doi: 10.1136/jcp.46.2.97 1993 46: 97-103J Clin Pathol

 B T Colvin and T W Barrowcliffe Thrombosis Task Force.second revision. BCSH Haemostasis andon the use and monitoring of heparin 1992: The British Society for Haematology Guidelines

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J Clin Pathol 1993;46:97-103

Leaders

The British Society for Haematology Guidelineson the use and monitoring of heparin 1992:Second revision

B T Colvin, T W Barrowcliffe on behalf of BCSH Haemostasis and Thrombosis TaskForce

Properties of unfractionated and lowmolecular weight heparinCHEMISTRY OF HEPARINUnfractionated heparin is a naturally occur-ring glycosaminoglycan produced by the mastcells of most species. It is extracted fromporcine or bovine mucosa, all the productscurrently used in the United Kingdom beingof porcine origin. It consists of alternatingchains of uronic acid and glucosamine, sul-phated to varying degrees, and has a molecu-lar weight range of 5000-35 000, with a meanof about 12 000-14 000.Low molecular weight heparin is manufac-

tured from unfractionated heparin by con-trolled depolymerisation using chemical(nitrous acid or alkaline hydrolysis) or enzy-matic (heparinase) methods. Although theseprocesses yield different end groups, there isno evidence that these differences in chemicalstructure affect biological function. The bio-logical properties of any low molecular weightheparin are primarily determined by its mole-cular weight distribution. The products cur-rently available have an average molecularweight between 4 000 and 6 000, and60-80% of the total polysaccharides liebetween 2 000 and 8 000.

greater than the anti-IIa or APTT activity. Inthe low molecular weight heparins currentlyavailable the ratio of anti-Xa to anti-Ila ac-tivity ranges from 1-8 to 3*5.

STANDARDISATIONWhen initially developed, low molecularweight heparins were assayed against theunfractionated heparin standard by a varietyof different methods and the units for the dif-ferent products could not readily be com-pared. An international standard for lowmolecular weight heparin was establisJed in19864 and all manufacturers now use it to cal-ibrate their products for both anti-Xa andanti-IIa activities. In some published and con-ference presentations, however, other unitsare still quoted. In particular, the Sanofiproduct, Fraxiparine, is often described in"Institut Choay Units" (ICU)-these being ameasure of anti-Xa activity-but they shouldbe divided by about 2-5 to obtain the equiva-lent in international units of anti-Xa activity.When this is done the dose requirement forprophylaxis of deep vein thrombosis in gener-al surgery falls within a fairly narrow range forall products: from 2000 to 3500 IU of anti-Xa activity, once a day subcutaneously.

During the preparation ofthis report the membershipof the Task Force was:

Chairman: Dr B T Colvin

Secretary: Professor S J

MachinMembers:Dr TW BarrowcliffeDr M GreavesDr C A LudlamDr I J MackieProfessor F E PrestonDr P RoseDr I D WalkerAdditional advice was givenby DrM P Colvin andDr M RafteryCorrespondence to:BCSH Secretary,British Society forHaematology,2 Carlton House Terrace,London SW1Y 5AY.

Accepted for publication8 July 1992

ANTICOAGULANT ACTIVITIESAll anticoagulant activities of unfractionatedheparin and low molecular weight heparindepend on the presence of a specific pentasac-charide sequence which binds with high affin-ity to antithrombin III (AT III) andpotentiates its activity2; this sequence is pre-sent in about one third of the chains inunfractionated heparin but in lower propor-tions in low molecular weight heparin becausesome of these sequences are destroyed by thedepolymerisation process. Acceleration ofinhibition of factor Xa (anti-Xa activity)requires only the pentasaccharide sequence(approximate molecular weight 1700), butpotentiation of thrombin inhibition (anti-Ilaactivity, also prolongation of APTT) requiresa minimum total chain length of 18 saccha-rides (molecular weight approximately5400).3 Therefore, in all low molecular weightheparin preparations the anti-Xa activity is

PHARMACOLOGYUnfractionated heparin is available as sodiumor calcium salt. After subcutaneous injectionof equal amounts the overall anticoagulantactivity is lower with calcium than with sodi-um salt, but this does not affect clinical effica-cy. There may be a lower incidence ofecchymoses after subcutaneous injection ofthe calcium than of the sodium salt, but thereis not clear evidence for any major differencesin the incidence of haemorrhagic effects. Alllow molecular weight heparins are in the sodi-um form except Fraxiparine, which is a calci-um salt.

