Abc of antithrombotic therapy

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Abc of antithrombotic therapy

  1. 1. ABC OFANTITHROMBOTIC THERAPY
  2. 2. To Peck Lin, Philomena, and AloysiusTo Janet, Edward, Eleanor, and Rosalind
  3. 3. ABC OF ANTITHROMBOTIC THERAPY Edited by GREGORY Y H LIPProfessor of cardiovascular medicine and director, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham and ANDREW D BLANN Senior lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham
  4. 4. © BMJ Publishing Group 2003 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 2003 by BMJ Publishing Group Ltd, BMA House, Tavistock Square, London WC1H 9JR www.bmjbooks.com British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 7279 17714 Typeset by BMJ Electronic Production and Newgen Imaging Systems Printed and bound in Spain by GraphyCems, NavarraCover image depicts a deep vein thrombosis scan of a leg vein blocked by a thrombus (blood clot, white)in a patient with deep vein thrombosis. With permission from James King-Holmes/Science Photo Library
  5. 5. Contents Contributors vi Preface vii1 An overview of antithrombotic therapy 1 Andrew D Blann, Martin J Landray, Gregory Y H Lip2 Bleeding risks of antithrombotic therapy 5 David A Fitzmaurice, Andrew D Blann, Gregory Y H Lip3 Venous thromboembolism: pathophysiology, clinical features, and prevention 9 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip4 Venous thromboembolism: treatment strategies 13 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip5 Antithrombotic therapy for atrial fibrillation: clinical aspects 16 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway6 Antithrombotic therapy for atrial fibrillation: pathophysiology, acute atrial fibrillation, and cardioversion 20 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway7 Antithrombotic therapy in peripheral vascular disease 24 Andrew J Makin, Stanley H Silverman, Gregory Y H Lip8 Antithrombotic therapy for cerebrovascular disorders 28 Gregory Y H Lip, Sridhar Kamath, Robert G Hart9 Valvar heart disease and prosthetic heart valves 31 Ira Goldsmith, Alexander G G Turpie, Gregory Y H Lip10 Antithrombotic therapy in myocardial infarction and stable angina 35 Gregory Y H Lip, Bernard S P Chin, Neeraj Prasad11 Antithrombotic therapy in acute coronary syndromes 38 Robert D S Watson, Bernard S P Chin, Gregory Y H Lip12 Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventions 42 Derek L Connolly, Gregory Y H Lip, Bernard S P Chin13 Antithrombotic therapy in chronic heart failure in sinus rhythm 46 Gregory Y H Lip, Bernard S P Chin14 Antithrombotic therapy in special circumstances. I—pregnancy and cancer 51 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip15 Antithrombotic therapy in special circumstances. II—children, thrombophilia, and miscellaneous conditions 55 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip16 Anticoagulation in hospitals and general practice 59 Andrew D Blann, David A Fitzmaurice, Gregory Y H Lip Index 63 v
  6. 6. ContributorsAndrew D Blann Sridhar KamathSenior lecturer in medicine, haemostasis, thrombosis and Research fellow, haemostasis, thrombosis and vascular biologyvascular biology unit, university department of medicine, City unit, university department of medicine, City Hospital,Hospital, Birmingham BirminghamBernard S P Chin Martin J LandrayResearch fellow, haemostasis, thrombosis and vascular biology Lecturer in medicine, haemostasis, thrombosis and vascularunit, university department of medicine, City Hospital, biology unit, university department of medicine, City Hospital,Birmingham BirminghamDerek L Connolly Gregory Y H LipConsultant cardiologist, department of cardiology and vascular Professor of cardiovascular medicine and director, haemostasis,medicine, Sandwell and West Birmingham Hospitals NHS thrombosis and vascular biology unit, university department ofTrust, Sandwell Hospital, West Bromwich medicine, City Hospital, BirminghamDwayne S G Conway Andrew J MakinResearch fellow, haemostasis, thrombosis and vascular biology Research fellow, haemostasis, thrombosis and vascular biologyunit, university department of medicine, City Hospital, unit, university department of medicine, City Hospital,Birmingham BirminghamDavid A Fitzmaurice Neeraj PrasadReader in primary care and general practice, Medical School, Consultant cardiologist, City Hospital, BirminghamUniversity of Birmingham, Edgbaston, Birmingham Stanley H SilvermanIra Goldsmith Consultant vascular surgeon, City Hospital, BirminghamResearch fellow in cardiothoracic surgery, haemostasis,thrombosis and vascular biology unit, university department of Alexander G G Turpiemedicine, City Hospital, Birmingham Professor of medicine, McMaster University, Hamilton, Ontario, CanadaRobert G HartProfessor of neurology, department of medicine (neurology), Robert D S WatsonUniversity of Texas Health Sciences Center, San Antonio, USA Consultant cardiologist, City Hospital, BirminghamBernd JilmaAssociate professor in the department of clinical pharmacology,Vienna University Hospital, Vienna, Austriavi
  7. 7. PrefaceThe seeds for this book were sown with the establishment of the haemostasis, thrombosis and vascular biology unit at the universitydepartment of medicine, City Hospital, Birmingham—with the coming together of clinicians and scientists interestedin thrombosis and vascular biology, bridging the previous divide in thrombosis between basic science research and the applicationto clinical practice. Indeed, thrombosis is the underlying pathophysiological process in a wide variety of conditions. A greaterunderstanding of the mechanisms leading to thrombosis, and newer developments in the field of antithrombotic therapy make thefield all the more dynamic and exciting. The multidisciplinary team effort and the wide range of research areas studied in our unit forms the core content of the ABC ofAntithrombotic Therapy. In major textbooks on thrombosis the scope is comprehensive, background details on physiology andpathophysiology are abundant, and treatment options are listed to exhaustion—the patient may sometimes almost disappear in thewealth of information. Our approach in this book—typical of the ABC series in the British Medical Journal —tries to synthesise andintegrate the extensive research and clinical data that are needed to manage a particular situation as masterly as it is possible. Wehope we have produced a patient-oriented guide with relevant information from clinical epidemiology, pathophysiology, commonsense clinical judgement, and evidence based treatment options, with reference to recently published antithrombotic therapyguidelines from the American College of Chest Physicians, British Society for Haematology, European Society of Cardiology,American College of Cardiology, and American Heart Association. Our expectant readers are physicians, general practitioners, medical or nursing students, nurses, and healthcare scientists whocare for patients presenting with thrombosis-related problems, and thus, the scope is necessarily wide, ranging from venousthromboembolism to atrial fibrillation and stroke, and to thrombosis in cancer and thrombophilic states. Chapters on clinicalpharmacology and bleeding risk, as well as anticoagulation monitoring are included. Furthermore, this book includes additionalchapters which were not included in the 14 issues of this series when it first appeared in the British Medical Journal. We thank our excellent colleagues for their help, encouragement and contributions, as well as Sally Carter at BMJ Books forencouraging us to complete the series and book, nearly to schedule. Gregory Y H Lip Andrew D Blann Birmingham, April 2003
