The use of viscoelastic haemostatic assays in the management of major bleeding

Abstract

Major haemorrhage is an important cause of morbidity and mortality, affecting up to 40% of all trauma patients (Stanworth et al, 2016) and 10% of cardiac surgery patients (Serraino & Murphy, 2017). Blood loss is one of the main causes of morbidity following liver transplantation (Gurusamy et al, 2011) and is one of the most common causes of death worldwide in women at the time of delivery (Say et al, 2014). Diagnosis of major bleeding is difficult and is often made using clinical measures (e.g. rising heart rate, falling blood pressure) but these measures can be insensitive, particularly in younger patients in whom blood loss can be masked and haemodynamic stability preserved or in elderly patients on cardiovascular modulating medication. Detection and correction of coagulopathy is therefore an important aspect of management of severe haemorrhage. The British Society for Haematology (BSH) guidelines (Hunt et al, 2015a) recommend the use of serial standard laboratory tests (SLTs), taken every 30–60 min, to monitor major haemorrhage in most clinical settings. There are, however, inherent difficulties with SLTs. Average turn-around-times are between 27 (Cotton et al, 2011) and 77 min (Davenport et al, 2011) which is often too slow for a rapidly evolving situation. Furthermore, the ability of SLTs to predict major bleeding and therefore allow pre-emptive treatment is limited (Segal & Dzik, 2005; Davenport et al, 2011). In liver transplantation for example, it is well known that the prothrombin time (PT) or the International Normalised Ratio (INR) does not differentiate between patients who will or will not bleed excessively (Massicotte et al, 2014), nor does an elevated INR exclude underlying hypercoagulability (Krzanicki et al, 2013). Viscoelastic haemostatic assays (VHA) are increasingly being used during the management of major bleeding. There are several recent comprehensive systematic reviews evaluating the available evidence (Whiting et al, 2015; Fahrendorff et al, 2017; Serraino & Murphy, 2017). Current National Institute for Health and Care Excellence (NICE) guidance recommends VHA use during cardiac surgery, but not for obstetric or trauma haemorrhage (Whiting et al, 2015). This BSH guideline recognises the limited available evidence but, within these constraints, aims to provide pragmatic and practical advice to practising clinicians as to how to interpret and use VHA results during the management of major bleeding in four common scenarios: obstetric haemorrhage, liver disease, cardiac surgery and trauma haemorrhage. This guideline was compiled according to the BSH process at www.b-s-h.org.uk/guidelines. Details of the methodology for inclusion of studies, including the PRISMA diagram, can be found in the online supplement (Appendix S1). 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. Review of the manuscript was performed by the BSH Guidelines Committee Haemostasis and Thrombosis Task Force, the BSH Guidelines Committee and the Haemostasis and Thrombosis sounding board of the BSH. It was also placed on the members section of the BSH website for comment. The Association of Anaesthetists of Great Britain and Ireland endorsed the document. Viscoelastic tests include thromboelastography (TEG), thromboelastometry (ROTEM) and Sonoclot. The most widely used machines are: TEG5000 (Haemonetics S.A., Signy, Switzerland), ROTEM delta (TEM International, GmbH, Munich, Germany) and Sonoclot (Sienco Inc, Morrison, CO, USA). Until recently, all three devices used similar principles based on a cup and pin method to measure the mechanical properties of clot formation in whole blood (Fig 1). A variety of activators are used for each device to examine different aspects of the haemostatic system (Tables 1-3) and, as the blood clots, a graphical representation is made. A typical trace for TEG and ROTEM is shown in Fig 2 and a Sonoclot trace is illustrated in Fig 3. Although TEG and ROTEM traces look identical, the parameters are not directly interchangeable and should not be regarded as equivalent (Coakley et al, 2006; Venema et al, 2010; Hagemo et al, 2015; Rizoli et al, 2016). Fresh WB Citrated WB ‘Plain cup’: Kaolin CK: Kaolin, Ca ‘Heparinase cup ’: Kaolin, heparinase CKH: Kaolin, heparinase, Ca rTEG: Kaolin, TF CRT: Kaolin, TF, Ca FF: TF, Reopro CFF: TF, Reopro, Ca Platelet inhibitor added: contribution of fibrinogen to clot