Both unfractionated heparin and low mole-cular weight heparin are given parenterally,either by intravenous or subcutaneous injec-tion. Metabolism is by a saturable mecha-nism, involving binding to endothelial cellsand clearance by the reticuloendothelial sys-tem, and a non-saturable mechanism involv-

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ing mainly renal clearance. Both mechanismsare important for unfractionated heparin, butrenal clearance predominates for low molecu-lar weight heparin. There is no evidence thateither unfractionated heparin or low molecu-lar weight heparin crosses the placenta.

DIFFERENCES BETWEEN UNFRACTIONATEDHEPARIN AND LOW MOLECULAR WEIGHTHEPARINThe principal aspects in which low molecularweight heparin differs from unfractionatedheparin are as follows:

PharmacokineticsLow molecular weight heparin has a longerhalf-life than unfractionated heparin, by bothintravenous and subcutaneous injection.5 6The intravenous half-life is about 2 hours,measured as anti-Xa activity, though some-what shorter (about 80 minutes) when mea-sured by anti-IIa assay. The half-life ofunfractionated heparin is dose-dependent butat normal intravenous doses is from 45-60minutes by both assay methods. The subcuta-neous half-life of low molecular weightheparin is about 4 hours, measured as anti-Xa activity. Unlike unfractionated heparin,which has a bioavailability of less than 50%,all low molecular weight heparins have abioavailability iafter subcutaneous injection of100%. These differences in pharmacokineticsand bioavailability are responsible for the suc-cessful use of once daily subcutaneous injec-tions of low molecular weight heparin forprophylaxis of deep vein thrombosis. There isno evidence for differences in pharmacokinet-ics between the different products.

Interaction with proteinsSeveral proteins interact strongly with heparinto antagonise its anticoagulant activity, themost important being platelet factor 4 (PF4)and protamine. Binding affinity to these pro-teins is reduced with decreasing molecularweight, so that low molecular weight heparinpreparations require higher concentrations ofPF4 or protamine to neutralise their activitythan does unfractionated heparin. Below 18saccharides heparin chains become increas-ingly resistant to neutralisation by either ofthese agents, so that all low molecular weightheparin preparations have a portion of theiranti-Xa activity which is non-neutralisable.37Animal studies indicate, however, that thisdoes not affect the ability of protamine toneutralise the haemorrhagic action of lowmolecular weight heparins.8

Interaction with celsLow molecular weight heparin binds lessstrongly than unfractionated heparin toendothelial cells, and this is partly responsiblefor the difference in pharmacokinetics,because endothelial binding and processing isan important mechanism of clearance forunfractionated heparin. Low molecularweight heparin also interacts with plateletsless readily than unfractionated heparin,whether measured as potentiation of sponta-

neous aggregation or inhibition of agonistinduced aggregation.9

Release of lipaseLow molecular weight heparin, when given insimilar doses to unfractionated heparin,releases lower concentrations of the enzymeslipoprotein lipase and hepatic lipase from thevascular endothelium.

Clinical use ofheparinHeparin is used in the treatment of estab-lished thromboembolic disease (therapeuticadministration) and to prevent thrombosisand embolism (prophylactic administration).It is also valuable in the maintenance of extra-corporeal circuits in cardiopulmonary bypassand haemodialysis.

