Guidelines on the use and monitoring of heparin

Abstract

The guideline group was selected to be representative of UK-based medical experts. The drafting group met and communicated by e-mail. Draft guidelines were revised by consensus. Since the initial guideline published by the British Committee for Standards in Haematology (BCSH; Colvin & Barrowcliffe, 1993) evidence-based guidelines on the use and monitoring of heparin have been included in the American College of Chest Physicians Consensus Conferences on Antithrombotic Therapy (ACCP; Hirsh & Raschke, 2004) and the Scottish Intercollegiate Guidelines Network (SIGN; http://www.sign.ac.uk/guidelines/fulltext/36/section12.html). Reference to these guidelines is advised for a comprehensive review of the evidence. The recommendations in this BCSH guideline generally reflect those of the ACCP and SIGN and are updated where appropriate to encompass recent studies. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com). The target audience for this guideline is healthcare professionals involved in the management of patients receiving heparin. This guideline will be reviewed in 2008. Interim addendums will be published as required on the BCSH website (http://www.bcshguidelines.com). Heparin remains the most widely used parenteral antithrombotic. The general adoption of low-molecular weight heparins (LMWHs) represents a significant therapeutic advance in terms of ease and convenience of administration. There may also be some advantages in terms of efficacy and fewer side-effects. A further development has been the introduction into clinical practice of the synthetic pentasaccharide factor Xa inhibitor, fondaparinux. This compound may have additional advantages although its role in prophylaxis and treatment has yet to be fully defined. Heparin is a naturally occurring glycosaminoglycan produced by the mast cells of most species. The pharmaceutical drug is extracted from porcine or bovine mucosa. All the products currently used in the United Kingdom are of porcine origin. Heparin consists of alternating chains of uronic acid and glucosamine, sulphated to varying degrees, and has a molecular weight (MW) range of 5000–35 000 Da. Samples of heparin over the last 50 years have shown a steady rise in MW with a concomitant rise in specific activity (Mulloy et al, 2000); current preparations have a mean MW of about 13 000–15 000 Da and specific activity of 180–220 IU/mg. Although unfractionated heparin (UFH) is still employed, for many indications there has been a trend towards use of fractionated or LMWHs. These are manufactured from UFH by controlled depolymerisation using chemical (nitrous acid or alkaline hydrolysis) or enzymatic (heparinase) methods. Although the processes yield different end groups, there is no evidence that these differences in chemical structure affect biological function. The biological properties of any LMWH are primarily determined by its MW distribution. As shown in Table I, the products currently available for clinical use have an average MW between 3000 and 5000 Da. They are heterogeneous in MW, although the polydispersity is less than that of UFH and 60–80% of the total polysaccharides lie between MW 2000 and 8000 Da. All anticoagulant properties of UFH and LMWH depend on the presence of a specific pentasaccharide sequence, which binds with high affinity to antithrombin and potentiates its activity (Lindahl et al, 1979). This sequence is present in about one-third of the chains in UFH but in lower proportions in LMWHs because some of these sequences are destroyed by the depolymerisation process. Acceleration of inhibition of factor Xa (anti-Xa activity) requires only the pentasaccharide sequence (approximate MW 1700 Da), but potentiation of thrombin inhibition [anti-IIa activity, also prolongation of activated partial thromboplastin time (APTT)] requires a minimum total chain length of 18 saccharides (MW approximately 5400 Da; Lane et al, 1984). Therefore, in all LMWH preparations the anti-Xa activity exceeds the anti-IIa activity. The ratio of anti-Xa to anti-IIa activity varies between 1·6 to 4·2 for all except one product, which has the lowest MW and an anti-Xa to anti-IIa ratio of 9·6 (Table I). There has been much debate about the relative importance of anti-Xa and anti-IIa activity in the anticoagulant of LMWHs in have shown that the with anti-IIa activity are for the inhibition of thrombin in et al, with only anti-Xa activity have activity in the synthetic which has been shown to be an in clinical et al, of the LMWHs with anti-Xa than anti-IIa activity and for anti-Xa activity is the only that be used for monitoring LMWHs. that of to the of although the efficacy of as an that anti-Xa activity is also heparins are in by