosis • Bleeding uncommon Trreatment of HIT • Discontinue all heparin • If need to continue anti-coagulation, use danaparoid (orgaran). • Avoid platelet transfusions • Thrombosis: use danaparoid or thrombin inhibitor Vitamin K-Dependent Clotting Factors Vitamin K VII IX X II Synthesis of Functional Coagulation Factors Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII IX X II Warfarin Synthesis of Non Functional Coagulation Factors Warfarin Enhances Antithrombin Activity 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 test However: – Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred – Problem addressed by use of INR (International Normalised Ratio) INR: International Normalised Ratio • A mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastin reagents • INR is the PT ratio one would have obtained if the “reference” thromboplastin had been used • Allows for comparison of results between labs and standardises reporting of the prothrombin time INR Equation ( ) Patient’s PT in Seconds ISI INR = Mean Normal PT in Seconds INR = International Normalised Ratio ISI = International Sensitivity Index Target INR •DVT, PE, Atrial Fibrillation: 2-3 •Artificial Cardiac Valve: 3-3.5 Changing over from Heparin to Warfarin • May begin concomitantly with heparin therapy • Heparin should be continued for a minimum of four days – Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR) • When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days) Warfarin: Dosing & Monitoring • Start low – Initiate 5 mg daily – Educate patient • Stabilise – Titrate to appropriate INR – Monitor INR frequently (daily then weekly) • Adjust as necessary • Monitor INR regularly (every 1–4 weeks) and adjust Relative Contraindications to Warfarin Therapy • Pregnancy • Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy – Uncontrolled alcohol/drug abuse – Unsupervised dementia/psychosis Signs of Warfarin Overdosage • Any unusual bleeding: – Blood in stools or urine – Excessive menstrual bleeding – Bruising – Excessive nose bleeds/bleeding gums – Persistent oozing from superficial injuries – Bleeding from tumor, ulcer, or other lesion 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 Inhibitors – Ximelagatran, hirudin, bivalirudin, and argatroban • Synthetic pentasaccharide • Acivated Protein C • Tissue Factor Pathway Inhibitor (TFPI) Why do we need new anticoagulation drugs? • • • • • Heparin-induced thrombocytopenia Heparin prophylaxis is imperfect Heparin-associated osteoporosis Warfarin takes several days for its effect Warfarin is not as effective in some situations e.g antiphospholipid syndrome • Warfarin interacts with many other drugs • Warfarin is dangerous if not monitored Synthetic Pentasaccharide • • • • • E.g Fonaparinux Synthetic, single molecular entity Targets Factor Xa Does not cause thrombocytopenia Shown promise in DVT prevention during orthopedic procedures. • Also being examined in ischaemic heart disease Ximelagatran • Promising oral direct thrombin inhibitor • Converted to the active form melagatran in vivo • No dosing problems • No monitoring needed. • Recent atrial fibrillation study showed it to possibly be superior to warfarin. Enhances Ximelagatran Antithrombin Activity Conclusion • Anticoagulant therapy is use extensively. • Current mainstays of treatment are heparin or heparin-like drugs and oral warfarin. • Both have problems but when monitored closely are generally safe. • New anticoagulation drugs are arriving and in particular ximelagatran may revolutionise oral anticoagulation therapy