Therapeutic administrationINDICATIONSTherapeutic heparin is given to treat condi-tions in which thrombosis or embolism hasoccurred. More heparin is required for thispurpose than for prophylaxis.

Currently accepted indications are: deepvein thrombosis; pulmonary embolism; myo-cardial infarction; unstable angina pectoris;acute peripheral arterial occlusion.

At present only unfractionated heparin canbe recommended for therapeutic use in nor-mal circumstances, although clinical trials oflow molecular weight heparin are being con-ducted and already indicate a potential role inthe outpatient management of deep veinthrombosis.'0O1Where possible, a coagulation screen and

platelet count should be performed beforebeginning treatment.

ROUTEHeparin can be given either intravenously bycontinuous infusion, using an infusion pump,or by intermittent subcutaneous injection intothe anterior or anterolateral wall of theabdomen near the iliac crest or thigh, usingsmall volume syringes with small bore needlesso that a precise dose can be delivered.'2 Therecommended concentration for subcuta-neous administration is 25 000 IU/ml.

DOSAGEDeep vein thrombosis and pulmonary embolismIn adults an intravenous loading does of5000 IU is given, save in severe pulmonaryembolism when 10 000 IU may be advisable.Anticoagulation is maintained by intravenousinfusion of 1-2000 IU/hour or subcutaneousinjection of 15 000 IU 12 hourly, adjusted ineach case by laboratory monitoring, 4-6hours after the treatment has started.

Children or small adults should receive alower loading dose and maintenance therapycan be calculated on the basis of15-25 IU/kg/hour intravenously or 250 IU/kg12 hourly subcutaneously.

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Myocardial infarctionHeparin is used to prevent:(a) Coronary reocclusion after thrombolysisCurrent regimens include (i) 2000 IU intra-venously followed by 12 500 IU subcuta-neously 12 hourly after streptokinase,1314 (ii)5000 IU followed by 1000 IU/hour intra-venously after tissue plasminogen activator.'5(b) Mural thrombosis Subcutaneous injec-tion of 12 500 IU subcutaneously 12 hourlyfor at least 10 days is effective.'3 16

Unstable angina pectorisAn intravenous regimen is used. The samedoses as for deep venous thrombosis and pul-monary emobolism given above apply.'7

Acute peripheral arteial occlusionSurgical treatment is often used in this condi-tion and thrombolytic treatment or full thera-peutic heparin treatment, or both, arefrequently used.

Disseminated intravascular coagulation (DIC)The use of heparin in DIC is not establishedbut its use is logical where the manifestationsare predominantly vaso-occlusive. Because ofthe risk of bleeding, it is unusual to adminis-ter more than 1000 IU/hour.

LABORATORY MONITORINGDaily laboratory monitoring is essential whentherapeutic heparin is prescribed. The APTTtechnique is the most widely used for thispurpose and a value of 1 5-2-5 times the mid-point of the normal range is common prac-tice. Depending on the APTT reagents used,this roughly corresponds to a heparin concen-tration of 0-2-0-4 IU/ml.'8 The calciumthrombin time is an alternative test. TheAPTT and calcium thrombin time are notsensitive to low molecular weight heparin andare inappropriate for monitoring treatmentwith this drug.

ADJUSTMENT OF DOSERoutine APTT tests should be performed atthe same time each day and in the same rela-tionship to subcutaneous doses. An intervalof 4-6 hours between injection and testing isappropriate. An increased dose may require asmall bolus injection of 3-5000 IU if animmediate effect is desired. If a reduction ofdose is necessary it is advisable to stop theintravenous infusion for 30-60 minutesbefore reducing the dosage.Where necessary, protamine can be given

intravenously to neutralise the effect ofheparin. The effect is instantaneous and 1 mgof protamine is roughly equivalent to 100units of heparin. If heparin neutralisation isrequired 60 minutes after heparin injectiononly 50% of the theoretical calculated dose ofprotamine should be given, while after 2hours from heparin injection only 25% of thecalculated dose is appropriate. Dose can alsobe calculated by a protamine neutralisationtest. Protamine should be given slowly over10 minutes because it can cause hypotensionand bradycardia, and not more than 40 mg of

protamine should be given in any one injec-tion except in the context of cardiopulmonaryby pass. Treatment may have to be repeatedbecause protamine is cleared from the circu-lation more rapidly than heparin. Allergic andeven anaphylactic reactions may occur, par-ticularly in diabetics who have received prota-mine zinc insulin.

