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1、Anticoagulant Therapy,Definition of Anticoagulation,Therapeutic interference(blood-thinning)with the clotting mechanism of the blood to prevent or treat thrombosis and embolism.,Overview,IndicationsA basic case studyHeparin/heparin like drugs and their complicationsWarfarinNew anticoagulant drugs,In
2、dications of Anticoagulant Therapy,Treatment and Prevention of Deep Venous ThrombosisPulmonary EmboliPrevention of stroke in patients with atrial fibrillation,artificial heart valves,cardiac thrombus.Ischaemic heart diseaseDuring procedures such as cardiac catheterisation and apheresis.,A basic case
3、 study,51 year old manHas severe osteoarthritisRequired surgery on his right kneeUnderwent 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
4、up to the popliteal vein.Was started on 12 hourly injections of the low molecular weight heparin clexane given as subcutaneous injectionSimultaneously 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
5、 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 warfari
6、n?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 chainsMW 3k to 30k Active in vitro and in vivoAdministration-parenteral-Do not inject IM-only IV or deep s.c.Half-life 1-2 hrs-monitor APTTAdverse
7、 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 infusi
8、on4-6 hours after changing dosing regimen,Low Molecular Weight Heparin,Changed management of venous thromboembolismStandard(Unfractionated)heparin 3k to 30kLMWH contains polysaccharide chains MW 5kEnriched with short chains with higher anti-Xa:IIa ratio,Differences in Mechanism of Action,Any size of
9、 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 thrombinLess than half of the chains of LMWH are long enough,Complications of Heparin,HaemorrhageHe
10、parin-induced thrombocytopaenia(HIT)Osteoporosis(long-term only),Heparin-Induced Thrombocytopaenia,Most significant adverse effect of heparin after haemorrhageMost common drug-induced thrombocytopeniaA large number of patients receive heparin in the hospital environment.,Non-immune heparin-associate
11、d thrombocytopaenia(“HIT Type I”),BenignUp to 10%patients on heparinRapid decline in platelet count within first 2 days of heparin administrationPlatelet count 100 000/ulReturns to normal within 5 days despite continued heparin use(or within 2 days if heparin is stopped).,Heparin-induced thrombocyto
12、paenia:“HIT type 2”,Potentially catastrophic thrombosis(Heparin-induced thrombocytopenia and thrombosis)8%of patients on heparin develop antibody without becoming thrombocytopenic1-5%patients on heparin develop thrombocytopaeniaOf those with thrombocytopaenia,30%develop venous and/or arterial thromb
13、osisBleeding uncommon,Trreatment of HIT,Discontinue all heparinIf need to continue anti-coagulation,use danaparoid(orgaran).Avoid platelet transfusionsThrombosis:use danaparoid or thrombin inhibitor,Vitamin K,Synthesis of Functional Coagulation Factors,VII,IX,X,II,Vitamin K-Dependent Clotting Factor
14、s,Warfarin,Synthesis of Non Functional Coagulation Factors,AntagonismofVitamin K,Warfarin Mechanism of Action,Vitamin K,VII,IX,X,II,Enhances Antithrombin Activity,Warfarin,Warfarin:Major Adverse EffectHaemorrhage,Factors that may influence bleeding risk:Intensity of anticoagulationConcomitant clinic
15、al disordersConcomitant use of other medicationsQuality 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-depend
16、ent clotting factors has occurredProblem 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 reagentsINR is the PT ratio one would have obtained if the“reference”thr
17、omboplastin had been usedAllows for comparison of results between labs and standardises reporting of the prothrombin time,(,),Patients PT in SecondsMean Normal PT in Seconds,INR=,ISI,INR=International Normalised Ratio ISI=International Sensitivity Index,INR Equation,Target INRDVT,PE,Atrial Fibrillat
18、ion:2-3Artificial Cardiac Valve:3-3.5,Changing over from Heparin to Warfarin,May begin concomitantly with heparin therapyHeparin should be continued for a minimum of four daysTime to peak antithrombotic effect of warfarin is delayed 96 hours(despite INR)When INR reaches desired therapeutic range,dis
19、continue heparin(after a minimum of four days),Warfarin:Dosing&Monitoring,Start lowInitiate 5 mg dailyEducate patientStabiliseTitrate to appropriate INR Monitor INR frequently(daily then weekly)Adjust as necessaryMonitor INR regularly(every 14 weeks)and adjust,Relative Contraindications to Warfarin
20、Therapy,Pregnancy Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapyUncontrolled alcohol/drug abuseUnsupervised dementia/psychosis,Signs of Warfarin Overdosage,Any unusual bleeding:Blood in stools or urineExcessive menstrual bleedingBruisingExcessive n
21、ose bleeds/bleeding gumsPersistent oozing from superficial injuriesBleeding from tumor,ulcer,or other lesion,Reversing action of warfarin,PlasmaRapid but short-lastingVitamin KNot rapid,but lasts 1-2 weeks.Do not use if wishing to restart warfarin within next week.,New Anticoagulation Drugs,Direct T
22、hrombin InhibitorsXimelagatran,hirudin,bivalirudin,and argatrobanSynthetic pentasaccharideAcivated Protein CTissue Factor Pathway Inhibitor(TFPI),Why do we need new anticoagulation drugs?,Heparin-induced thrombocytopeniaHeparin prophylaxis is imperfectHeparin-associated osteoporosisWarfarin takes se
23、veral days for its effectWarfarin is not as effective in some situations e.g antiphospholipid syndromeWarfarin interacts with many other drugsWarfarin is dangerous if not monitored,Synthetic Pentasaccharide,E.g FonaparinuxSynthetic,single molecular entityTargets Factor XaDoes not cause thrombocytope
24、niaShown promise in DVT prevention during orthopedic procedures.Also being examined in ischaemic heart disease,Ximelagatran,Promising oral direct thrombin inhibitorConverted to the active form melagatran in vivoNo dosing problemsNo monitoring needed.Recent atrial fibrillation study showed it to poss
25、ibly be superior to warfarin.,Enhances Antithrombin Activity,Ximelagatran,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,