  8. 8. 1 An overview of antithrombotic therapyAndrew D Blann, Martin J Landray, Gregory Y H LipMany of the common problems in clinical practice today relateto thrombosis. The underlying final pathophysiological process Agonists Plasmain myocardial infarction and stroke is thrombus formation Exposed sub Collagen endothelium Adrenaline(thrombogenesis). Common cardiovascular disorders such as ADPatrial fibrillation and heart failure are also associated with Thromboxane Thrombin Fibrinogenthrombogenesis. Thrombosis is also a clinical problem invarious cancers and after surgery, especially orthopaedic. el recepto gpIIb/IIa ogr r block p id ers C loPathophysiology Receptors gpIIb/IIaOver 150 years ago Virchow recognised three prerequisites Secondfor thrombogenesis: abnormal blood flow, vessel wall messengersabnormalities, and blood constituent abnormalities. This Arachadonic acid pathway Di pyconcept has been extended by modern knowledge of the rid am oleendothelial function, flow characteristics, and blood Soluble Shape change inconstituents including haemorheological factors, clotting coagulation pir granule release factors As aggregationfactors, and platelet physiology. As thrombus consists ofplatelets and fibrin (and often bystanding erythrocytes andwhite blood cells), optimum antithrombotic prophylactic Thrombosistherapy can and should be directed towards both. Routes to inhibiting platelet functionAntiplatelet drugsAspirin and agents acting on the cyclo-oxygenase pathway Cellular components Soluble components of the blood of the bloodAspirin irreversibly inhibits cyclo-oxygenase by acetylation of (eg platelets) (eg fibrinogen)amino acids that are next to the active site. In platelets, this is Smoking, inflammationthe rate limiting step in synthesis of thromboxane A2, andinhibition occurs in the megakaryocyte so that all budding Activated platelets Hyperfibrinogenaemiaplatelets are dysfunctional. Because platelets are unable to Thrombusregenerate fresh cyclo-oxygenase in response, the effect ofaspirin remains as long as the lifespan of the platelet (generally Pro-coagulant changes (eg increased VWF, factor V releaseabout 10 days). A severe weakness of aspirin is that its specificity decreased membrane thrombomodulin)for cyclo-oxygenase means it has little effect on other pathwaysof platelet activation. Thus aspirin fails to prevent aggregation Components of the blood vessel wallinduced by thrombin and only partially inhibits that induced byADP and high dose collagen. Antithrombotic doses used in Key components of Virchow’s triad (VWF=von Willebrand factor)clinical trials have varied widely from less than 50 mg to over1200 mg/day, with no evidence of any difference in clinicalefficacy. Absorption is over 80% with extensive presystemic Contraindications to aspirinmetabolism to salicylic acid. Only the parent acetylsalicylic acid Absolute Relativehas any significant effect on platelet function. x Active gastrointestinal x History of ulceration or dyspepsia Adverse effects of aspirin include haemorrhage, ulceration x Children under 12 years oldhypersensitivity and skin rashes, alopecia, and purpura. x Hypersensitivity x Bleeding disorders Sulfinpyrazone also inhibits cyclo-oxygenase (thus x Thrombocytopenia x Warfarin treatmentproducing an aspirin-like state), but is reversible, and alsoinhibits serotonin uptake by platelets. Iloprost is a prostacyclinanalogue that exerts its effects by promoting vasodilatation and Arachadonic acidinhibiting platelet aggregation induced by ADP, therebyopposing the effects of thromboxane A2. Aspirin Cyclo-oxygenase EndoperoxidesDipyridamoleDipyridamole inhibits phosphodiesterase, thus preventing theinactivation of cyclic AMP, intraplatelet levels of which are Prostacyclin Thromboxaneincreased, resulting in reduced activation of cytoplasmic second synthetase synthetasemessengers. However, it may also exert its effect in other ways,such as stimulating prostacyclin release and inhibiting Prostacyclin Thromboxanethromboxane A2 formation. The influence of this drug on thesepathways causes reduced platelet aggregability and adhesion in Platelet metabolism influenced by aspirin 1
  9. 9. ABC of Antithrombotic Therapyvitro with increased platelet survival in vivo. Its effect is relativelyshort lasting, and repeated dosing or slow release preparations Warfarinare needed to achieve 24 hour inhibition of platelet function.Clopidogrel and ticlopidine Vitamin K quinol Vitamin K epoxideThese thienopyridine derivatives inhibit platelet aggregationinduced by agonists such as platelet activating factor and Carboxylasecollagen, and also dramatically reduce the binding of ADP to aplatelet surface purinoreceptor. The mechanism of thisinhibitory action seems to be independent of cyclo-oxygenase. N-terminal glutamyl residue γ-carboxy-glutamyl residue of vitamin K dependent proteinsThere is also impairment of the platelet response to thrombin,collagen, fibrinogen, and von Willebrand factor. The peak Biological functionaction on platelet function occurs after several days of oraldosing. Adverse effects include evidence of bone marrow Vitamin K metabolism and the effect of warfarinsuppression, in particular leucopenia, especially with ticlopidine.Other receptor blockersSignal transduction generally occurs when specific receptors onthe surface are occupied by ligands such as ADP, leading tostructural modification of the glycoprotein IIb/IIIa receptor onthe surface of the platelet. This is the commonest receptor on Factors that influence the efficacy of warfarin*the platelet surface and represents the final common pathway Patient factorsfor platelet aggregation, resulting in crosslinking of platelets. x Enhanced anticoagulant effect—Weight loss, increased age ( > 80 years), After intravenous administration of glycoprotein IIb/IIIa acute illness, impaired liver function, heart failure, renal failure, excessreceptor inhibitors such as abciximab, platelet aggregation is alcohol ingestion x Reduced anticoagulant effect—Weight gain, diarrhoea and vomiting,90% inhibited within two hours, but function recovers over the relative youth ( < 40 years), Asian or African-Caribbean backgroundcourse of two days. The major adverse effect is haemorrhage, Examples of drug interactions with warfarinand concurrent use of oral anticoagulants is contraindicated. x Reduced protein binding—Aspirin, phenylbutazone, sulfinpyrazone,Eptifibatide is a cyclic heptapeptide that mimics the part of the chlorpromazinestructure of fibrinogen that interacts with glycoprotein IIb/IIIa. x Inhibition of metabolism of warfarin—Cimetidine, erythromycin,Thus it is a fraction of the size of abciximab and is targeted at sodium valproatethe same structure on the platelet surface. x Enhanced metabolism of warfarin—Barbiturates, phenytoin, Clinical trials with oral glycoprotein IIb/IIIa receptor carbamazepine x Reduced synthesis of factors II, VII, IX, X—Phenytoin, salicylatesinhibitors have been disappointing, with no beneficial effects x Reduced absorption of vitamin K—Broad spectrum antibiotics,seen and even some evidence of harm. laxatives x Enhanced risk of peptic ulceration—Aspirin, NSAIDs, corticosteroids x Thrombolytics—Streptokinase, tissue plasminogen activatorAnticoagulant drugs x Antiplatelet drugs—Aspirin, NSAIDsWarfarin *This list is intended to be illustrative not exhaustiveThis 4-hydroxycoumarin compound, the most widely usedanticoagulant in Britain and the Western world, inhibits thesynthesis of factors dependent on vitamin K (prothrombin;factors VII, IX, and X; protein C; protein S). Factor VII levels fallrapidly (in < 24 hours) but factor II has a longer half life andonly falls to 50% of normal after three days. Warfarin isapproximately 97% bound to albumin, and free warfarin entersliver parenchymal cells and is degraded in microsomes to an Intrinsic pathway Extrinsic pathwayinactive water soluble metabolite that is conjugated and Factors IX, XI, XII Factor VIIexcreted in the bile. Partial reabsorption is followed by renalexcretion of conjugated metabolites. There is a considerable variability in warfarin’s effect on Prothrombinase complexpatients, its effectiveness being influenced by age, racial Factors V, X, calcium phospholipidsbackground, diet, and co-medications such as antibiotics. Thus itdemands frequent laboratory monitoring, the prothrombin Factor XIIItime being compared with a standard to produce the Factor II Factor IIainternational normalised ratio. The degree of anticoagulation Prothrombin Thrombinrequired varies with clinical circumstance, but the target Factor XIIIainternational normalised ratio usually ranges from 2 to 4.Phenindione is an alternative oral vitamin K antagonist, but Fibrinogen Soluble fibrinconcerns regarding the potential for hepatotoxicity,nephrotoxicity, and blood dyscrasias have reduced its rolelargely to individuals with documented hypersensitivity to Insoluble fibrinwarfarin. Adverse effects of warfarin include haemorrhage,hypersensitivity and skin rashes, alopecia, and purpura. Simplified coagulation cascade2