DURATION OF TREATMENTParenteral treatment should continue until itis no longer required or until oral anticoagu-lants have achieved a therapeutic effect. Thisgenerally takes at least three days even if theINR falls within the appropriate therapeuticrange earlier because of the different half-livesof the vitamin K dependent factors. Four tofive days of heparin treatment is usually suffi-cient, but longer courses of nine to 10 daysmay be advisable for patients with massiveilio-femoral thrombosis or major pulmonaryembolism.'9 20

CONTRAINDICATIONSThere are no absolute contraindications toheparin but the main risk is abnormal bleed-ing.

Full treatment is more hazardous aftermajor trauma or recent surgery (especially tothe eye or nervous system).

It is not desirable to treat patients who areseverely thrombocytopenic with heparinbecause the drug itself can reduce the plateletcount (see complications) and because of theadditional haemostatic defect. If it is neces-sary to give heparin to patients with thrombo-cytopenia a reduced loading and maintenancedose should be given.

Other relative contraindications include:congenital or acquired haemorrhagic diathe-ses; recent cerebral haemorrhage; uncon-trolled hypertension; hepatic dysfunctionincluding oesophageal varices; renal failure;peptic ulceration; known hypersensitivity toheparin.

Prophylactic administrationINDICATIONSProphylactic heparin is given to prevent deepvenous thrombosis and pulmonary embolism,particularly in patients at risk when undergo-ing a surgical procedure under general anaes-thesia which lasts for over 30 minutes andrequires a stay in hospital after surgery.

In the context of general surgery high riskpatients include those aged over 40, thosewho are obese, those who have a malignancy,those who have had prior deep vein thrombo-sis or pulmonary embolism, those with anestablished thrombophilic disorder and thoseundergoing large or complicated surgical pro-cedures. Any patient undergoing majororthopaedic surgery has a higher risk ofthromboembolism and special techniqueshave been developed to address this problem.The prevention of deep vein thrombosis andpulmonary embolism in these and other situ-ations was the subject of a consensus confer-ence held by the US National Institutes of

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Health in 1986.21 This remains a usefulsource of information and advice, althoughlow molecular weight heparin was not avail-able at that time. It also contains a valuablereview of the indications for other methods ofprophylaxis such as low dose warfarin, dex-tran, external pneumatic compression andgraduated-compression elastic stockings. Amore recent account of the prophylaxis ofdeep vein thrombosis has been published.22

General surgeryThe recommended regimen for generalsurgery using unfractionated heparin is23:Preoperative 2 hours-5000 IU subcutaneouslyPostoperative -5000 IU subcutaneously

every 8-12 hours for 7days or until patient ismobile.

Low molecular weight heparins have notbeen shown to be more effective than unfrac-tionated heparin in this group. There is noconsistent evidence of a clinically importantalteration in postoperative bleeding.24Dose requirements for each product have

been established following extensive clinicaltrials, and manufacturers' dose recommenda-tions should be strictly followed. It should benoted that overdosage with low molecularweight heparins may cause bleeding without asignificant prolongation of the APTT.No laboratory monitoring is necessary for

standard prophylactic doses of unfractionatedheparin or low molecular weight heparins. Ifit is decided that monitoring of prophylacticheparin is desirable then anti-Xa assaysshould be used. These assays may be per-formed by coagulation methods but are sim-pler by chromogenic substrate techniques,and commercial assay kits are available. Bothmethods should be controlled by the appro-priate international heparin standard. In theevent of overdose it may be more difficult toneutralise the effect of low molecular weightheparin because of its longer half-life andlesser sensitivity to protamine.

