Diagnosis and management of heparin‐induced thrombocytopenia: Third edition

Abstract

This guideline was compiled according to the BSH process at (https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature search was carried out using the terms given in Appendix until August 2022. The review of the guideline followed the standard BSH guidelines procedure. Following review of the draft guideline by the BSH Haemostasis and Thrombosis Task Force and the BSH Guidelines Committee, it was placed on the members section of the BSH website for comment (sounding board). This guideline updates and widens the scope of the previous British Society for Haematology (BSH) Clinical guidelines for Diagnosis and Management of Heparin-Induced Thrombocytopenia: Second Edition1 to include functional assays in the diagnosis of heparin-induced thrombocytopenia (HIT), when to use direct-acting oral anti-coagulants, and the role of intravenous (IV) immunoglobulins and plasma exchange in the management of HIT and spontaneous HIT. HIT is an immune-mediated, highly pro-thrombotic disorder of platelet activation caused by pathogenic antibodies against a platelet factor 4 (PF4)–heparin complex. It is the most frequent drug-induced immune thrombocytopenia and may lead to life-threatening thrombosis. There are two distinct forms of HIT: type I, also known as heparin-associated thrombocytopenia, which is a non-immunological response to heparin treatment, mediated by a direct interaction between heparin and circulating platelets causing platelet clumping or sequestration, and type II, which is immune mediated. Type I HIT is more frequent than type II, affects around 10%–30% of patients and occurs early, within the first 48–72 h following heparin exposure.2 It generally causes transient, mild thrombocytopenia, and the platelet count returns to normal within 4 days of heparin discontinuation. Type I HIT is benign and is not associated with thrombosis. In contrast, type II HIT is much less frequent, and its incidence ranges from 0.1% to 7% depending on the type of heparin, duration of heparin exposure and patient population. Unfractionated heparin (UFH) is associated with ~10-fold greater risk of HIT than low molecular weight heparin (LMWH).3, 4 HIT typically occurs within 5–14 days of first exposure to heparin and is associated with a significantly increased risk of thrombosis.5 Unlike type I HIT, thrombosis is more frequent in type II HIT and occurs in around 25%–50% of patients.6, 7 When used hereafter in this guideline, ‘HIT’ refers to type II HIT. The complex formed by the binding of heparin to PF4 acts as an immunogen, leading to immunoglobulin (Ig)G antibody production by B cells. Although IgG is the main driver in the pathogenesis of HIT, there is some evidence to suggest IgM and IgA may also have a pathogenic role.8, 9 The antibodies form a heparin–PF4-IgG molecular complex that binds to platelets via platelet FcγRIIa causing platelet activation and aggregation with the release of more PF4 and microparticles, leading to complement and coagulation activation. Furthermore, activation of monocytes through FcγRIIa leads to the expression of tissue factor and binding of HIT antibodies to PF4/glycosaminoglycan complexes on the surface endothelial cells (ECs) causing their activation, creating a pro-coagulant state.10 Platelet activation, aggregation and the activation of complement, monocytes and ECs all lead to thrombosis with thrombocytopenia. Removal of immune complex-coated platelets by the reticuloendothelial system contributes further to thrombocytopenia.11 Anti-PF4–heparin immune complexes are able to induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil–platelet interactions. In a microfluidic system and mouse model, it has been shown that HIT immune complexes are able to induce thrombi containing neutrophils, extra-cellular DNA, citrullinated histone H3 and platelets, whereas depletion of neutrophils abolished thrombus formation.12 Thrombosis in HIT may be venous, arterial, microvascular or a combination and can affect virtually any tissue or organ.10, 13, 14 The immunogenicity of PF4–heparin complexes is affected by heparin chain length and the level of sulphation.15 This may explain the higher incidence of HIT following exposure to UFH compared to LMWH and the near absence of risk with fondaparinux.16, 17 The diagnosis of HIT is based on the key aspects of the clinical history combined with confirmation of PF4-heparin antibodies presence by laboratory tests. Final confirmation can come from a demonstration that the antibodies can mediate platelet activation. In these disorders, the antigen site(s) on PF4 that support anti-PF4 antibodies with heparin-independent reactivity are distinct from those with heparin-dependent reactivity seen in classical HIT. Several reviews have addressed the incidence of HIT in different circumstances.24 The incidence of PF4–heparin antibodies is much higher than the HIT syndrome itself.25 Several factors have been reported to affect the incidence of HIT, but these are not consistent between studies, and most of the studies include only a small number of patients. In general, it appears that lower frequencies are seen with LMWH versus UFH, prophylactic versus therapeutic doses, medical versus surgical patients and minor versus major trauma.4, 26 However, to determine which patients merit monitoring, the absolute risk should be considered. In the meta-analysis by Martel, which contained predominantly orthopaedic patients, the incidences were 0.2% with LMWH and 2.6% with UFH.4 The reported incidence of HIT following cardiac surgery was 1.1%, and in patients supported with extracorporeal membrane oxygenation (ECMO), it