  10. 10. An overview of antithrombotic therapyMelagatranThis oral thrombin inhibitor undergoing phase III trials seems Low molecular weight heparin Unfractionated heparinto be well tolerated, with few clinically significant bleeding Enoxaparin sodium (Lovenox) [3.8:1]problems, in patients with venous thromboembolism. Although Nadroparin calcium (Fraxiparin) [3.6:1]considerable pharmacokinetic and animal data exist, solid Dalteparin sodium (Fragmin) [2.7:1]evidence of its effectiveness compared with warfarin and 0.7 % of compositionheparin in patients at high or low risk is still awaited. 0.6Heparin 0.5Heparin is a glycosaminoglycan whose major anticoagulant effectis accounted for by a pentasaccharide with a high affinity for 0.4antithrombin III. This binding results in a conformational change 0.3in antithrombin III so that inactivation of coagulation enzymesthrombin (IIa), factor IXa, and factor Xa is markedly enhanced. Its 0.2short half life means it must be given continuously, and its 0.1extensive first pass metabolism means it must be givenparenterally, preferably by continuous intravenous infusion, and it 0 0 5000 10 000 15 000 20 000is therefore inappropriate for home use. The effect on the Molecular weight (Da)intrinsic clotting cascade must be monitored carefully by Greater antithrombin activitymeasuring the activated partial thromboplastin time (APTT), Greater anti-Xa activity Less anti-Xa activitygenerally aiming for a value 1.5 to 2.5 times that of control. Resistant to PF4 Sensitive to PF4 Unfractionated heparin consists of a heterogeneous mixture Little non-specific binding Non-specific bindingof polysaccharides with an average molecular weight of Greater inhibition of thrombin generation Less inhibition of thrombin generation15 000 Da. Low molecular weight heparins (4000-6000 Da) areweaker inhibitors of thrombin but inhibit factor Xa to a similar The three low molecular weight heparins that have been evaluated in clinical trials of acute coronary syndromes are shown with their respective anti-Xaextent. Different commercial preparations of low molecular and antithrombin activity (PF4=platelet factor 4)weight heparin vary in the ratio of anti-Xa to antithrombinactivity, although the clinical relevance of this is uncertain. Betterabsorption after subcutaneous administration and reducedprotein binding result in greatly improved bioavailability. Theeffective half life after subcutaneous injection is four hours,allowing an injection once daily in most circumstances. Thesemore predictable pharmacokinetics allow the dose to becalculated on the basis of the patient’s weight and reduce the Comparison of low molecular weight and unfractionatedrequirement for frequent monitoring. In those rare cases where heparinsmonitoring is deemed necessary, measurement of plasma levelsof anti-Xa activity is needed. Tests of APTT are unhelpful. Unfractionated Low molecular Major adverse effects of heparin include haemorrhage, heparin weight heparinosteoporosis, alopecia, thrombocytopenia, and hypersensitivity. Action Anti-XIIa, XIa, IXa, VIIa, Mostly anti-Xa antithrombinAt present, the risk of haemorrhage seems to be similar with Route of Subcutaneous Subcutaneouslow molecular weight and unfractionated heparin. However, the administration Intravenousrisk of heparin induced thrombocytopenia seems to be less with Absorption from Slow Improvedthe low molecular weight form. subcutaneous route Protein binding Proteins in plasma and on ReducedHirudin and direct thrombin inhibitors endotheliumHirudin, a 65 amino acid residue anticoagulant peptide with a Bioavailability Subcutaneous—10-30% at > 90%relative molecular mass of 7000 Da purified from the leech low doses, 90% at higherHirudo medicinalis, binds thrombin with high specificity and dosessensitivity. With a true half life of about an hour and a half life Intravenous—100%effect on the APTT of two to three hours, it may be seen as an by definitionalternative to heparin in indications such as unstable angina Effective half life Subcutaneous—1.5 hours 4 hoursand in coronary angioplasty. Intravenous—30 min Many derivatives are available, with hirulog and argatroban Between and within Extensive Minimal individual variationamong the best developed. However, trials of the former have Monitoring APTT Not requiredbeen discouraging: no clear benefit over heparin was shown. (anti-Xa activity)Conversely, argatroban may have a role in the anticoagulation Elimination Liver and kidney Kidneyof patients unable to tolerate heparin as a result of heparininduced thrombocytopenia. Furthermore, in a clinical trial ofpatients with heparin induced thrombocytopenia, use ofargatroban was associated with a reduction in levels of plasmaplatelet activation markers.Thrombolytic agentsThese agents lyse pre-existing thrombus, either by potentiatingthe body’s own fibrinolytic pathways (such as streptokinase) or 3
  11. 11. ABC of Antithrombotic Therapyby mimicking natural thrombolytic molecules (such as tissue Fibrinolytic drugsplasminogen activator). The common agents in clinical use arederived from bacterial products (streptokinase) or Examples Source Mechanism of actionmanufactured using recombinant DNA technology Streptokinase Group C haemolytic Complexes with and(recombinant tissue plasminogen activator). Newer drugs aim to streptococci activates plasminogenbe less antigenic and more thrombus specific in an attempt to Urokinase Trypsin-like chemical Direct actingincrease efficacy and specificity of various agents; on present produced by kidney plasminogen activatorevidence, however, the differences between thrombolytic agents Reteplase Recombinant DNA Acivates plasminogen,are only marginal. Because of the lack of site specificity for these (recombinant technology non-immunogenicdrugs, the major adverse effect is that of haemorrhage tissue plasminogen(gastrointestinal, intracranial, etc). The other important adverse activator)effect is that of hypersensitivity reaction, especially withstreptokinase. This usually manifests as flushing, breathlessness,rash, urticaria, and hypotension. Severe anaphylaxis is rare.Hypersensitivity reactions are avoided by using tissue Contraindications to thrombolysisplasminogen activator or recombinant tissue plasminogenactivator, which are not antigenic. Absolute Relative x Recent or current haemorrhage, x Previous peptic ulceration trauma, or surgery x WarfarinStreptokinase x Active peptic ulceration x Liver diseaseDerived from streptococci, this product is an effective x Coagulation defects x Previous use of anistreplasethrombolytic agent for the treatment of acute myocardial x Oesophageal varices or streptokinase within fourinfarction and pulmonary thromboembolism. Acting by x Coma years (use alternative agent)converting plasminogen to plasmin, the main fibrinolytic x Recent or disabling x Hypersensitivity cerebrovascular accident (anistreplase, streptokinase)enzyme, it potentiates fibrinolysis. However, it is not site specific, x Hypertension x Heavy vaginal bleedinglysing thrombus anywhere in the body. Being bacteria derived, it x Aortic dissectionis antigenic, and repeated administration results in neutralisingantibodies and allergic reactions. For example, a singleadministration of 1.5 MU for acute myocardial infarction resultsin neutralising antibodies that have been shown to persist forup to four years and are sufficient to neutralise a repeat Insolubleadministration