remains. When trace is compared to a standard kaolin trace the platelet contribution can be estimated INTEM: Ellagic acid ‘ROTEM sigma complete cartridge’: Includes: FIBTEM, EXTEM, INTEM and APTEM channels EXTEM: TF ‘ROTEM sigma complete +hep cartridge’: Includes: FIBTEM, EXTEM, INTEM and HEPTEM channels HEPTEM: Ellagic acid, heparinase FIBTEM: TF + cytochalasin C FIBTEM: Platelet inhibitor added: contribution of fibrinogen to clot remains. Can compare results to EXTEM trace to get idea of platelet contribution APTEM: TF + aprotinin kACT: Kaolin Son ACT: Celite aiACT: Celite, clay gbACT+: Glass beads H-gbACT+: Glass beads + heparinase One of the major drawbacks of VHA machines has been the need for users to be trained in basic pipetting: the TEG5000 and Sonoclot operate with manual pipetting, the ROTEM delta with automated pipetting. In response to this challenge, the TEG and ROTEM manufacturers have developed cartridge-based techniques designed to improve ease of use and precision – the TEG6s and the ROTEM sigma. TEG6s has microfluidic cartridges pre-loaded with reagents and uniquely uses resonance technology to record clot formation (Fig 4). Each cartridge has four channels, containing different reagents (Table 1). Despite a different methodology, observational data have shown good correlation between TEG5000 and TEG6s (R time, K time, alpha angle) (Gurbel et al, 2016) in 157 healthy volunteers and 300 cardiac patients. But, similarly to all VHA devices, theTEG6s remains sensitive to vibration (Gill, 2017), an important consideration for road- or air-based analysis. TEG6s cartridges to detect anti-thrombin and anti-Xa agents are in development and a pilot study (Bliden et al, 2017) showed high sensitivity and specificity for direct oral anticoagulant (DOAC) therapies. Only one study has compared ROTEM sigma and delta, evaluating EXTEM and FIBTEM in 30 pregnant volunteers. This study showed no differences between FIBTEM A5 values but reported significantly lower EXTEM A5 and shorter EXTEM clotting time (CT) values with the sigma (Crighton et al, 2017). Further comparative data are needed for exploring new versus older technologies, as switching devices may require significant adjustments to the corresponding VHA-based transfusion algorithm. Native whole blood samples need immediate analysis. Anticoagulated samples should be analysed within four hours of venesection. No specific rest period is recommended by manufacturers prior to analysing citrated blood samples. Users of ROTEM devices have variously recommended resting samples between 30 (Andreasen et al, 2011; Armstrong et al, 2011) and 120 (Theusinger et al, 2010) minutes, whilst others report immediate testing (Oswald et al, 2010; Ogawa et al, 2012a,b). Pragmatically, it is reasonable to perform immediate testing for all VHA tests. Precision of VHA testing has not been widely reported, although operator variation seems to have an important effect. Coefficients of variation of 2·6–11·2% for ROTEM delta and 7·4–19% for TEG5000 parameters were reported in one study with seven operators (Anderson et al, 2014). Inter-laboratory comparison with external quality assurance (EQA) samples shows much poorer precision: 7–49% for TEG5000 and 7–83% for ROTEM delta (Kitchen et al, 2010). Notably this EQA programme used lyophilised citrated plasma samples, which may explain the wide variability. There are no EQA data for the TEG6s or ROTEM sigma. There is no consensus on the desirable frequency of Internal Quality Control (IQC) – reports have ranged from eight-hourly (Pommerening et al, 2014) to weekly (Jeger et al, 2012). As with all IQC, this methodology checks the quality control of the user, and the reagents as well as the device. TEG manufacturers recommend daily electronic checks and monthly IQC for low volume users and more frequent analysis for higher users. ROTEM recommends weekly quality control checks and Sonoclot recommends a viscosity check daily and a monthly reference plasma quality control. These are minimum recommendations and users should take into account volume of testing when deciding on frequency of IQC. The UK National External Quality Assurance Scheme (NEQAS) for Blood Coagulation programme provides a VHA EQA service for TEG5000 and ROTEM delta which uses lyophilized citrated plasma samples with plans in place to offer EQA for TEG6s and ROTEM sigma. The External quality Control of diagnostic Assays and Tests (ECAT) Foundation also offers an EQA scheme using