the or United by the and There is a between the products available in are in using the on prolongation of the of LMWHs were the UFH by a of different and the for the different products be for LMWHs was in et al, heparin is available as or of the anticoagulant activity is lower with than with but this affect clinical There may be a lower of of the than of the but there is no evidence for any differences in the of All LMWHs are in the except which is a UFH and LMWHs are by or is by a to cells and by the and a are for but for LMWHs. This is as of LMWHs may with in There is no evidence that UFH or LMWHs the The in which UFH and LMWHs is in weight heparins have than and et al, The is about as anti-Xa activity, although by anti-IIa The of UFH is is by methods. The of LMWHs is about as anti-Xa activity although there are some differences in between LMWHs. which has a of all LMWHs have a of These differences in and are for the clinical use of of with heparin to its anticoagulant activity, the most factor and affinity to these is with MW, that LMWH preparations of or to activity than 18 heparin chains to by of these that all LMWHs have a of anti-Xa activity that is & Lane et al, 1984). that this affect the of to the of LMWHs & although the of a fully of of LMWHs has been as a in to clinical practice weight heparins less than UFH to and this is for the in because and is an of for LMWHs also with less than as potentiation of or inhibition of et al, LMWHs lower of the and from the than The clinical of this is about LMWH be as a drug or be as a & As in Table I, there are differences in the in properties of the has to specific on the and clinical of a there are a of for LMWHs as a of They the of and although produced by different chemical have The differences in MW and anticoagulant activity in are to be of in for the with high affinity to antithrombin to have a MW than the there is a the MW which have the anti-IIa activity, are the MW and anticoagulant of the of the products are to be much than from of in a clinical of the evidence published that any differences in and the be although there have been this may only for the group of LMWHs. as which has a lower MW and much lower anti-IIa activity than the (Table and the synthetic pentasaccharide with only anti-Xa activity and no anti-IIa activity and a of clinical further are differences relative to the LMWHs with mean MW are to be the United Kingdom LMWHs have UFH as the in many clinical LMWH is the treatment of for the and treatment of and treatment of in most A further recent development has been the introduction of for the of in patients with and those total or on which heparin and to for The and the of or The of and with the or of the The relative efficacy of different heparin preparations and and the relative with these The recommendations in this BCSH guideline generally reflect those of the ACCP and SIGN and are updated where appropriate to encompass recent studies. The to the of the British for on for indications and of heparin in some the of LMWHs over UFH has been but the lower of with generally use over UFH et al, of the of LMWHs are recommendations have been in this be for of and prophylaxis to the of Consensus heparin and be as are most et al, UFH a of 5000 the of and and because of in patients general and et al, & LMWHs are as and are et al, there is a lower of and LMWHs be by et al, be for LMWH or UFH The of in is et al, et that UFH in a significant in all of efficacy in the and clinical clinical and This also a in total for all patients primarily because of in LMWHs have been with UFH in and have shown in and efficacy and in some a but significant in efficacy et al, et al, total the of is as shown in the of patients et al, This to patients were receiving with a patients be to have a of that that the of may have over recent this is to the in British which have been and to and and are and et al, et al, has also been in the of lower The that of and for the of the of by approximately one-third no on the of this and also no on in or The and of the have been and recommendations have been use & et al, many use with than a LMWH or There has been no of with UFH or a Scottish Intercollegiate Guidelines Network in that patients total or be for LMWH or The has been et al, Although this was as a A the was that be no was between LMWH and the Consensus of the American College of Chest Physicians on Antithrombotic that LMWH is the for and & Raschke, UFH was an but and was to be less and was UFH and were for The of prophylaxis or remains is for but may for to prophylaxis the of total and and by et al, The ACCP LMWH prophylaxis for with prophylaxis for of has been shown to the of in patients with LMWH et al, The of as to or or into a was to be there was a