Guidelines on the diagnosis and management of heparin‐induced thrombocytopenia: second edition

Abstract

The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). The 2006 guideline (Keeling et al, 2006) was reviewed along with additional information published since 2005. A search was performed of PubMed and Embase using the term ‘heparin induced thrombocytopenia’ combined with ‘diagnosis’, ‘treatment’ and ‘clinical presentation’. The search covered articles published from January 2006 to April 2012. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK Haematologists, the BCSH, and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the clinical features of heparin-induced thrombocytopenia (HIT), the indications for monitoring of patients on heparins for HIT, the investigation of suspected HIT and the treatment of HIT. The pathophysiology of HIT has been described in several reviews (Warkentin, 2003; Kelton, 2005; Greinacher et al, 2010). HIT is caused by the development of IgG antibodies directed against a complex of platelet factor 4 (PF4) and heparin. The antibodies primarily recognize a heparin-induced conformational change in the PF4 tetramers (Horsewood et al, 1996) which is affected by the chain length and degree of sulphation of the heparin. This partially explains the differences in incidence of HIT observed with different preparations. Theoretically, the optimal concentration of heparin to produce conditions that favour the development of HIT are thought to be associated with prophylactic rather than therapeutic doses of heparin. The IgG/PF4/heparin complexes bind to and activate platelets through their Fc receptors and may also generate thrombin by other actions (Qian et al, 2010) resulting in a prothrombotic condition that is associated with venous and arterial thrombosis. The frequency of HIT in different settings has been comprehensively reviewed (Lee & Warkentin, 2004; Linkins et al, 2012). It is important to distinguish between the frequency of antibody detection, antibody formation with thrombocytopenia (HIT), and HIT with thrombosis. The incidence of HIT is greater with bovine than with porcine heparin and for thromboprophylaxis is greater with unfractionated heparin (UFH) than with low molecular weight heparin (LMWH) (Martel et al, 2005). All heparins used in the United Kingdom are of porcine origin. The frequency of HIT is greater in surgical than medical patients. In trauma cases the severity of injury and the need for major surgery strongly affects the risk of developing HIT (Lubenow et al, 2010). In orthopaedic patients given subcutaneous prophylactic heparin, the incidence is approximately 5% with UFH and 0·5% with LMWH (Warkentin et al, 2000; Lee & Warkentin, 2004). We previously recommended platelet count monitoring in orthopaedic patients receiving LMWH thromboprophylaxis. This has become a significant issue with the move to extended thromboprophylaxis in hip and knee surgery. The American College of Chest Physicians (ACCP) recently made a 2C recommendation that platelet count monitoring be restricted to those where the risk is >1% (Linkins et al, 2012), whereas previously monitoring was recommended where the risk was >0·1% (Warkentin & Greinacher, 2004a; Keeling et al, 2006; Warkentin et al, 2008a); we agree with this approach. In medical patients given therapeutic porcine UFH the risk of HIT is approximately 0·7% (Lee & Warkentin, 2004) and in medical patients given subcutaneous UFH a rate of 0·8% was reported (Girolami et al, 2003). A study in medical patients given LMWH for prophylaxis or treatment reported an incidence of 0·8% (Prandoni et al, 2005). This was surprising given that, in a meta-analysis, LMWH had been found to carry a 10-fold lower risk than UFH (Martel et al, 2005), and while this analysis contained mostly orthopaedic studies, other studies in medical patients had shown a similar pattern (Lindhoff-Last et al, 2002; Pohl et al, 2005). The results reported by Prandoni et al (2005) was the principal reason our previous guideline (Keeling et al, 2006) recommended monitoring the platelet count in medical patients receiving LMWH in contrast to the 2004 ACCP guideline (Warkentin & Greinacher, 2004a). The 2008 ACCP guideline (Warkentin et al, 2008a) reconsidered this paper but at that time concluded that it overestimated the incidence of HIT and still did not recommend routine platelet count monitoring in medical patients receiving LMWH (Warkentin et al, 2008a). The 2012 ACCP guidelines (Linkins et al, 2012) do not recommend routine platelet count monitoring in medical patients receiving LMWH as the risk is under the new 1% threshold. This is a particularly important issue given the move towards higher rates of thromboprophylaxis for medical patients. Further, a recent study has suggested that higher rates of venous thromboembolism (VTE) prophylaxis do not increase the rate of HIT and that surveillance in patients on VTE prophylaxis may have a very low yield (Jenkins et al, 2011). A recent analysis of 25 653 medical in-patients found rates of ≤0·2% in patients on prophylactic LMWH, treatment dose LMWH, and prophylactic UFH, but 0·7% on treatment dose UFH (Kato et al, 2011). The risk of HIT is very low in obstetric patients given LMWH. A systematic review identified 2777 pregnancies in which LMWH was given (Greer & Nelson-Piercy, 2005). In the 2603 given LMWH as prophylaxis there were two cases of thrombocytopenia not thought to be related to heparin, and in the 174 given LMWH