lyophilised plasma. Viscoelastic haemostatic assays tests are poorly standardised and, apart from manufacturers’ reported reference ranges, there is no published consensus for normal ranges. Hospitals should therefore determine local references ranges as is standard practice for the majority of laboratory tests. Determining local ranges may not be practical in the paediatric setting – reference ranges have been reported for children using the ROTEM delta (Oswald et al, 2010) and the TEG5000 (Chan et al, 2007). Viscoelastic haemostatic assays tests are generally insensitive to anti-platelet agents (except α2bβ3 blockers) (Tynngård et al, 2015). Standard ROTEM tests (EXTEM/INTEM CT) can detect DOACs (dabigatran, edoxaban, rivaroxaban) at therapeutic levels, but appear insensitive to apixaban (Seyve et al, 2018). Sonoclot measures are set out in Fig 3. Viscoelastic haemostatic assays are most useful in major obstetric bleeding when the obstetric haemorrhage protocol is activated, though tests may be run earlier if coagulopathy is expected, e.g., with placental abruption or amniotic fluid embolism. The coagulation system at term is procoagulant and normal ranges for many TEG and ROTEM parameters differ at delivery from non-pregnant values. On the ROTEM delta, CTs are shorter and EXTEM and FIBTEM A5 (amplitude at 5 min), A10 and MCF are higher for women in the third trimester of pregnancy (Armstrong et al, 2011; Oudghiri et al, 2011; et al, et al, 2014). On the and K are shorter and alpha and higher at term et al, 2011; et al, 2012). This that an or MCF that is normal for the non-pregnant may a coagulopathy in a term ROTEM or TEG trace may to clinicians to the of an amniotic fluid or placental There are no published data on the normal for Sonoclot during FIBTEM and EXTEM on to the delivery or bleeding are not of bleeding et al, 2017). a low FIBTEM A5 and taken at the time of haemorrhage is of the need for transfusion of blood operator the and who to a FIBTEM A5 of that not a FIBTEM A5 of et al, 2014). TEG clot strength using an of TEG5000 are also of major obstetric et al, 2017). There are no published data on the of Sonoclot for of obstetric bleeding. fibrinogen and FIBTEM well during haemorrhage and can be used to women with a fibrinogen et al, A of women to severe showed that a FIBTEM A5 a fibrinogen for et al, observational study showed that the of an EXTEM and FIBTEM A5 was with et al, acid during if within of delivery 2017). There are no data to the use of APTEM or TEG clot parameters to acid APTEM or TEG clot results should not be used to There are no published data to the platelet with ROTEM or TEG parameters during developed for causes of bleeding may not be in this clot strength parameters are at the time of guidance does not the use of to blood during and recommends (Whiting et al, 2015). A study women with to severe and a FIBTEM A5 to fibrinogen or No in transfusion or blood loss was analysis that if the FIBTEM A5 was fibrinogen was not et al, In the of the women were not with plasma if FIBTEM A5 was or bleeding This not in women significant haemostatic as bleeding with a or normal et al, et al, observational study showed that fibrinogen when FIBTEM A5 was or with severe and when was fluid and to the compared to the use of transfusion with in a of in a and study et al, observational study compared standard with mechanical transfusion et al, 2017). There was a significant in blood loss and transfusion in the The report does not TEG parameters were used to or platelet It not to which of the to the et al, 2017). A for obstetric bleeding has been published but no data were on the et al, 2012). There are no published data on the of Sonoclot to blood use during Viscoelastic haemostatic assays have a for bleeding in liver et al, 2015; et al, et al, 2017) and SLTs et al, A study and ROTEM in bleeding in liver patients found that several ROTEM parameters bleeding shown in EXTEM INTEM FIBTEM A10 and FIBTEM MCF and compared to no tests et al, 2017). In ROTEM values were with EXTEM MCF values bleeding and FIBTEM MCF and these values were with lower levels et al, 2017). A observational study in patients with transfusion based on found the that platelet transfusion was A10 and, for an A10 et al, with a and of and A analysis of ROTEM in patients that the EXTEM and FIBTEM A5 measures can be used to et 2014) with an EXTEM A5 platelet and FIBTEM A5 fibrinogen with values these ranges were to Standard laboratory tests a in