Orthopaedic surgeryStandard heparin prophylaxis can reduce therisk of thromboembolism in patients under-going major orthopaedic procedures butdespite its use 25% of patients will still devel-op deep vein thrombosis.25 Several solutionshave been proposed.Adjusted dose heparin-A dose adjusted regi-men using APTT monitoring to maintainminimal prolongation of the test has beenshown to reduce further the incidence ofthrombosis in hip surgery.2627 This approachrequires close cooperation between surgicaland laboratory staff.Low molecular weight heparin-Several studieshave shown that low molecular weightheparin in a fixed dose can reduce the inci-dence of venous thrombosis to about 15%. 24

Turpie et al conducted a randomised trialof enoxaparin compared with placebo inpatients undergoing total hip replacementusing a fixed dose regimen and showed afourfold reduction in thrombosis.28 The over-

all incidence of venous thrombosis in thetreated group was 12% with a 4% incidenceof proximal thrombosis. There was no evi-dence of an increase in bleeding. Leyvraz et alcompared their adjusted dose unfractionatedheparin regimen with a fixed dose ofFraxiparine and showed that the low molecu-lar weight heparin was more effective in pre-venting proximal venous thrombosis after hipreplacement, with comparable bleeding com-plications.29Thus low molecular weight heparin seems

to be the treatment of choice in majororthopaedic surgery to the lower limbbecause of its effectiveness and because theonce daily regimen requires no laboratorymonitoring.Warfarin prophylaxis-Although this is effec-tive, some surgeons are reluctant to operateon patients taking warfarin.Heparin plus dihydroergotamine-Dihydroergo-tamine 0.5 mg subcutenously is given witheach standard heparin dose.30 The disadvan-tage of this approach is the risk of peripheralischaemia.

OTHER PREPARATIONSSeveral other preparations are being devel-oped which may have a role in the preventionof venous thromboembolism. Of these, der-matan sulphate, heparan sulphate, and thelow molecular weight heparinoids are relatedto heparin and have been considered bySamama and Desnoyers.24

PregnancyHeparin is the drug of choice for women whorequire anticoagulation during pregnancybecause it does not cross the placenta. It doescarry the risk of causing maternal osteoporo-sis, however, particularly if the dose exceeds20 000 IU/24 hours for more than 5months.'8 There are no conclusive scientificdata on this subject and information is oftencontradictory. Dahlman, Lindvall, andHellgren found no correlation between osteo-porosis and heparin dose or duration of treat-ment in pregnancy, and in their study thechanges were reversible in most cases," find-ings which contrast with those of the earlierstudy by de Swiet et al.32 It should be remem-bered that oral anticoagulation can be rein-troduced immediately after delivery wherenecessary and that women taking warfarinmay safely breastfeed.

PROPHYLAXIS OF THROMBOEMBOLISMTo prevent thromboembolism in motherswith a history of deep vein thrombosis or pul-monary embolism an initial dose of 5000 IU12 hourly by self administered subcutaneousinjection has been recommended. An increasein dose may be needed in the last trimester toprolong the APIT to 1-5 times an averagecontrol value at the midinterval22 althoughthis can be difficult to achieve. Letsky recom-mends 10 000 IU 12 hourly subcutaneouslythroughout the antenatal period, only chang-ing the dose by reducing it if levels of more

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than 0 3 IU/ml are found by anti-Xa assay.33Titrated heparin has been used successfully inthe management of antithrombin III deficien-cy, antithrombin III concentrate being usedto cover delivery.4 Some authorities cautionagainst the prescription of warfarin at anystage of pregnancy because of the risk ofembryopathy in the first trimester and fetalhaemorrhage later, but others approve its usefrom 16-36 weeks, maintaining the INRbetween 2-0-3-0. The exact time at whichany prophylaxis is started will depend on thenature of the risk, the previous obstetric his-tory, and the mother's own wishes but it maybe possible to delay drug treatment until latein pregnancy when the greatest risk of throm-boembolism develops.