of a similar dose of the agent in half of cases. fibrin clot Plasminogen PlasminTissue plasminogen activatorIn clinical use this is produced by recombinant DNAtechnology and mimics an endogenous molecule that activates PAI-I Solublethe fibrinolytic system. Thus, recombinant tissue plasminogen D-dimersactivator does not elicit an allergic response and is considered tPAmore clot specific. Nevertheless, it has a short half life and needs uPA Streptokinasecontinuous infusion to achieve its greatest efficacy. Acceleratedadministration of tissue plasminogen activator gives a slightmortality advantage over streptokinase at the cost of a marginal Simplified fibrinolysis (PAI-1=plasminogen activator inhibitor, tPA=tissueincrease in stroke rate. plasminogen activator, uPA=urokinase plasminogen activator)Further readingx Antiplatelet Trialists’ Collaboration. Collaborative overview of thrombin inhibitor, in patients with a DVT. Thromb Haemost 1999;81: randomised trials of antiplatelet therapy, I: Prevention of death, 358-63 myocardial infarction, and stroke by prolonged antiplatelet therapy x International Stroke Trial Collaborative Group. The international in various categories of patients. BMJ 1994;308:81-106 stroke trial (IST): a randomised trial of aspirin, subcutaneousx Blann AD, Lip GYH. Virchow’s triad revisited: the importance of heparin, or both, or neither among 19 435 patients with acute soluble coagulation factors, the endothelium, and platelets. Thromb ischaemic stroke. Lancet 1997;349:1569-81 Res 2001;101:321-7 x Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walengax CAPRIE Steering Committee. A randomised, blinded, trial of JM, et al. Argatroban anticoagulant therapy in patients with clopidogrel versus aspirin in patients at risk of ischaemic events heparin-induced thrombocytopenia. Circulation 2001;103:1838-43 (CAPRIE). Lancet 1996;348:1329-39 x Nurden AT. New thoughts on strategies for modulating plateletx Catella-Lawson F. Direct thrombin inhibitors in cardiovascular function through the inhibition of surface receptors. Haemostasis disease. Coron Artery Dis 1997;8:105-11 1996;20:78-88x Eriksson H, Eriksson UG, Frison L. Pharmacokinetic and x Stirling Y. Warfarin-induced changes in procoagulant and pharmacodynamics of melagatran, a novel synthetic LMW anticoagulant proteins. Blood Coagul Fibrinolysis 1995;6:361-73The figure showing percentage of composition of unfractionated and lowmolecular weight heparin in terms of molecular weight is adapted fromLevine GN, Ali MN, Schafer AI. Arch Intern Med 2001;161: 937-48.4
  12. 12. 2 Bleeding risks of antithrombotic therapyDavid A Fitzmaurice, Andrew D Blann, Gregory Y H LipMany of the common cardiovascular disorders (especially in Questions to ask when considering oral anticoagulationelderly people) are linked to thrombosis—such as ischaemic x Is there a definite indication (such as atrial fibrillation)?heart disease, atrial fibrillation, valve disease, hypertension, and x Is there a high risk of bleeding or strong contraindication againstatherosclerotic vascular disease—requiring the use of anticoagulation?antithrombotic therapy. This raises questions regarding the x Will concurrent medication or disease states increase bleeding riskappropriate use of antithrombotic therapy in older people, or interfere with anticoagulation control?especially because strategies such as anticoagulation with x Is drug compliance and attendance at anticoagulant clinic for monitoring likely to be a problem?warfarin need regular monitoring of the international x Will there be regular review of the patient, especially with regard tonormalised ratio (INR), a measure of the induced haemorrhagic risks and benefits of anticoagulation?tendency, and carry a risk of bleeding. The presence ofconcomitant physical and medical problems increases theinteractions and risks associated with warfarin, andanticoagulation in elderly patients often needs an assessment of S Dthe overall risk:benefit ratio. Physical frailty in elderly people may reduce access to patient’s prothrombin time ISI INR=anticoagulant clinics for INR monitoring. The decline in mean normal timecognitive function in some elderly patients also may reduce ISI=international sensitivity ratio. Thecompliance with anticoagulation and the appreciation of mean normal prothrombin time is oftenbleeding risks and drug interactions. However, in recent studies generated from samples from local healthy subjects or a commerciallyof anticoagulation in elderly people, no significant associations available standard. The exact value of theof anticoagulant control were found with age, sex, social ISI depends on the thromboplastin usedcircumstances, mobility, domicillary supervision of medication, in the prothrombin time methodor indications for anticoagulation.WarfarinBleeding is the most serious and common complication ofwarfarin treatment. For any given patient, the potential benefitfrom prevention of thromboembolic disease needs to bebalanced against the potential harm from inducedhaemorrhagic side effects.Minor bleedsMost bleeding problems are clinically minor, although patientsare unlikely to view such bleeds in these terms. The problemsinclude nose bleeds, bruising, and excessive bleeding afterminor injury such as shaving. Patients should be made aware ofthese common problems and be reassured that these events areexpected in patients receiving warfarin treatment. Menorrhagiais surprisingly rare as a major clinical problem, even though itcan be severe.More serious problemsPatients need access to medical care if they have seriousproblems. Such problems are generally due to a high INR.Usually, spontaneous bruising, any bleeding that is difficult toarrest, frank haematuria, any evidence of gastrointestinalbleeding, and haemoptysis, need urgent assessment. Thedefinition of minor or major bleeding lacks clarity: in manycases the patient presents with a concern that may need follow Purpura, petechiae, and haematoma secondary to over-anticoagulationup, and a minor bleed can only be defined as such in retrospect.In most cases, evidence of bleeding suggests some underlyingpathology but may also be due to drug interactions. Forexample, a patient with recurrent haemoptysis may be found tohave hereditary telangectasia. Further investigation of the cause Sudden, unexplained changes to theof bleeding should always be considered, particularly if the efficacy of warfarin may be caused by thebleeding is recurrent. It is also important in these instances to consumption of over the countercheck for concomitant drug use, particularly drugs received multivitamin tablets or foodstuffs that contain high levels of vitamin Kover the counter. Patients should be aware that aspirin and 5
  13. 13. ABC of Antithrombotic Therapynon-steroidal anti-inflammatory drugs are particularly Patients at high risk of bleeding with warfarindangerous in combination with warfarin; however, even x Age > 75 yearssupposedly safe drugs such as paracetamol can affect a patient’s x History of uncontrolled hypertension (defined as systolic bloodbleeding tendency. pressure > 180mm Hg or diastolic blood pressure > 100 mm Hg) x Alcohol excess (acute or chronic), liver diseaseIncidence of bleeding problems x Poor drug compliance or clinic attendanceThe incidence of severe bleeding problems that may bring x Bleeding lesions (especially gastrointestinal blood loss, such aspatients to an accident and emergency unit has probably been peptic ulcer disease, or recent cerebral haemorrhage) x Bleeding tendency (including coagulation defects,overestimated. The annual incidence of fatality caused by thrombocytopenia) or concomitant use of non-steroidalwarfarin administration has been estimated to be 1%. However, anti-inflammatory drugs and antibioticsthis is based on old data, and, although difficult to prove, the x Instability of INR control and INR > 3overall improvement in anticoagulation control in the past10-15 years means that a more realistic figure is about 0.2%.Methodological problems have hampered the