patients with liver disease, a from to In a of patients with TEG parameters were within normal although the in to the of liver and of 2012). A good correlation has been reported between the MCF and platelet and fibrinogen levels et al, 2010). But, although TEG and FIBTEM well with can low levels at the time of and should be with et al, 2014). is a significant cause of bleeding in with the A observational study in ROTEM and TEG et al, 2016) showed that ROTEM tests were more sensitive kaolin TEG in study was limited by using VHA manufacturers’ for an standard measure A to of at the time of is on VHA et al, but this to bleeding is It is recommended that TEG heparinase assays or HEPTEM are run et al, The of TEG and ROTEM for haemostatic has to a standard of in many the of high quality The Society of guidelines recommend VHA use during et al, 2017). a practical the major is for patients with a high of bleeding for and difficult and In this setting ROTEM has been shown to significantly blood use and to et al, 2013). observational have shown that VHA-based transfusion during et al, et al, 2010) and the of patients. One study showed a of patients from to with of transfusion from to et al, 2015). the of TEG versus a significant in in the TEG with a to transfusion et al, 2010). A (Gurusamy et al, 2011) that VHA may blood loss and transfusion in There are a of treatment developed by different The consensus in the is not to VHA there is bleeding. The values that pre-emptive treatment have not been and may significantly normal ranges et al, 2012). The clot strength is a measure of and VHA of fibrinogen can to transfusion of et al, 2011) with et al, that include TEG or FIBTEM for fibrinogen in patients who are bleeding the use of fibrinogen but significantly transfusion et al, 2010; et al, 2016). There is for to prothrombin or but a of used a as a for and a INTEM of for transfusion et al, 2014). This study showed an use of and in the patients however, this a significantly higher the that not coagulation The use of VHA has been in the setting of cardiac One compared all three in a observational study of using at and compared with and found TEG to be the most sensitive in platelet and fibrinogen et al, 2014). Sonoclot was the although of the patients and clinical were not et al, 2014). The majority of at of bleeding have been and have used of major which comparison of VHA testing as an has not been shown to predict bleeding. VHA testing is of most have shown that the values are often in the normal and that the between the and the values bleeding et al, et al, et al, 2010; et al, et al, et al, 2014). A in of the VHA is most often with of bleeding. Viscoelastic haemostatic management has been reported to improve clinical cardiac surgery et al, et al, et al, 2015; et al, and in bleeding and lower need for et al, of was also et al, 2017). a recent systematic of patients found no significant in mortality, or (Serraino & Murphy, 2017), with being the in transfusion when used in with as a et al, 2017), or a of et al, 2017) clinical have been significantly A can use of by up to compared to SLTs et al, a in blood use has been with ROTEM & et al, et al, 2015; et al, 2017), and in the setting of cardiac for cardiac surgery et al, 2010; et al, 2013). et showed that using the TEG time and to management to a significant in platelet and use when compared to transfusion TEG These results were in a study et al, 2012). reviews of et al, 2017) and (Serraino & Murphy, 2017) patients have been to management or have results with to volume of platelet the new platelet testing and when specific values of platelet tests have been used to direct of surgery, this has in a significant in rate, use of and use of platelet et al, 2017). In paediatric cardiac surgery, management has in more of bleeding compared to et al, 2012). have shown the following with significant in bleeding and blood et al, et al, 2015). of of ROTEM parameters in showed EXTEM EXTEM A10 and FIBTEM A10 be used to management et al, 2015). have also found good correlation between FIBTEM and fibrinogen in et al, et al, 2016) and children et al, 2014) and levels of fibrinogen can be et al, 2013). et showed of FIBTEM VHA can be used as a of fibrinogen to fibrinogen in to complete of and et al, In in blood use may be when by VHA or but appear to be transfusion et al, and the in for SLTs the need for in the management of these patients. observational have VHA can predict bleeding. a VHA that be used