as treatment there was one case of thrombocytopenia also not thought to be related to heparin treatment. If HIT develops the platelet count typically begins to fall 5–10 d after starting heparin, although in patients who have received heparin in the previous 3 months it can have a rapid onset due to pre-existing antibodies. Occasionally, the onset can occur after more than 10 d of heparin exposure but it is rare after 15 d. In patients undergoing cardiopulmonary bypass a significant fall in platelet count is very common in the 72 h post-surgery (Nader et al, 1999). In these patients platelet recovery followed by a secondary fall in counts between post-operative days 5–14 is much more suspicious of HIT than a low count that persists beyond 4 d (Selleng et al, 2010). A very rare prothrombotic disorder characterized by thrombocytopenia that is similar to HIT, but occurs without heparin exposure has been described (Warkentin et al, 2008b). In HIT the platelet count normally falls by >50%; the median nadir is 55 × 109/l (Warkentin & Kelton, 2001; Warkentin, 2003). Severe thrombocytopenia (platelet count <15 × 109/l) is unusual. Ten to 20 percent of patients who develop HIT whilst receiving subcutaneous injections develop skin lesions at the heparin injection site (Warkentin, 1996). Half of the patients who develop HIT will have associated thrombosis. Furthermore, in those presenting without thrombosis (isolated HIT) the risk of subsequent thrombosis is up to 50% if heparin is not stopped and an alternative anticoagulant given in therapeutic doses (Warkentin & Kelton, 1996). If HIT is suspected in a patient receiving heparin on the basis of a fall in the platelet count, the probability of HIT should initially be judged on clinical grounds. Four features are particularly helpful in estimating the likelihood of HIT (Warkentin, 2003): the degree of thrombocytopenia, the timing of the onset, the presence of new or progressive thrombosis, and whether an alternative cause of thrombocytopenia is likely. A ‘4Ts’ scoring system (Table 1) was devised to assess the pre-test probability (Warkentin, 2003; Warkentin & Heddle, 2003). It has subsequently been shown that if the score is low, HIT can be excluded without the need for laboratory investigation (Lo et al, 2006; Pouplard et al, 2007; Bryant et al, 2008; Sachs et al, 2011). If the pre-test probability is not low, heparin should be stopped and an alternative anticoagulant given whilst laboratory tests are performed. An alternative, more detailed, HIT Expert Probability (HEP) score has been developed (Cuker et al, 2010). This scoring system demonstrates greater inter-observer agreement and better concordance between laboratory testing and expert diagnosis, potentially enabling more patients to have the diagnosis appropriately excluded clinically (52% vs. 38% in this preliminary study). Further evaluation of this tool is awaited. A possible further use of clinical scores is that they may allow the use of more rapid but less sensitive tests to rule out the diagnosis in patients with intermediate pre-test probability, for example no patient who had an intermediate pre-test probability 4Ts score and a negative particle gel immunoassay had HIT in two studies (Pouplard et al, 2007; Bryant et al, 2008) (n = 79 and n = 105 respectively); a positive result mandates an alternative anticoagulant whilst more specific tests are performed. Tests for HIT antibodies can be classified as platelet activation assays or immunological assays using PF4 or heparin as the antigen. Standard light transmission platelet aggregometry (LTA) using platelet-rich plasma (PRP) has been used to detect aggregation of normal platelets in the presence of patient plasma and heparin (Chong et al, 1993; Warkentin & Greinacher, 2004b). HIT antibodies produce activation of platelets at 0·1–0·5 iu/ml heparin that is no longer seen at 100 iu/ml heparin. At best, the sensitivity of this method is 85% (Warkentin & Greinacher, 2004b). Donor selection is important, as platelet responsiveness to HIT antibodies varies among normal donors, with approximately one in seven donors being responsive. Greater sensitivity can be achieved using washed platelet assays. The Heparin Induced Platelet Activation Assay (HIPA) (Greinacher et al, 1991; Eichler et al, 1999) and the Serotonin Release Assay (SRA) (Sheridan et al, 1986; Warkentin et al, 1992) are generally accepted as the reference standard assays for HIT. However, they are only available at a few centres because the use of washed platelet assays is difficult (Eichler et al, 1999) and the SRA requires working with radiation. The multiple electrode platelet aggregometer Multiplate® (Verum Diagnostics, Munich, Germany) has recently generated a renewed interest in impedance aggregation-based HIT assays. This uses whole blood, avoiding any platelet preparatory step, but still requires a HIT reactive donor. It has recently undergone a multi-centre validation which has shown it to be superior to LTA and as good as the SRA with a reported sensitivity of 90% (Morel-Kopp et al, 2012). There are five commercial enzyme-linked immunosorbent assays (ELISAs) available to detect either IgG only or IgG/A/M antibodies. They vary in the way PF4 is presented in the assay, e.g., surface-bound PF4-heparin (Asserachrom HPIA; Diagnostica Stago, Asnières, France) or polyvinylsulphate-PF4 surface bound (GTI-PF4; Quest, Knowle, UK). One ELISA variation is to use heparin bound to a solid phase (Zymutest; Hyphen, Quadratech, Surrey, UK), which allows heparin complexes and other chemokines that exhibit heparin affinity to bind to the so-called functionally active heparin. The following commercial companies all produce IgG-only ELISAs available in the UK, Stago Diagnostica, GTI, AESKU, Pathway diagnostics, Hyphen. All assays take approximately 1–2 h to perform and have quality control material provided. If positive, the ELISA can be repeated using high dose heparin (100 iu/ml). of a positive result by more than 50% in the is of clinically significant HIT antibodies et al, 2010). high levels may not using the in the presence of very HIT antibodies et al, 2011). immunological tests have a very high sensitivity but the is A strongly positive a much greater likelihood of HIT than a positive (Warkentin, 2005; Warkentin et al, Furthermore, higher ELISA have been with thrombosis et al, 2004). with HIT and an an risk of thrombosis out of with those with between and out of Warkentin et al whether the additional of and antibody or They found that additional of and antibodies by the immunoassay by antibodies. A new that is has recently become available Asnières, the 10 to perform et al, 2011). There is validation of this method available at the There are other rapid tests available of which are HIT IgG/A/M and IgG specific and IgG/A/M assay, UK). the gel particle method UK), using with that as the solid or the Quadratech, Surrey, UK). All of these assays provide rapid results but although the sensitivity of may standard ELISAs they all also have In clinically suspected HIT, activation assays and and assays have similar high sensitivity and a negative HIT is less using standard platelet aggregometry with (Greinacher et al, is greater with the activation assays and with as the are more to detect clinically antibodies (Warkentin et al, The of the pre-test probability of HIT should be with the of used and result to the probability of HIT (Warkentin et al, 2003). We the by heparin, and the for a positive rather than the as positive or The and likelihood for tests on the It has been that a positive SRA and a strongly positive have likelihood of 20 and for HIT surgery (Warkentin & Greinacher, 2004b). We recognize that, in routine clinical do not have to platelet activation assays and the diagnosis of HIT should be by a but in the of will the patient using pre-test probability of HIT with the results of an et al, 2012). In the United the alternative for use in HIT are and and have UK but not for this specific use of is and will be The use of will be for the specific cases of and bypass The of treatment is that patients with a high or HIT UFH or LMWH and treatment with an alternative The anticoagulant treatment of HIT should be the whether or not it is by thrombosis at the time of LMWH is not an alternative if HIT develops treatment with UFH because there is in in approximately 50% of and are demonstrates in (Pouplard et al, which is only in & while is but is not by antibodies generated that it should be associated with a low risk of developing HIT (Warkentin et al, used in can increase the risk of thrombosis in HIT and should be there has been of the It should then be with of the alternative anticoagulant (Warkentin et al, et al, is being used is in the of the is in HIT. and platelet has been in a of patients with suspected HIT on good clinical and laboratory & There is that platelet to risk (Greinacher & Warkentin, 2004). on it is to platelet for patients with HIT and but prophylactic platelet is generally not alternative anticoagulant is it is important to it in therapeutic doses as as there is for treatment in cases where doses for prophylaxis in other have been used in active HIT. This to all cases whether or not they are by thrombosis at the time of The for this is the high rate of a prophylactic dose of or in to dose or higher doses of followed by in the Heparin studies et al, the treatment of HIT with an alternative anticoagulant (Greinacher et al, should the and of the available treatment because of of the and can the prothrombotic in HIT. In of it is suggested that should be and at the diagnosis of HIT and that is only after the platelet count has the normal and then using low dose rather than high dose (Linkins et al, 2012). is a of and It to a It has a dose and a of approximately not the time and has a on the time which be used to If monitoring is a specific for should be The is not affected by that may the as anticoagulant or may be of only in patients with and weight et al, is in the for use in two use of a low dose of or and a higher dose which of a injection followed by a dose by weight followed by for 4 h then for 4 h then or as a studies of patients et al, et al, reported using or 10 However, studies that low dose are associated with a higher rate of new than therapeutic doses of or et al, with HIT by thrombosis were given a dose while those with HIT without thrombosis were given lower on patients that at d there were no differences between for the of or new thrombosis. There was a increase in new in patients given at low doses to dose or with low dose were more to the combined than those with = that low dose is treatment in patients with active HIT. the other dose to at new thrombosis. In a study of was superior to (Chong et al, is a thrombin that is The that it in the of HIT is in a condition that is by or developing The in HIT are two studies et al, where it was with by of heparin along with using a The quality of these studies