interpretation ofpreviously reported data, particularly with regard to definitionsof major and minor bleeding episodes, with some investigatorsaccepting hospital admission for transfusion of up to 4 units ofblood as being “minor.” Certainly, the most serious “major”bleed is an intracranial haemorrhage. Reviews of observationaland experimental studies showed annual bleeding rates of0-4.8% for fatal bleeding and 2.4-8.1% for major bleeds. Minorbleeds are reported more often, with about 15% of patientshaving at least one minor event a year.Risk factors for bleedingAge is the main factor that increases risk of bleeding. One studyshowed a 32% increase in all bleeding and a 46% increase inmajor bleeding for every 10 year increase above the age of 40. Early studies suggested an increased risk with increasingtarget INR, but the data were difficult to interpret because resultswere reported in both INR and prothrombin time. The actual riskof bleeding should be taken into account as well as the degree ofanticoagulation (as measured by the INR). One study whichachieved point prevalence of therapeutic INRs of 77% reportedno association between bleeding episodes and target INR. Data from an Italian study in 2745 patients with 2011patient years of follow up reported much lower bleeding rates,with an overall rate of 7.6 per 100 patient years. The reportedrates for fatal, major, and minor bleeds were 0.25, 1.1, and 6.2per 100 patient years respectively. This study confirmed anincreased risk with age and found a significantly increased risk Computed tomography scan showing intracerebral haemorrhageduring the first 90 days of treatment. Peripheral vascular andcerebrovascular disease carried a higher relative risk ofbleeding, and target INR was strongly associated with bleedingwith a relative risk of 7.9 (95% confidence interval 5.4 to11.5,P < 0.0001) when the most recent INR recorded was > 4.5. Datafrom a trial in a UK community showed 39.8 minor, 0.4 major,and no fatal haemorrhagic events per 100 patient years for thetotal study population, with 3.9 serious thromboembolic eventsper 100 patient years, of which 0.79 were fatal. Warfarin is therefore a relatively safe drug, particularly iftherapeutic monitoring is performed well. Analogies are often Risk of bleeding associated with warfarin treatmentmade between therapeutic monitoring of warfarin and x Rate of bleeding episodes associated in the general patientmonitoring of blood glucose for diabetic patients. Given the population is decreasing (possibly due to better management)increase in numbers of patients receiving warfarin, particularly x Risk increases with agefor atrial fibrillation, the scale of the problem is likely to be the x Risk of bleeding is directly related to the achieved intensity of INRsame. There is no reason why warfarin monitoring cannot rather than the target INR (a clear dose-response effect)become as routine as glucose monitoring in diabetes: relevant x Temporal association between measured INR and risk of bleedingsmall machines are available for generating an INR (with x Relative risk of bleeding is increased in patients with cerebrovascular disease and venous thrombosisassociated standards and quality control).OveranticoagulationExcessive anticoagulation without bleeding or with only minorbleeding can be remedied by dose reduction or discontinuation.The risk of bleeding is decreased dramatically by lowering theintended INR from 3-4.5 down to 2-3, although this increases6
  14. 14. Bleeding risks of antithrombotic therapythe risk of thrombosis. If bleeding becomes substantial, 2-5 mgof oral or subcutaneous vitamin K may be needed. In patients ASPwith prosthetic valves, vitamin K should perhaps be avoided Myocardial infarction (P=0.002) 36% reduction, PLAbecause of the risk of valve thrombosis unless there is life but only 45 fewer eventsthreatening intracranial bleeding. Alternatives to vitamin Kinclude a concentrate of the prothrombin group of coagulationfactors including II, IX, and X, fresh frozen plasma 15 ml/kg, Stroke (P=0.88)and recombinant factor VIIa.Aspirin 0 1 2 3 4 5 Events per 100 patient yearsAspirin has little effect in terms of bruising but can causeserious gastrointestinal bleeding. The risk of gastrointestinal GI bleeds Cerebral bleedsbleeding is related to dose and should not be problematic at ASP 107 14 (fatal=5)doses of 75 mg/day given as thromboprophylaxis. There iscurrently no consensus as to optimal dose of aspirin for stroke PLA 55 15 (fatal=3)prevention in atrial fibrillation. A meta-analysis of randomisedcontrolled trials using aspirin showed that a mean dose of273 mg/day, increased absolute risk of haemorrhagic stroke to Myocardial infarction, stroke, and bleeding in the hypertension optimal treatment trial (HOT) study (ASP=aspirin, PLA=placebo)12 events per 10 000 people. This relatively small increase mustbe weighed against the reduced risk of myocardial infarction (to137 events per 10 000) and ischaemic stroke (to 39 events per10 000). However, in one trial of patients with well controlledhypertension, use of aspirin 75 mg prevented 1.5 myocardial Aspirin daily No of Events/patients Odds ratio Odds 2P dose (mg) trials* Aspirin Control (95% CI random) reductioninfarctions per 1000 patients a year, which was in addition to (%) (%) Aspirin:control (SD)the benefit achieved by lowering the blood pressure, with no 500-1500 34 1621/11 215 1930/11 236 19% (3) <0.00001effect on stroke. Although there was no increase in the number (14.5%) (17.2%)of fatal bleeding events (seven in patients taking aspirin, 160-325 19 1526/13 240 1963/13 273 25% (3) <0.00001 (11.5%) (14.8%)compared with eight in the placebo group), there was a 1.8% 75-150 12 370/3370 519/3406 32% (6) <0.00001increase in non-fatal, major bleeding events (129 events in (11.0%) (15.2%)patients taking aspirin, compared with 70 in the placebo group) <75 3 316/1827 354/1828 13% (8) NS (17.3%) (19.4%)and minor bleeds (156 and 87, respectively). Total 65 3833/29 652 4766/29 743 23% (2) <0.00001 (12.9%) (16.0%) 0 0.5 1 1.5 2 Heterogeneity between 4 dose categories: Aspirin AspirinRisk of bleeding χ2=3; df=7.7; P=0.06 better worse *Some trials contributed to more than one daily dose category.There have been conflicting results concerning the role of ageas an independent risk factor for haemorrhage induced by Typical odds ratio for each category shown as square (with area proportional to the variance of observed-expected) together with its 99% confidence interval (horizontal line). Typical odds ratioanticoagulants. Advanced age ( > 75 years), intensity of for the total shown as diamond with its 95% confidence interval (horizontal line = width ofanticoagulation (especially INR > 4), history of cerebral vascular diamond). Vertical dotted line passes through point estimate of typical odds ratio for total.disease (recent or remote), and concomitant use of drugs that Effect of different doses of aspirin in secondary prevention of vascular eventsinterfere with haemostasis (aspirin or non-steroidal (There is no significant difference in benefit with different aspirin doses, but atanti-inflammatory drugs) are probably the most important higher doses adverse effects are more likely)variables determining patients’ risk of major life threateningbleeding complications while they are receiving anticoagulationtreatment. Generally elderly people have increased sensitivity to the Variables that may influence the risk of bleeding inanticoagulant effect of warfarin, and require a lower mean daily elderly peopledose to achieve a given anticoagulant intensity. For example, x Increased sensitivity to the effect of anticoagulation, perhaps due topatients aged > 75 years need less than half the daily warfarin increased receptor affinity or lower dietary vitamin K intakedose of patients aged < 35 for an equivalent level of x Concurrent use of drugs that increase bleeding risk x Associated comorbidity and other diseases that decreaseanticoagulation. Whatever the mechanism it is clear that warfarin compliance and increase the risk of