significant of in the group and an that in patients receiving clinical and for may be to LMWH for the of in this group of patients as but some have still to be to with be for LMWH for and of are in patients than those total or and the of but there are to the on or et al, to the of in the there was no on was shown to be than a LMWH in a et al, A recent has shown the of with in a significant in and clinical & Scottish Intercollegiate Guidelines Network has that all patients with The Consensus of the American College of Chest Physicians on Antithrombotic LMWH for patients was as was less with LMWH be for patients present there is no evidence that heparins the of or in A of UFH et al, A LMWH the of in patients with UFH et al, with LMWH be for by weight heparins have been shown to the of in with lower et al, et al, et al, on has been to be high of with lower may be for with LMWH of the of in patients the role of heparin has been less defined. UFH and LMWHs the of there is a significant of & and for this of may be the most of be to the relative from in to is or and is or The of to of and the is to the Scottish Intercollegiate prophylaxis of for further recommendations in specific of those and of in there are fewer with heparin and is less and than in has shown that heparin the of but there is no of LMWHs over UFH et al, a lower and a lower of the use of LMWH et al, are required to which of medical patients be LMWH in the patients than years with an of and or or a medical with an additional factor for in the were to or with was with a of or was the of a the efficacy and of 5000 with as in a total of medical patients for a total of were for the presence of and a significant in was in the treatment group et al, to the has the use of the factor Xa inhibitor, in of medical A significant in and in was et al, patients determined to be high of be for with LMWH of heparin that patients with with LMWHs for have a This has also been in some in which patients were to a LMWH or in to et al, et al, The remains and has yet been are required to a and as and of this that patients heparin as an clinical many patients with will into a group for and be for with The of LMWH anticoagulant for the of in patients with et al, that with a LMWH was than with anticoagulant in a of patients with and are for use as clinical Antithrombotic has yet been shown to the or of The of is The BCSH Haematology has an that be for all patients to for than there are additional for as a of or of a A LMWH is an additional factor for and be into in the for in in be for LMWH from LMWHs the and are the anticoagulant of for and treatment of of prophylaxis and treatment have been in Guidelines for have been published by the BCSH et al, and for treatment by the College of and The to the a for LMWHs is anti-Xa monitoring is anti-Xa activity be to appropriate is available on the therapeutic use of LMWH in the of the be in the of to of this is LMWH is used in and in this monitoring is the of therapeutic in the with is As is with in the and and as the for some a of is in therapeutic be for the in the that there are no additional of the of LMWH or UFH to levels be of and the be advised that is in or that is in any further heparin. be on to and further be by medical the use of in to heparin be by the in the the of and be by an to be in This may to the of heparin between heparin LMWHs is and different heparins may have to be may be by or There are to on the efficacy of heparin in this is also to the et al, but there is of its use in to Heparin has been shown to the of in patients with & and to in a of et al, et al, LMWHs are as as UFH for treatment of and et al, LMWHs are in of the lower of with be for treatment with Society Standards of which be by heparin LMWH therapeutic be used in patients with are for anticoagulant treatment with be as with a LMWH as in et al, et al, and treatment of patients with has also been There are on the use of LMWHs for or and there is no evidence that LMWHs are to be less some UFH the treatment of because of its and because of clinical treatment with UFH is an initial of 5000 is by a The is generally used to UFH is as as in patients with et al, and be the as for There are no on to patients with UFH is used for treatment of a of 5000 be by an of 18 with of the to with any an be by heparin has been shown to be heparin treatment is is to et al, et al, therapeutic 000 to the may be the is a to treatment et al, There are no on the use of LMWHs. with be with heparin. UFH is used be a therapeutic to the ratio to that of a LMWH is used be a therapeutic is less than is is is and heparin is as with evidence of is to and than are or Heparin has been used in is also with anticoagulant There is no evidence for treatment of with anticoagulant