was 6.6%.27, 28 Although PF4–heparin antibodies developed after cardiac surgery within 30 days in 50% of around 950 cases (as measured in a polyspecific enzyme-linked immunosorbent assay [ELISA]29 using a cut-off optical density [OD] of 0.4 with >50% inhibition by excess heparin), this was not associated with any increase in death or thromboembolism. Therefore, HIT testing should be confined to cases with sufficiently high clinical suspicion that HIT may be present. Audits have confirmed that using lower-specificity assays alone can lead to substantial overdiagnosis of HIT.30 A retrospective analysis of 25 653 medical inpatients found rates of HIT of ≤0.2% in patients on prophylactic LMWH, treatment dose LMWH and prophylactic UFH, but 0.7% on treatment dose UFH.31 In another study of medical inpatients, the incidence of HIT with subcutaneous UFH was 0.8% (CI 0.1–1.6) and 1.3% for those on prophylaxis.32 A study of neurology patients showed similar results.33 A prospective study of medical patients given LMWH for prophylaxis or treatment reported an incidence of 0.8%, but this figure may be an overestimate.34, 35 A Cochrane review concluded the risk of UFH following surgery was 2.2%, compared to 0.5% in patients receiving LMWH.36 The risk of HIT is very low in obstetric patients given LMWH. A systematic review identified 2777 pregnancies in which LMWH was given.37 In the 2603 pregnancies 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. In a large administrative database including 66 468 antepartum hospitalisations, 66 741 delivery hospitalisations and 16 325 postpartum readmissions where women received pharmacological prophylaxis, 10 women during antepartum, one during delivery and 14 during postpartum had readmissions involving HIT.38 Of these women, none had arterial thrombosis, limb amputation, heart failure or death related to HIT.38 These factors form the basis of the ‘4Ts’ scoring system (Table 1) to assess the pretest probability of HIT.43 A low 4Ts score (≤3) carries a high negative predictive value (0.998; 95% confidence interval, 0.970–1.000) and so heparin use (platelet count permitting) can continue without further testing. An alternative, more detailed HIT Expert Probability (HEP) score was developed and performed better than the 4Ts score in a retrospective study,44 but in a subsequent prospective study, its sensitivity and specificity were similar to the 4Ts score. However, it performed better than the 4Ts score for trainees and in ICU patients, where assessment is complicated by multiple alternative aetiologies.45, 46 Either system is therefore acceptable, but in both cases, the positive predictive value is poor, and a positive score (≥4) should be followed by laboratory testing. The positive predictive value of the 4Ts score in identifying HIT in patients post cardiopulmonary bypass and ECMO was only 0.562 (18/32) and 0.25 (15/60), respectively,27 suggesting that in these patient populations, a low 4Ts score may not be sufficient to exclude HIT.27 A large variability in calculating the 4Ts score by clinicians was noted, and the experience of attending physicians in calculating the score was crucial. The value of the 4Ts score in the diagnosis or exclusion of HIT can be markedly improved by its calculation jointly by the treating physician and an on-call haematologist with experience in the diagnosis and management of HIT.27, 47 There is a good case for platelet monitoring in patients who have a significant risk of developing HIT. The risk/benefit has not been calculated formally, but consensus exists that an incidence <0.1% in a particular patient group does not require monitoring but >1% does. As detailed above, many groups appear to fall between these limits, and recommendations are therefore somewhat subjective. The value of detecting HIT is high. Even if heparin is discontinued, the risk of developing thrombosis within 30 days is 50%.48 In the Nationwide Inpatient Sample (NIS) study of 97 508 discharges coded for HIT, the in-hospital mortality was 10·1% (SE 0.2) compared to 2.1% (0.01) of 149 811 discharges for The from monitoring from the positive the of the 4Ts score and laboratory testing of in an increase in major to therapeutic in patients, with with a higher The of monitoring is a count which is for clinical should be The may be high for patients not in but this is to be may also increase when monitoring of is A platelet count should be heparin The of cases days after platelet monitoring can be to this When there has been exposure to heparin in the days monitoring should the of the the of and the of a it to on at functional platelet aggregation platelet activation or release assays assay in the presence of heparin, were the only for the demonstration of complex Although these the standard for the are complex and to assays have on and the to In some cases, there has been a in sensitivity and specificity for The use of more than one has been reported to increase the sensitivity and specificity of testing where functional assays are not based on demonstration of complex antibodies are on a of within are in with a high of the is a of specificity for those antibodies that platelet activation the of Furthermore, there is of the antibody of which has been used in the assessment of the of developing clinical assays antibodies to PF4–heparin complexes that are to as a IgG complexes are the membrane to a The assay a sensitivity of with compared to have shown that be with from or The to antibodies for PF4–heparin complexes to as are through a The on the of in the presence of through a membrane sensitivity specificity have been reported for both assays at the of have been A is on the in which the PF4-heparin