bleedingtherapy needs careful justification for being given to elderlypatients, and the dose needs modification and careful monitoring. As there is an exponential increase in bleeding risk with alinear increase in anticoagulant effect, there will be a substantialincrease in bleeding risk with overanticoagulation. For example, Possible reasons for increased sensitivity to anticoagulationthe annual risk of bleeding rises from 1.6% in elderly people in elderly peoplenot treated with anticoagulant drugs (based on the “Sixty-Plus” x Lower body weightstudy), to 5% (relative risk 3) at an INR of 2.5, and to 50% x Differences in pharmacokinetics, with a tendency towards reduced(relative risk 30) at an INR of 4. In another study, total bleeding drug clearance in the elderly either due to decreases in renal orevents were 39% in a group of 31 patients with an INR of 7 hepatic blood flow and function with age per se or diseasecompared with 13% in a group of 100 with a stable INR (odds processesratio 5.4, 95% CI 2.1-13.9). The greatest risk factor for being in x Change in receptor sensitivity x Lower dietary vitamin K intake in the elderly may perhaps be thethis group was (apart from having a high target INR) antibiotic more important causetherapy in the preceding four weeks. 7
  15. 15. ABC of Antithrombotic Therapy Multiple drug therapy or polypharmacy is quite common, Further readingwith the consequence of adverse drug interactions, the risk of x Blann AD, Hewitt J, Siddique F, Bareford D. Racial background is awhich rises exponentially with the number of drugs given determinant of average warfarin dose required to maintain the INRsimultaneously and with concurrent diseases. Typical drug between 2.0 and 3.0. Br J Haematol 1999;10:207-9interactions include changes in absorption across intestinal x Erhardtsten E, Nony P, Dechavanne M, Ffrench P, Boissel JP,mucosae and hepatic metabolism. Patients should be cautioned Hedner U. The effect of recombinant factor VIIa (NovoSevenTM) inabout the risk of warfarin-drug interactions when their healthy volunteers receiving acenocoumarol to an Internationalmedication list is altered. The decline in cognitive function in Normalized Ratio above 2.0. Blood Coag Fibrin 1998;9:741-8some elderly patients may mean they do not realise that some x Fitzmaurice DA, Hobbs FDR, Murray ET, Hodder, RL, Allan TF, Rose, PE. Oral anticoagulation management in primary care withdrugs can interact with anticoagulants and so they do not the use of computerised decision support and near-patient testing.mention their use of oral anticoagulants to doctors or A randomised controlled trial. Arch Intern Med 2000;160:2323-48pharmacists. However, elderly patients are likely to attend clinic x Gurwitz JH, Goldberg RJ, Holden A, Knapic N, Ansell J. Age-relatedless often than younger patients, suggesting a greater degree of risks of long term oral anticoagulant therapy. Arch Intern MedINR stability. 1988;148:1733-6 Many diseases associated with stroke and thromboembolism x He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of haemorrhagic stroke. JAMA 1998;280:1930-5are more common with increasing age. Older patients are often x Haemostasis and Thrombosis Task Force of the British Society forat highest risk, and appropriate anticoagulation therapy reduces Haematology. Guidelines on oral anticoagulation: third edition. Br Jmorbidity and mortality. Careful and continuing evaluation of Haematol 1998;101:374-87patients is necessary to ensure that the risks of bleeding do not x Landefeld CS, Beyth RJ. Anticoagulant related bleeding: clinicaloutweigh the benefits from anticoagulation. epidemiology, prediction, and prevention. Am J Med 1993;95:315-28 x Levine MN, Hirsh J, Landefeld CS, Raskob G. HaemorrhagicThe diagram showing the results of the hypertension optimal treatment complications of anticoagulant treatment. Chest 1992;102:352-63Strial is adapted from Hansson L, et al. Lancet 1998;351:1755-62. The figure x Panneerselvan S, Baglin C, Lefort W, Baglin T. Analysis of riskshowing the effect of different doses of aspirin in secondary prevention of factors for over-anticoagulation in patients receiving long-termvascular events is reproduced from Clinical Evidence (June issue 7), BMJ warfarin. Br J Haematol 1998;103:422-4Publishing Group, 2002. x Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348:423-8 x van der Meer FJM, Rosendaal FR, Vandenbroucke, Briet E. Bleeding complications in oral anticoagulant therapy. Arch Int Med 1993;153:1557-62 x Hutton BA, Lensing AWA, Kraaijenhagen RA, Prins MH. Safety of treatment with oral anticoagulants in the elderly. Drugs and Aging 1999;14:303-128
  16. 16. 3 Venous thromboembolism: pathophysiology,clinical features, and preventionAlexander G G Turpie, Bernard S P Chin, Gregory Y H LipVenous thromboembolism is a common complication amonghospital inpatients and contributes to longer hospital stays,morbidity, and mortality. Some venous thromboembolisms maybe subclinical, whereas others present as sudden pulmonaryembolus or symptomatic deep vein thrombosis. UltrasonicDoppler and venographic techniques have shown deep veinthrombosis of the lower limb to occur in half of all major lowerlimb orthopaedic operations performed without antithromboticprophylaxis. Deep vein thrombosis of the lower limb is also seenin a quarter of patients with acute myocardial infarction, andmore than half of patients with acute ischaemic stroke. Deep vein thrombosis of the lower limb normally starts inthe calf veins. About 10-20% of thromboses extend proximally,and a further 1-5% go on to develop fatal pulmonaryembolism. Appropriate antithrombotic measures can reducethis complication. Until recently, some clinicians were reluctantto provide such prophylaxis routinely. As unfounded fears ofmajor bleeding complications from anticoagulant regimenswane, preventive treatments are used more often with medicaland surgical patients. However, the risk of bleeding can beserious and this has particular bearing in postoperative patients. Venous thromboembolism can also arise spontaneously in Pulmonary angiography showing large pulmonary embolus in leftambulant individuals, particularly if they have associated risk pulmonary arteryfactors such as thrombophilia, previous thrombosis, or cancer.However, in over half of these patients, no specific predisposingfactors can be identified at presentation.Pathophysiology Venous thromboembolism often manifests clinically as deep veinThrombus formation and propagation depend on the presence thrombosis or pulmonary embolism, andof abnormalities of blood flow, blood vessel wall, and blood is possibly one of the preventableclotting components, known collectively as Virchow’s triad. complications that occur in hospitalisedAbnormalities of blood flow or venous stasis normally occur patientsafter prolonged immobility or confinement to bed. Venousobstruction can arise from external compression by enlargedlymph nodes, bulky tumours, or intravascular compression byprevious thromboses. Increased oestrogens at pharmacologicallevels, as seen with oral contraceptive use and with hormone Risk factors and conditions predisposing to venousreplacement therapy in postmenopausal women, have been thromboembolismassociated with a threefold increased risk in the small initial risk x History of venous thromboembolismof venous thromboembolism. Cancers, particularly x Prolonged immobilityadenocarcinomas and metastatic cancers, are also associated x Prolonged confinement to bed or lower limb paralysiswith increased venous thromboembolism. Indeed, on x Surgery, particularly lower limb orthopaedic operations, and majorpresentation, some idiopathic venous thromboembolisms have pelvic or abdominal operationsrevealed occult cancers at follow up. Both oestrogens at x Trauma—For example, hip fractures and acute spinal injurypharmacological levels and cancer can also activate the clotting x Obesity x Major medical illnesses such as acute myocardial infarction,system. ischaemic stroke, congestive cardiac failure, acute respiratory failure x Oestrogen use in pharmacological doses—For example, oral contraception pills, hormone replacement therapyClinical presentation and diagnosis x Cancer, especially metastatic adenocarcinomas x Age > 40 yearsDeep vein thrombosis x Aquired hypercoagulable states—Lupus anticoagulant andDeep vein thrombosis commonly presents with pain, erythema, antiphospholipid antibodies, hyperhomocysteinaemia,tenderness, and swelling of the affected limb. Thus, in lower dysfibrinogenaemia, myeloproliferative disorders such aslimb deep vein thrombosis, the affected leg is usually swollen polycythaemia rubra verawith the circumference of the calf larger than the unaffected x Inherited hypercoaguable states—Activated protein C resistance (factor V Leiden mutation), protein C deficiency, protein Sside. Other causes of leg swelling, erythema, and tenderness deficiency, antithrombin deficiency, prothrombin gene mutationinclude a ruptured Baker’s cyst and infective cellulitis. The 9