Patients receiving full therapeutic doses ofheparin must reduce their heparin dose onthe day of delivery to a dose of 10 000-15 000 IU/24 hours intravenously (or 5000-7500 12 hourly subcutaneously). Patientsreceiving prophylactic doses of heparinshould generally continue their treatmentunchanged during labour and delivery. In anyevent the APTT must be checked to ensurethat anticoagulation is not excessive.

Epidural analgesia for those women whohave been receiving heparin during pregnancyremains a difficult and controversial problem,but providing the coagulation screen is withinnormal limits it is probably safe to introducean epidural catheter.'5

ANTIPHOSPHOLIPID SYNDROMESPatients with lupus anticoagulant or anticar-diolipin antibodies, or both, who have experi-enced previous thrombotic episodes shouldalso receive heparin prophylaxis. Wherepatients have suffered recurrent miscarriagesdespite low dose aspirin treatment, heparinprophylaxis should be considered in subse-quent pregnancies. If heparin monitoring isperformed the APTT test may be unreliableand an anti-Xa assay is better.

PROSTHETIC HEART VALVESThe management of pregnant women withprosthetic heart valves is difficult and contro-versial. The problems have been highlightedby Iturbe-Alessio et al.36 They found that lowdose heparin 5000 IU 12 hourly subcuta-neously was ineffective in preventing valvethrombosis while the incidence of embryopa-thy in patients receiving coumarin derivativesfrom the 6th to the 12th week of gestationwas between 25 and 30%. A higher dose ofheparin (15 000 IU 12 hourly subcutaneous-ly) has been recommended by Hirsh.'8Women with artificial heart valves who wishto become pregnant therefore require carefulcounselling. It is important to emphasise thatthere is no perfect solution to the problemand that the choices of management will liebetween:(i) Continuing warfarin throughout pregnan-cy and accepting the risk of embryopathy.(ii) Using heparin throughout pregnancy andaccepting the risk of osteoporosis as well as apossible increased risk of thrombosis.

(iii) Using heparin until 12-16 weeks, fol-lowed by warfarin up to 36 weeks, and thenreverting to heparin until delivery.When using the higher dose heparin pro-

phylaxis it would be wise to monitor APTT,aiming to achieve values about 1-5 times anaverage control value at the mid interval.

LOW MOLECULAR WEIGHT HEPARINIt is still too early to give any specific recom-mendations on these preparations in pregnan-cy. They have the advantage of once dailyadministration but there is no reason tobelieve that osteoporosis will be less likely tooccur with prolonged use.

In circumstances where higher doses arerequired anti-Xa assays are necessary for lab-oratory monitoring.

Extracorporeal circulation andhaemodialysisCARDIOPULMONARY BYPASSHeparin is universally used as the anticoagu-lant during cardiopulmonary bypass proce-dures.The bypass machine is primed with a crys-

talloid solution to which 1000 IU of heparinare added to each 500 ml. If stored blood isalso used for priming 3000 IU are added toeach unit of blood.

Before the cannulation of the heart andmajor blood vessels, which is required beforebypass surgery can begin, heparin is givenintravenously through a cannula placed in alarge central vein. The dose is determined onthe basis of the surface area or weight of thepatient. Usually the initial dose is 300 IU/kg.The administration of heparin is controlled

both before, during, and after bypass by mon-itoring the activated clotting time (ACT) inan automated system in the operating theatre.Estimations are made every 30 minutes. Inpatients not receiving heparin the normalACT in one system is 100-140 seconds.During cardiopulmonary bypass the saferange is between 400-500 seconds and fur-ther increments of 5000 IU are given tomaintain this level, as necessary.'7When bypass is discontinued heparin can

be reversed readily with protamine. A stan-dard dose is usually given, but it is moresophisticated, though more time consuming,to titrate the dose of protamine with ACTmeasurements using ACT tubes to whichknown amounts of protamine have beenadded.38

Protamine, unlike heparin, may have toxiceffects on the cardiopulmonary circulationand it is usual to adminster protamine cau-tiously after bypass.