antibodies with with antibodies for This the presence of patient antibodies to PF4-heparin the in an The of this assay is that it is performed on a with sensitivity and specificity to using of and in with assays with the standard for the of anti-PF4 antibodies in the of immunoglobulin that is and in the that PF4 is for antibody include a heparin confirmation In general, have with (CI reported in one meta-analysis using the optical density between and and out HIT. patients PF4-heparin antibodies of IgA and IgM but IgG antibodies are thought to have the for platelet The of IgA and IgM contributes to the lower specificity of polyspecific that all in The specificity of was to polyspecific with of (CI for IgG and (CI for polyspecific in one with similar in another predictive of and polyspecific were both (CI in a It is to use assays positive predictive value at (CI compared to polyspecific at (CI fall of those by functional alone does not the presence of HIT. There is variability between the by different but in general, the the in an the more it is that a functional assay be positive and therefore that a diagnosis of HIT can be The probability of positive HIT antibodies 50% or more when the was or higher in an A positive in the with of the two a low probability of HIT, as by a positive In another study, patients with an using a a increased risk of thrombosis compared to cases with an of of a higher the specificity of assays to anti-PF4 which can and can be associated with of more than in and polyspecific are used for HIT with variability between with different used HIT assays have an analysis of 35 much than which This a and the to The sensitivity of the is The specificity of was to in multiple studies and 66 when using the cut-off of as a for A specificity of was reported in most 66 the combination of and for HIT diagnosis in the absence of a functional Platelet activation assays can be assays that platelet aggregation or a of platelet activation. these assays require a of platelets that have been to be to the presence of patient containing anti-PF4 antibodies in to assays are on the of platelet activation in the presence of from HIT patients and an of of HIT is supported by inhibition of activation in the presence of an excess heparin of platelets may be platelets or plasma should only be performed in The on the of platelet aggregation to in the presence of high and low of heparin in a with a The assay on of known to testing. sensitivity has been reported by using of in the by some a and have a good for positive HIT cases, in a retrospective on detecting increased that with the of platelet in the presence of both patient plasma and heparin and which is by an increased of heparin in the with has been reported to be more than using sensitivity has been reported to be between and can also be performed using release as a of platelet activation. are as aggregation in or of HIT antibody is confirmed by inhibition of aggregation or release by more than 50% in the presence of also to as heparin-induced as a of platelets and has been reported to with a sensitivity from to has been reported to be which to using The has been to as a functional to its high level of specificity and However, at is not in the Several alternative have been developed to the use of and to and for the of assays include and to the against sensitivity and A of laboratory assays for the diagnosis of HIT is in In with pretest probability can exclude a number of cases with with and for This if scoring or are more complex or In this immune and assays are and can h in a of testing 66 of these assays with or have been reported to near to the standard and be assays are for as a in with These criteria from patients with spontaneous HIT be to for or another functional assay as the heparin-induced platelet activation This should not the treatment for these patients. However, criteria as overdiagnosis in patients with thrombocytopenia and positive PF4-heparin antibodies by The of in laboratory for HIT has been in a number of cases of spontaneous there are case of with of clinical following a developing anti-PF4 causing clinical It is to have high clinical suspicion and for the anti-PF4 antibodies using but not by or as the two assays typically negative for there is evidence to the duration of treatment with a in patients who spontaneous HIT. HIT is a pro-thrombotic with an alternative is in a with HIT when the is high or the diagnosis is The of is on the previous history of HIT. with confirmed HIT should be given a at from the of a HIT is in In all cases of or HIT, any form of heparin should be including heparin In to the pro-thrombotic of complexes in patients with HIT, with an to heparin is The include both and oral The duration of treatment in a patient with confirmed HIT, in the absence of thrombosis, is an alternative for at 4 or until the platelet count is greater than is HIT is associated with a of therapeutic is The two direct that can be used in this are and and both require intravenous The dose of may require in patients with by dose is in to for It has been that monitoring be performed using an with a therapeutic of the patients A number of studies have major of for monitoring 97 including the of based on the and used for assessment of as as by and factor of is the of monitoring, with a of by a A guideline a of in patients with a to as it is not to use to in A retrospective study of patients with compared two assays for assay patients, and assay with monitoring by patients, by The study showed a in by without an increase in thrombosis. There was in the incidence of between the two However, assays to levels are not in many in the at present. can be used in HIT