  17. 17. ABC of Antithrombotic Therapydiagnosis of deep vein thrombosis is therefore more likely when Modified pretest probability for deep vein thrombosisrisk factors are present and less so if there are featuressuggesting alternative diagnoses. For example, ruptured Clinical feature ScoreBaker’s cysts commonly appear in the context of osteoarthritis Tenderness along entire deep vein system 1.0and rheumatoid arthritis. Infective cellulitis is unlikely to Swelling of the entire leg 1.0be bilateral, with clearly demarcated areas of erythema Greater than 3 cm difference in calf circumference 1.0extending proximally. Breaks in the skin, particularly between Pitting oedema 1.0the toes, and coexistent fungal infection are additional clues to Collateral superficial veins 1.0cellulitis. Risk factors present: Objective diagnosis of venous thromboembolism is Active cancer 1.0important for optimal management. Although the clinical Prolonged immobility or paralysis 1.0diagnosis of venous thromboembolism is imprecise, various Recent surgery or major medical illness 1.0probability models based on clinical features have proved to be Alternative diagnosis likely (ruptured Baker’s cyst in − 2.0practical and reliable (interobserver reliability, = 0.85) in rheumatoid arthritis, superficial thrombophlebitis, orpredicting the likelihood of venous thromboembolism. These infective cellulitis)models should be used in conjunction with objective diagnostic Score > 3 = high probablility; 1-2 = moderate probability < 0 = low probabilitytests. Compression ultrasonography remains the non-invasiveinvestigation of choice for the diagnosis of clinically suspecteddeep vein thrombosis. It is highly sensitive in detecting proximaldeep vein thrombosis although less accurate for isolated calfdeep vein thrombosis. In patients with suspected thrombosis D-dimer µg/Land a negative compression ultrasound result, the test should berepeated in seven days because studies have shown that patientswith two or more negative tests over a week who are untreated 20 000have a less than 2% risk of proximal extension or subsequent 10 000deep vein thrombosis. Impedance plethysmography is slightly less specific and 5000sensitive than ultrasonography but may still have a role inpregnant women and suspected recurrent deep veinthrombosis. The gold standard is invasive contrast venography,which is still used when a definitive answer is needed. Newer 1000imaging techniques are being developed, and tools such as 500magnetic resonance venography or computed tomographycould possibly detect pelvic vein thromboses, but further testingis needed to establish their role in the diagnosis of deep veinthrombosis. 100 Blood tests such as fibrin D-dimer add to the diagnosticaccuracy of the non-invasive tests. In one study, the sensitivityand specificity of a D-dimer concentration of > 500 g/l for the 0 Pulmonary No pulmonarypresence of pulmonary embolism were 98% and 39%, embolism embolismrespectively, which give positive and negative predictivevalues of 44% and 98%. The sensitivity of the test even Plasma D-dimer concentrations on day of presentation accordingremained high at three and seven days after presentation to final diagnosis(96% and 93%).Investigations for suspected venous thromboembolism by pretest clinical probabilityPretest probability Fibrin D-dimer Other investigations CommentDeep veinthrombosis: Low Negative No further investigations needed Low or moderate Positive Negative ultrasound compression Consider venography or repeat ultrasound after a week Moderate or high Positive Positive ultrasound compression Treat with anticoagulants High Positive Negative ultrasound compression Consider venography to rule out deep vein thrombosis, especially in high risk patients and those with recurrent pulmonary emboliPulmonaryembolism: Low Negative No No further investigation needed Low or moderate Positive Proceed to ventilation-perfusion If non-diagnostic ventilation-perfusion scan consider serial scan compression ultrasound over two weeks to rule out venous thromboembolism High Positive Proceed to ventilation-perfusion If non-diagnostic ventilation-perfusion scans, proceed to scan (or ultrasound) venography or pulmonary angiography as needed10
  18. 18. Venous thromboembolism: pathophysiology, clinical features, and preventionPulmonary embolism Clinical probability for pulmonary embolismPatients presenting with acute pulmonary embolism oftencomplain of sudden onset of breathlessness with haemoptysis Clinical feature Scoreor pleuritic chest pain, or collapse with shock in the absence of Deep vein thrombosis suspected:other causes. Deep vein thrombosis may not be suspected Clinical features of deep vein thrombosis 3.0clinically, but its presence, along with thrombotic risk factors, Recent prolonged immobility or surgery 1.5will make the diagnosis of pulmonary embolism more likely. A Active cancer 1.0similar clinical probability model to that for deep vein History of deep vein thrombosis or pulmonary 1.5thrombosis has been developed for pulmonary embolism. embolism Pulmonary angiography is the gold standard investigation Haemoptysis 1.0for pulmonary embolism, but it is invasive and associated with Resting heart rate > 100 beats/min 1.50.5% mortality. A ventilation-perfusion scan using technetium No alternative explanation for acute breathlessness or 3.0DTPA (ditriaminopentaric acid) is more widely used. However pleuritic chest painthis investigation is non-specific, and is diagnostic in only 30% > 6 = high probability (60%); 2-6 = moderate probability (20%); < 1.5 = lowof cases. Spiral computed tomography scans are more reliable probability (3-4%)but diagnosis is limited to emboli in larger vessels only.Measurement of fibrin D-dimer levels, used for deep veinthrombosis, is helpful, as is compression ultrasound in thedetection of occult deep vein thrombosis. Thromboembolic risk stratification for surgery patientsPrevention strategies x Low risk—Uncomplicated surgery in patients aged < 40 years with minimal immobility postoperatively and no risk factorsAn appropriate strategy for the prevention of venous x Moderate risk—Any surgery in patients aged 40-60 years, majorthromboembolism include pharmacological or physical surgery in patients < 40 years and no other risk factors, minormethods. To optimise treatment, patients should be stratified surgery in patients with one or more risk factorsinto risk categories to allow the most appropriate prophylactic x High risk—Major surgery in patients aged > 60 years, major surgerymeasure to be used. in patients aged 40-60 years with one or more risk factors x Very high risk—Major surgery in patients aged > 40 years with Prophylactic drugs include unfractionated heparin, low previous venous thromboembolism, cancer or knownmolecular weight heparin, oral anticoagulants (such as hypercoagulable state, major orthopaedic surgery, electivecoumarins), thrombin inhibitors (such as hirudin), and specific neurosurgery, multiple trauma, or acute spinal cord injuryfactor Xa inhibitors (such as fondaparinux). The recentlyapproved