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1、Anticoagulant TherapyDefinition 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 drugsI
2、ndications 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 c
3、ase 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 exte
4、nding 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 clexa
5、ne 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 wa
6、rfarin?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
7、Adverse effect-haemorrhage-antidote-protamine sulphateEnhances Antithrombin ActivityHeparin mechanism of actionHeparinAntithrombin IIIThrombinMonitoring Heparin Activated Partial Thromboplastin Time(APTT)Normal range:25-40 seconds Therapeutic Range:55-70 seconds Timing 4-6 hours after commencing inf
8、usion 4-6 hours after changing dosing regimenLow 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 ratioDifferences in Mechanism of Action Any si
9、ze 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 enoughComplications of Heparin Haemorrh
10、age 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-ass
11、ociated 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 thr
12、ombocytopaenia:“HIT type 2”Potentially catastrophic thrombosis(Heparin-induced 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 arteri
13、al thrombosis Bleeding uncommonTrreatment of HIT Discontinue all heparin If need to continue anti-coagulation,use danaparoid(orgaran).Avoid platelet transfusions Thrombosis:use danaparoid or thrombin inhibitorVitamin K-Dependent Clotting FactorsAntagonismofVitamin KWarfarin Mechanism of ActionEnhanc
14、es Antithrombin ActivityWarfarinWarfarin:Major Adverse EffectHaemorrhage Factors that may influence bleeding risk:Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of managementWarfarin-induced Skin NecrosisProthrombin Time(PT)Historically,a mos
15、t reliable and“relied upon”clinical testHowever: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 mathem
16、atical“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 timeINR=International Normalised Ratio ISI=International Sensitivity IndexINR EquationTarget INRDVT,PE,Atrial Fibrillation:2-3Artificial Cardiac Valve:3-3.5Changing over from Heparin to Warfarin May begin concomitantly wi