patients. is by intravenous or is given of these are through the and can be measured if using HIT is a pro-thrombotic and can anti-coagulants, should be only after the platelet count has in confirmed days of are during the should be when direct and to the the may be affected by the In the case of during the the should be at is two are in the therapeutic and a should be performed h to an In the there have been studies, and case of the use of and and an oral for patients with HIT with and without An in many of these cases is that a was used first to the In a systematic review that patients with HIT with thrombosis at HIT only one patient had thrombus had major but It is to that should not be used when an arterial occurs during The of in patients with HIT, depending on the clinical is in or oral platelet count to or to The of these is may by heparin-independent platelet antibodies against high molecular weight reported the use of and a combination of in HIT cases used alone and cases used and A platelet count was in of cases within an of The suggest may be in or PF4–heparin with the review cases of HIT with alternative reported between and were cases of with thrombocytopenia (platelet and a high of thrombosis, of which were as an and had a to a first of with the it is to use the dose of h based on as the treatment are seen when patients lower than the dose of with be in patients who have HIT with a case of when there is a of to a or in cases where significant the use of therapeutic to heparin following the history of HIT, including management of patients with HIT cardiac and who developed HIT should with heparin, that alternative are this should be given an and that should not in the by a require or a may be to the of the HIT However, UFH is the for patients cardiac surgery and In clinical there are to support the use of UFH in patients with previous HIT The basis for this is that there is between the of and previous heparin in patients who HIT, the previous exposure to heparin is more in the and HIT antibodies are and generally with a of depending on the the to negative for heparin-dependent antibodies in patients who had positive tests. The to a negative according to the analysis was days according to and days in the case of the antigen When it was to heparin during cardiac surgery and surgery in patients with previous HIT has been reported A systematic review that patients with a history of HIT had of heparin Of these patients, the had after following the diagnosis of HIT, and had within between and and and following the diagnosis of HIT surgery was the most for to heparin, and surgery was the for of the patients. patients had to the PF4-heparin antibodies to to heparin, were used as or combination treatment following the in of patients. Following the to heparin, a of HIT in 2.1% of the an with a previous diagnosis of HIT an where heparin is the most first to determine the antibodies are the antibodies have with heparin in the has been by some In patients, and use of UFH or LMWH should be and following the of the an alternative as or should be if the patient or This of the that a of 4 days is to the HIT a HIT diagnosis has been in the previous surgery should be if it is to until the of the with a for is used if the surgery be or the antibodies are with UFH combined with a platelet for has been used in patients with negative PF4-heparin has been used for patients with a history of HIT is for use in patients without and it is to use it for patients with a history for this is not therapeutic to HIT antibodies can be with the use of UFH if In patients with heparin, platelet count monitoring is in the following given the risk of HIT, when heparin is not on more than a heparin and with a as or or the use of to be exposure to heparin the risk of the patient has HIT, require and therefore against the use of HIT is in with most cases following exposure to and only a reported after to the low monitoring of the platelet count is not if with This is supported by a study of women who received with for a of of none developed PF4-heparin The diagnosis of HIT in women is the as in women, be when using scoring to the diagnosis of thrombocytopenia in the different of A study of women that HIT after a of days of alternative that may be used in include and management are for and postpartum as these have may be to the and a risk of and postpartum A small number of case the use of it to be and to an alternative to In a review of pregnancies with its use in appears it does not the and is not found in is in with reported cases and A retrospective study of women who received in confirmed a of obstetric similar to that in the obstetric population. the to a small in but this is to be of clinical It is to the different of compared to LMWH, with a for prophylactic and h in women receiving treatment of The is to in patients receiving therapeutic in is the to and the including the The to for in the literature BSH Haemostasis and Thrombosis Task Force members at the of this guideline and The to the BSH and the BSH Guidelines for their support in this The BSH the during the of this have a of to the BSH and Task Force which may be on of the have any of to of the group the group if any evidence that the strength of the recommendations in this or it The be by the Task and the literature search be to search for any evidence that may have been The be and from the BSH guidelines website if it recommendations are an be on the BSH guidelines website the and in this is to be and at the of to the the BSH the any for the of this A can be found for the group to The is not for the or of any by the than should be to the for the

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