Heparin use is on the in patients with and of in and are with anticoagulant Heparin may be is but patients with a may be with heparin is a LMWH or UFH be UFH was et al, but therapeutic have also been has been used with in some is and is with anticoagulant with be for treatment with heparin. UFH is used may be or a therapeutic to the ratio to that of a LMWH is used be or therapeutic of are some patients have or into the may This is most with of the A recent review of the available that therapeutic or of LMWH and of but there are to any in the development of et al, is may be to a than as a may with because of in the of and heparin is a of be a LMWH or UFH be used heparin treatment is be LMWH or UFH or therapeutic The management of may and and have a role but heparin is also and and to reflect and will be primarily for in these but will be to on the role of the of and the management of from heparin and are for patients with a heparin was shown to the of in patients with with et al, the ACCP Consensus on Antithrombotic Therapy that all patients be anticoagulant a specific & Raschke, The SIGN guideline on this and of heparin on the specific drug that is UFH is for the with therapeutic LMWH or in patients high of or for those of or evidence of and All patients be for LMWH or UFH fully to weight heparin be for all patients with high of or be for initial treatment with UFH therapeutic with may be for initial treatment with UFH therapeutic for the The is generally used to and or are as may be patients with therapeutic of UFH the of or additional to the of et al, LMWHs and UFH in a in and but LMWH is with a lower of for and et al, and are also used to patients with and also these treatment weight heparin from and in the British or UFH therapeutic be in patients with in to the of is practice to heparin and and to this for to the using the activated time to heparin Heparin is in patients a but in patients There are a of of heparin use in that a recent of UFH with a LMWH et al, have shown that UFH a LMWH et al, have a in patients with This is because any is by the of patients be for and for heparin is used of UFH or LMWH be and heparin is used in patients There is no on heparin is is generally that therapeutic heparin be a of heparin or in patients there was no in or but there was a in in the heparin group et al, heparin is to be therapeutic There is no evidence to of a of heparin in patients with heparin is therapeutic heparin is be therapeutic is in patients with et al, the of but the role of and for heparin the time of is is practice to a of UFH or a LMWH the end of the and a of heparin may also be used to the is with of heparin and with or of the and management of with is to that with Heparin is used and to the is to a of UFH by a the is is heparin is by the in much the as treatment of with a by an to the ratio to also be heparin for with or in some patients anticoagulant There is no from which to a heparin and no evidence-based guidelines have been A of of use of LMWHs in that there is with UFH in to efficacy and but that are required et al, the of the of and its is to on the management of Heparin is used generally but in which may be and Heparin is to patients with or UFH is to LMWHs as there is a high of and by a heparin is The of UFH has been determined but a lower than that used to is an of which to is may be appropriate. some patients the heparin may be to the clinical for a rise in may be used to heparin in patients with with as in or many years UFH was used in patients with The of all acid on the has the for heparin in most The of heparin in patients is are and with a of recent and recent or of heparin be in with or patients to heparin. The LMWH which may of its of LMWH be used with in with is to be or a of is UFH may be therapeutic is use of UFH with monitoring of the is an LMWH is as prophylaxis or treatment there is a of and be used with clinical for using anti-Xa also be in to high anticoagulant but the of this to monitoring be is a of heparin the be A high of for the of is the is to be with of from of or of is but may be to in some for with a LMWH is used in the to be where a LMWH is in or of the is of to heparin. The and management is the of a BCSH evidence-based guideline in There is some evidence that UFH and LMWHs may a rise in inhibition of development of to be in the of an additional of et al, heparin use but the of is et al, have been in approximately of patients receiving treatment of UFH for than a of heparin receiving heparin lower with et al, of receiving heparin in A further in of patients receiving 000 UFH for et al, The for these is the only were for in the all were for in the were The by which heparin its on to be a in the of cells and a in the of the to its on heparin the activity