HAEMODIALYSIS AND HAEMOFILTRATIONNone of the membranes used in haemodialy-sis and haemofiltration is sufficiently biocom-patible to enable the dialysis process to becarried out without anticoagulation of the cir-cuit. In modern haemodialysis machines aheparin pump is incorporated and heparin isinfused directly into the exit line of the extra-

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corporeal circuit. Current clinical practice isto administer a loading dose of heparin at thestart of the session, and to give a continuousinfusion, which is usually discontinued aboutone hour before dialysis is due to stop toallow adequate haemostasis to take placewhen the dialysis needles are removed.The dose requirements of the patients

receiving dialysis vary widely according to theindividual. The anticoagulant effect is usuallymonitored by whole blood clotting time and,in patients without potential bleeding compli-cations, the clotting time is usually main-tained in excess of 40 minutes. In practice, toachieve this will require a loading dose whichvaries from 1-5000 IU and a maintenancedose of 1-2000 IU hour which gives aheparin concentration of > 0 5 IU/ml.39 Thedose variability depends on the weight of thepatient, the volume of the extracorporeal cir-cuit, the pump speed, which can vary from150-450 ml/minute, and the biocompatibilityof the dialysis membrane. In patients who areactively bleeding, or who have a knownbleeding tendency it is possible to dialyse forshort periods without heparin, using highpump speeds and short dialysis circuits.Usually, however, lines will begin to clotbetween 60 and 120 minutes after startingdialysis. Alternatively, regional heparin treat-ment can be given; heparin is infused into thecircuit as the blood leaves the patient and aneutralising dose of protamine is infused intothe circuit as the blood is returned to thepatient.

Low molecular weight heparinsA potential advance in this area has been theintroduction of low molecular weightheparins which have a much prolonged half-life in renal failure and therefore may havethe advantage of avoiding maintenance infu-sion. Lipolytic effects tend to be less.Interestingly, patients receiving maintenancehaemodialysis will be anticoagulated withheparin for about 900 hours a year and thequestion of whether heparin induces osteo-porosis has been much discussed. This bonylesion has been very difficult to extrapolatefrom the complex picture of renal osteodys-trophy, however, and there is no hard evi-dence that it is a major clinical problem orthat low molecular weight heparins will beless likely to contribute to it.

Monitoring of low molecular weightheparins in haemodialysis by anti-Xa assays isstill not fully established, although the lowmolecular weight international standard willbe useful, and the new technique has not yetachieved wide acceptance.

ComplicationsHAEMORRHAGEHaemorrhage usually results from excess doseor idiosyncratic response to conventionaldose. Serious concurrent illness, chronicheavy consumption of alcohol, and concomi-tant use of aspirin have also been impli-cated.18

The management of heparin overdose hasalready been considered in the section onadjustment of dosage.

THROMBOCYTOPENIAThis is a rare complication of heparin treat-ment in the United Kingdom and may becommoner with the bovine then the porcinepreparation. It can occur at any dose andwhether heparin is given by the intravenousor subcutaneous route. Both unfractionatedheparin and low molecular weight heparin areassociated with thrombocytopenia and regu-lar monitoring of the platelet count is advis-able.

Clinically important thrombocytopenia isusually delayed, occurring 6-10 days after thestart of treatment and is immune mediated.Paradoxical thrombosis is common and theheparin should be stopped immediately.'8

Heparin from a different source or lowmolecular weight heparin may be tried butcross-reactivity has been described and it isdifficult to judge the appropriate dose of lowmolecular weight heparin for therapeutic use.The heparinoid ORG 10172 has minimalcross-reactivity with heparin. Hirudin andancrod are other potential alternative drugs.An immediate decline in the platelet count

after starting therapy is also occasionallyobserved, and is thought to be a direct effectdue to platelet aggregation and probably doesnot occur with low molecular weight heparin.It is of little clinical importance.