as a which transfusion was more to be but data on the of reported VHA the majority of the that transfusion of clot Only one of these A5 which a is to be at high of has been (Davenport et al, – by Hagemo et al, the of the results to the Davenport et that an EXTEM A5 of or more a high for transfusion The of reported with TEG as has also been with patients who have transfusion VHA are insensitive to and should not be used to et al, 2013). systematic reviews have the limited of the available evidence et al, et al, 2015; et al, et al, Viscoelastic haemostatic assays tests have been used in a variety of to A common method has been to the between VHA and SLTs. report good with the majority coagulopathy using a trauma patients are found to have clotting using ROTEM using SLTs et al, 2010). No comparative data are available for Viscoelastic haemostatic assays measures which are used to trauma coagulopathy but can be by three main of clot in clot strength and in The most common in A and MCF (ROTEM) et al, 2011; et al, et al, 2014) and in et al, et al, – all measures of clot and low clot strength is as an important higher bleeding no consensus is – for Davenport et used an EXTEM A5 of as diagnostic of trauma coagulopathy Hagemo et used reported VHA include of and and of alpha (ROTEM) et al, et al, 2014) and et al, 2017). Viscoelastic haemostatic transfusion for management of severe trauma bleeding have been widely reported using TEG and TEG according to although the principles were similar all There are ROTEM data available and most from the et al, 2011; et al, 2017). These provide ROTEM values for transfusion of fibrinogen and with no for platelet transfusion and no of The observational provide low quality data that transfusion & et al, 2010; et al, et al, transfusion when compared to et al, et al, 2016) and transfusion et al, 2011; et al, 2014). from a and study use of blood and ROTEM into et al, 2017) similar and of This study that VHA-based transfusion may the need for and fibrinogen One using et al, 2016) reported a significant in death at with VHA to death were shorter in the VHA and of lower This study provides evidence that transfusion may be for the management of bleeding in and the of the the be it was a of were used in were to study according to the of the and the VHA was of the were It is to this have on but the of the A used to compare with and et al, 2017). The used ROTEM measures A10 EXTEM in with a clinical measure of bleeding to of with the of As a of high treatment in the to coagulopathy and need for with the study was The reported an between bleeding and ROTEM that be used as a to A evaluating and transfusion in trauma haemorrhage is to be in and the results are The published on the use of to of coagulopathy and to transfusion of blood a practical of it is important to VHA tests transfusion to assess the of haemostatic treatment and to determine that there is no in the haemostatic in the of bleeding. in the clinical the of normal coagulation is one of the most aspects of does this transfusion of blood but it also clinical management to the underlying cause of haemorrhage. This is not to but is by clinicians in with to There are no the principles of how to transfusion are set out in clotting low fibrinogen use use use be if or the normal is not recommended if results normal be at may are in most if results not recommended Viscoelastic haemostatic assays devices have practical as devices for major haemorrhage including of results and a set of parameters that a coagulation the of a systematic to with low quality published data that has not been to important clinical at the evidence to practice is The to and the Blood and Review for in the The BSH Haemostasis and Thrombosis Task was The to the BSH sounding and the BSH guidelines for in this the and to the and of the The BSH the during the of this have made a of to the BSH and Task which may be on The following have the following of from and from and from from 2017; has from and for using for has and from for has and from has and from and The members of the have no of to The will be by the Task and the will be every to for or data that is new or that may have been The will be and from the BSH guidelines website if it new recommendations are made an will be published on the BSH guidelines website the advice and in this guidance is to be and at the time of to the the BSH nor the for the of this The is not for the or of by the should be to the corresponding for the