of cells that et al, for of these heparin by of of an was shown that the of heparin on are et al, an that is to the of heparin to the of the that is only because heparin binds to of evidence that LMWHs are with a lower of than a by et the LMWH was to UFH in patients with for of the patients UFH with only one of receiving of has been to LMWHs et al, and of in may et al, of also a of with LMWHs with UFH et al, The from these are that LMWH is for use and and patients be of the of and this the ratio of heparin heparin has a administration. its anticoagulant is and using The of is determined by the heparin of of UFH of the heparin is required is a because of the of the anticoagulant of LMWHs et al, et al, although there is evidence of clinical in the et al, has no significant on fondaparinux. As from the of of is for of the anticoagulant and be used for this factor has been used in the management of because of a LMWH et al, although of use of for this is has been shown to the anticoagulant of in et al, in the of clinical is of the of the anticoagulant of heparins has been in the treatment of in an to of monitoring has to be to for UFH and LMWHs. Although the thrombin time has been in the monitoring of the to heparin of the thrombin time monitoring and using this which a high of has been but has been widely et al, The has been used most widely for monitoring of therapeutic of UFH in A target ratio of range of is This is on the efficacy and of a heparin by of which to an ratio of in some The evidence that of this is has been et al, et al, between in the of heparin using the has been because of the and in the which in in to heparin. from different and different and heparin by is with ratio et al, the anticoagulant employed, the the used for as as the in the additional et al, et al, et al, Therefore, of the for of be in the of the therapeutic range for UFH is to be as as of the is widely used an anti-Xa may be used for A range of anti-Xa to heparin by to the of heparin activity over time in be by use of as an or of is The is generally to LMWHs and be used for The anti-Xa is but there are significant As the of of LMWHs the anti-IIa activity, in to anti-Xa activity but this varies between LMWH preparations et al, et al, is that the significant anti-IIa activity to the anticoagulant the antithrombin activity to be the in et al, et al, & Therefore, the of by different LMWHs may be the anti-Xa the of the of LMWHs is fully and may depend anti-Xa and anti-IIa heparin factor from and this some of the of LMWHs et al, LMWHs in with and heparin present in and these may also the anticoagulant LMWHs have been the Heparin but there is evidence that this has in an of the anti-Xa and of the anti-IIa activity & et al, The of monitoring of LMWHs by anti-Xa are by the that between available is et al, et al, to be LMWH and this is that anti-Xa to have for or in receiving a in the by et in which were to a LMWH or UFH as for general anti-Xa levels with and only with in a of treatment of using a between and anti-Xa to efficacy although some between of inhibition and efficacy was by a between in and anti-Xa and anti-IIa levels et al, to with LMWH for as be the is a of in the and this is of the anti-Xa et al, this clinical was the most factor monitoring of LMWH using anti-Xa requires an of the anticoagulant and is of efficacy and of some of the of the LMWH in an of the of an for monitoring of LMWHs is that have the efficacy and of LMWH in and monitoring for the treatment of et al, is that monitoring is required as a for and treatment with a clinical have of the and those with and the may be for has been that the of LMWHs in than 3 et al, and may also in et al, et al, et al, the are monitoring by anti-Xa may some on in these monitoring of LMWH is is that an anti-Xa is The be a of the the for LMWH may be Samples are for of anti-Xa of LMWH is for in additional a on a the last may be The of of the and Committee of the Society for and has the recommendations on monitoring of heparin of of UFH is of of LMWH is required be to drug and of in of therapeutic of LMWH is required of therapeutic of UFH be using the of the be to the target of anti-Xa may some to the of LMWH used to in those in or is to be with the the and may also be of some in the of in a receiving a anti-Xa is to LMWH for the heparin in use is and the of the in terms of and of LMWH be are on of of prophylaxis or treatment and are are on and and for the and treatment of that reflect evidence-based guidelines and these be incorporated into and clinical activity. the and in these guidelines is to be and the time of to the the British Society for Haematology the any for the of these has and and has to has to heparins and has from has and clinical from many pharmaceutical and