fondaparinux reduces the risk of venousthromboembolism after orthopaedic surgery by more than halfcompared with low molecular weight heparin and seems likelyto become the treatment of choice after universal availability. Prophylactic physical methods include the use ofcompression elastic stockings, intermittent pneumaticcompression (which provides rythmic external compression at35-40 mm Hg for about 10 seconds every minute), and earlymobilisation to improve venous blood flow in conditionspredisposing to venous stasis.General surgeryPatients at low risk undergoing general surgery do not needspecific prophylaxis other than early mobilisation. In moderaterisk patients, fixed low doses of unfractionated heparin (5000 IUevery 12 hours) or low molecular weight heparin (3400 anti-Xaunits or equivalent) once daily is sufficient. Higher doses of lowmolecular weight heparin (more than 3400 IU anti-Xa daily)should be reserved for high risk general surgery andorthopaedic operations. Compression elastic stockings andintermittent pneumatic compression may protect high risk Ventilation-perfusion scan showing massive pulmonary thromboembolism,patients when used with anticoagulants. They are also effective showing a mismatch between (left) perfusion and (right) ventilation scanswhen used alone in moderate risk patients whereanticoagulants are contraindicated.Orthopaedic surgeryIn very high risk patients, such as those undergoing major Key pointsorthopaedic operations, high dose low molecular weight x Understanding Virchow’s triad aids the treatment of venousheparin or warfarin is appropriate. The current recommended thromboembolismlength of anticoagulant prophylaxis is 7-10 days with low x Numerous situations and risk factors can contribute to venousmolecular weight heparin or warfarin. Extended use may thromboembolismprovide additional benefit. Routine screening with duplex x Diagnosis of venous thromboembolism depends upon a combination of history, risk factors, and investigationsultrasonography is not helpful. Hirudin seems to be superior to x Antithrombotic prophylaxis is safe and effectivelow molecular weight heparin and low dose unfractionated 11
  19. 19. ABC of Antithrombotic Therapyheparin as prophylaxis in patients undergoing elective hip Evidence based use of antithrombotic prophylaxisreplacements but is still not universally available. General surgery x Low risk— Early mobilisationNeurosurgery, multiple traumas, and spinal cord injuries x Moderate risk—UH 5000 IU 12 hourly starting two hours beforeIntermittent pneumatic compression is the prophylaxis of surgery, or low molecular weight heparin < 3400 anti-Xa IU daily*,choice for elective neurosurgery. Among the low molecular or compression elastic stockings, or intermittent pneumaticweight heparins, only enoxaparin 30 mg twice daily has been compressionshown to reduce venous thromboembolism without excess x High risk—Low molecular weight heparin > 3400 anti-Xa IU daily†bleeding after elective neurosurgery, multiple traumas, or spinal plus compression elastic stockings, or unfractionated heparin 5000cord injuries and so may be used in these situations. Other low IU eight hourly starting two hours before surgery plus compression elastic stockings, or intermittent pneumatic compression ifmolecular weight heparins have either not been tested or have anticoagulation contraindicatednot conclusively been shown to be of benefit in this setting. x Very high risk—Perioperative warfarin (INR 2-3), low molecular weight heparin > 3400 anti-Xa IU daily† plus compression elasticMedical conditions stockings, or prolonged low molecular weight heparin therapy plusIn general medical patients including heart failure and compression elastic stockingsrespiratory failure, both unfractionated heparin and low Major orthopaedic surgerymolecular weight heparin have been shown to be effective in x Elective hip replacement—Recombinant hirudin 15 mg twice daily,reducing the risk of venous thromboembolism. Low molecular unfractionated heparin 3500 IU eight hourly with postoperative adjustments (APTT 1.2-1.5), or low molecular weight heparinweight heparin has been shown to be more effective than > 3400 anti-Xa IU daily†, or perioperative warfarin (INR 2-3), orheparin in stroke. Low dose heparin has been shown to be fondaparinux 2.5 mg dailyeffective in acute myocardial infarction but this is now largely x Elective knee replacement—Low molecular weight heparin > 3400historic because myocardial infarction patients receive anti-Xa IU daily†, or perioperative warfarin (INR 2-3), ortherapeutic dose anticoagulants. fondaparinux 2.5 mg daily, intermittent pneumatic compression x Surgery for hip fracture—Low molecular weight heparin > 3400 anti-Xa IU daily†, or perioperative warfarin (INR 2-3), orOther considerations fondaparinux 2.5 mg dailyCombined approaches using drugs and physical methods may Elective neurosurgerybe better at preventing thromboembolism than physical x Intermittent pneumatic compression, enoxaparin 30 mg twice dailymethods alone. However, compression elastic stockings and Acute spinal cord injuryintermittent pneumatic compression may be used for moderate x Enoxaparin 30 mg twice dailyor high risk patients when anticoagulation is contraindicated or Traumabest avoided. Inferior vena cava filter placement should be x Enoxaparin 30 mg twice dailyreserved for patients at very high risk of venous Acute myocardial infarctionthromboembolism where anticoagulation as well as physical x Low dose unfractionated heparin 5000 IU twice daily, full dosemethods are contraindicated. Inferior vena cava filter placement unfractionated heparin 40 000 IU infusion over 24 hours, elastictends to cause a long term increase of recurrent deep vein stockings, and early mobilisationthrombosis, even though the immediate risk of postoperative Ischaemic strokepulmonary embolism is reduced. x Low dose unfractionated heparin 5000 IU twice daily Other medical conditions including congestive heart failure x Enoxaparin 40 mg once daily or 30 U twice daily, dalteparin 2500Further reading IU daily, low dose unfractionated heparin 5000 IU twice dailyx Haemostasis and Thrombosis Task Force of the British Society for Cancer patients receiving chemotherapy Haematology. Guidelines on anticoagulation: third edition. Br J x Low dose warfarin (INR < 2), dalteparin 2500 IU daily Haematol 1998;101:374-87x Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V, et *Dalteparin 2500 IU once daily starting two hours before surgery Enoxaparin 20 mg once daily starting two hours before surgery al. Antithrombotic therapy for venous thromboembolic disease. Nadroparin 3100 IU once daily starting two hours before surgery Chest 2001;119:176-93S Tinzaparin 3500 IU once daily starting two hours before surgeryx Kearon C, Hirsh J. Management of anticoagulation before and after †Dalteparin 5000 IU once daily starting 10-12 hours before surgery Danaparoid 750 IU twice daily starting one to two hours before surgery elective surgery. N Engl J Med 1997;336:1506-11 Enoxaparin 40 mg once daily starting 10-12 hours before surgery or 30 mgx Simonneau G, Sors H, Charbonnier B, Page Y, Labaan JP, Azarian twice daily starting after surgery R et al. A comparison of low molecular weight heparin with Tinzaparin 50 IU/kg once daily starting two hours before surgery unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997:337;663-9x Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinus vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomised double blind studies. Arch Intern Med 2002;162:1833-40 The box showing evidence based use of antithrombotic prophylaxis isx Walker ID, Greaves M, Preston FE. Guideline: Investigation and adapted from the 6th ACCP guidelines Geerts WH, et al. Chest management of heritable thrombophilia. Br J Haematol 2001;119:132-75S. The figure showing Plasma D-dimer concentrations on 2001:114;512-28 day of presentation according to final diagnosis is adapted from Bounameaux H, et al. Lancet 1991;337:196-200.12

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