was further by the that a of the patients in the analysis were found to be HIT antibody negative on testing et al, 1999) and by the that of the patients had a rather than an of HIT. The combined from these studies the for patients with HIT, of were with for to an of with et al, treatment in a significant in the of a of due to thrombosis, secondary to thrombosis, or new thrombosis d of for patients with HIT without thrombosis at diagnosis and with thrombosis at diagnosis patients the for patients with and without thrombosis at the time of diagnosis and from thrombosis by a fall in of or that to of of or that was the or a was similar in with no significant in the There has been the of in in HIT patients. rates in patients with and with that, while has with risk for and for (Warkentin et al, 2008a). It has been suggested that the of on the may result in of & 2005). it has been suggested that, in the studies, or were to the of that these should not be treatment et al, requires no dose in but it is in and expert dose in patients in the et al, 2012). of is performed using an The in the of is that used in the two studies et al, an of but not 100 A consensus suggested laboratory should generate dose to recommend concentration should be et al, 2012) but a of the Society for Thrombosis and Haemostasis found that the were similar seven different & 2005). standard is with as a with dose on the has in for dose in patients and the an dose of on clinical scoring for evaluation of as and and have been et al, 2012) and a for this group of patients is given in Standard dose in routine patients without repeated h of any dose and at repeated 4 h of any dose and at of the and this to be in the of patients to and should be for at d and an of should be observed for two days is An for the in this is not given but at very high levels the patient may be We that, at an the should be for 4 h and the two recent & Warkentin et al, there are case patients that is not only an anticoagulant in the of HIT, but it to have a low risk of all patients reported in these no new after treatment with which that can provide in patients with HIT 2011). The of these patients was patients were given prophylactic doses of whilst were given therapeutic doses on their weight and 10 on the associated with the use of prophylactic doses of we that therapeutic doses should be given with of and HIT is in in the rates of HIT in patients receiving are low that routine monitoring of this is not (Greer & Nelson-Piercy, 2005). There are few on the in and a clinical using a scoring as combined with laboratory testing as In strongly suspected HIT and in HIT, heparin exposure should be and an alternative anticoagulant There are on the use of and in HIT in The of is on the use of (Lindhoff-Last et al, 2005). In pregnancies given for heparin or HIT (n = were in given up to and was in a further pregnancies to for a of not related to treatment. There were two of which were were due to There were which were not to There are a of case the use of in et al, 2008; et al, et al, 2012). In two of these was used in with with et al, et al, 2012), and in was used for with a good et al, The for subcutaneous injection the use of and in where is there are using the in et al, 2010). patients with HIT and thrombosis we HIT as a risk factor and recommend with for 3 months (Keeling et al, et al, 2012). HIT not by thrombosis we recommend therapeutic for 4 to the of thrombosis as suggested from studies (Warkentin & Kelton, & is where a patient with previous HIT requires a of or anticoagulant prophylaxis an alternative to UFH or LMWH should be and may be as may new as and on the clinical e.g., and may be used as as orthopaedic surgery. and have been used 2004). for the use of in are given in In the of with UFH, the and the rapid that use should be There is a and that the use of UFH in patients with previous HIT. in patients who develop HIT, there is no between the of onset and previous heparin Further, in patients with rapid onset HIT, there is an with recent heparin exposure 100 but not with more heparin HIT antibodies are with a median time to of d. that the antibodies that HIT are that there is no in HIT and that onset HIT due to renewed heparin There are of heparin to and surgery in patients with previous HIT et al, 2000; Warkentin & Kelton, 2001; et al, 2003). In patients with recent or HIT who surgery the risk associated with further heparin exposure is much greater and it should be if the use of UFH by the use of an as or have been reported et al, 2001; et al, 2000; et al, The of patients in these is and the to very few The 2012 ACCP guideline (Linkins et al, 2012) the use of for cases of HIT where surgery is primarily on the results of two studies in and surgery et al, 2007; et al, 100 and patients clinical by of and were observed in and of patients at The of use in this reported in of patients et al, and was seen in the patients with pre-existing but there were no In patients using a dose post-operative in of patients. In were seen in the in a of patients et al, There are published for the use of and in surgery (Warkentin & Greinacher, 2003; & 2004; Warkentin & 2005). for in this have been and these can be by a time If the is by with the of the and the of an may There is of the use of for in the UK and it is for use in patients who do not have HIT et al, 2003). the and information in these guidelines is to be and at the time of to the the British Society for Haematology the any for the of these