OSTEOPOROSISThis complication of heparin treatment hasonly been described with prolonged use andis probably independent of molecular size. Itis discussed in the section on pregnancy.

ABNORMAL LIVER FUNCTION TESTSAn increase in serum aminotransferasetivity has been reported in patients whobeing treated with heparin. This doesseem to be of any clinical importance.40

ac-arenot

OTHER SIDE EFFECTSLocalised skin necrosis and anaphylaxiscaused by hypersensitivity have been de-scribed. Alopecia is very rare.

Medical auditThe use and monitoring of heparin treatmentis a suitable topic for medical audit whichmight include local reviews of indications,therapeutic and prophylactic doses, and con-trol.

Protocols might be drawn up for the use ofheparin in pregnancy and agreement reachedon the indications for the various heparinpreparations available.

These guidelines should be read in conjunction withGuidelines on oral anticoagulation: second edition 1990' andGuidelines on the prevention, investigation, and managementof thromboembolism in pregnancy 1992 (to be published)which have also been prepared by the Task Force.The advice contained in these guidelines is believed to rep-

resent the state of the art at the time of going to press. It ispolicy to revise the guidelines as new developments occur. Itmay not be possible to do this at the time of such changes,

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however, and the guidelines should always be used with dueregard to current acceptable practice.Comments are invited to assist the review process.

1 BCSH Haemostasis and Thrombosis Task Force.Guidelines on oral anticoagulation: Second edition. JfClin Pathol 1990;43:177-83.

2 Lindahl U, Backstrom G, Hook M, Thunberg L,Fransson L, Linker A. Structure of the antithrombin-binding site in heparin. Proc Nad Acad Sci USA 1979;76:3198-202.

3 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U.Anticoagulant activities of heparin oligosaccharides andtheir neutralization by platelet factor 4. Biochem J 1984;218:725-32.

4 Barrowcliffe TW, Curtis AD, Johnson EA, Thomas DP.An International Standard for low molecular weightheparin. Thromb Haemostas 1988;60:1-7.

5 Boneu B, Caranobe C, Sie P. Pharmacokinetics of heparinand low molecular weight heparin. In: Hirsh J, ed.Antithrombotic therapy. Bailliere's clinical haematology.1990;531-44.

6 Albada H, Nieuwenhuis HK, Sixma ]J. Pharmacokineticsof standard and low molecular weight heparin. In: LaneDA, Lindahl U, eds. Heparin-chemical and biologicalproperties-clinical applications. London: Edward Arnold,1989:417-32.

7 Harenberg J, Wurzner B, Zimmermann R, Schettler G.Bioavailability and antagonization of the low molecularweight heparin CY 216 in man. Thromb Res 1986;44:549-54.

8 Van Ryn-McKenna J, Cai L, Ofosu FA, Hirsh J,Buchanan MR. Neutralization of Enoxaparine-inducedbleeding by protamine sulfate. Thromb Haemostas 1990;63:271-74.

9 Salzman EW, Rosenberg RD, Smith MH, Lindon JN,Favreau L. Effect of heparin and heparin fractions onplatelet aggregation. J Clin Invest 1980;65:64-73.

10 Hirsh J, Levine MN. Low molecular weight heparin.Blood 1992;79:1-17.

11 Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous lowmolecular weight heparin compared with continuousintravenous heparin in the treatmnent of proximal-veinthrombosis. NEnglJMed 1992;326:975-82.

12 Bentley PG, Kakkar W, Scully MF, et al. An objectivestudy of alternative methods of heparin administration.Thromb Res 1980;18: 177-87.

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