British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding

This guideline was compiled according to the BSH process at (http: //www. bcshguidances. com/BCSHPROCESS/42EVIDENCELEVELSANDGRADESOFRECOMMENDATION. html). 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. Recommendations are based on the systematic review of English language literature published since the previous guideline publication, from January 2004 to July 2016 (see Appendix S1 for further details). A literature search was undertaken in Medline and Embase from 2004 to 2016, using the following key search terms: blood component transfusion, FFP, fresh frozen plasma, plasma, transfusion, prophylaxis, thaw, prethaw, SDFFP, MBFFP, uniplas, octaplas, FP24, pathogen inactivated or pathogen reduced, cryoprecipitate, supernatant or cryosupernatant. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Transfusion Task Force, the BSH Guidelines Committee and the Transfusion sounding board of the BSH. It was also placed on the members section of the BSH website for comment. Fresh frozen plasma (FFP) is given primarily for three indications: to prevent bleeding (prophylaxis), stop bleeding (therapeutic) or for plasma exchange. Prophylactic transfusions are mainly used prior to surgery or invasive procedures. Many possible indications in patients without major bleeding are not substantiated by robust trial data. Between 2008 and 2012 there was a steady increase in the use of FFP in the UK, possibly influenced by the publications of observational studies in trauma demonstrating that early transfusion of FFP in bleeding patients improves outcomes (Holcomb et al, 2007). From 2012 onward there has been a reduction in the total number of units of FFP issued in the UK, while during the same period the number of units of solvent detergent-treated FFP (SDFFP) issued has increased (Fig 1B). In 2009 a UK-wide audit demonstrated that in adult patients 43% of FFP transfusions were administered to patients with no documented bleeding, as prophylaxis before interventions because of abnormal coagulation tests (Stanworth et al, 2011a). There is no evidence validating FFP use in these settings; this practice potentially exposes patients to unnecessary transfusion. Since 2004 use of cryoprecipitate has steadily increased; in 2015/16 the number of cryoprecipitate units issued by NHS Blood and Transplant (NHSBT) had more than doubled compared with 2003 (Fig 1A). The reasons for this increase remain unclear; an audit in 39 hospitals (2009/2010) in England showed that, of 423 cryoprecipitate transfusions, 25% were transfused prophylactically and 75% were administered for bleeding, the commonest cause for all age groups being cardiac surgery, followed by trauma (Tinegate et al, 2012). In the UK, FFP is produced from whole blood donations which undergo centrifugation, or by apheresis. FFP is leucocyte depleted by filtration during whole blood processing or integral to the apheresis process. Plasma is rapidly frozen to ≤−25°C to maintain the activity of labile coagulation factors. Factor VIII (FVIII) is used for quality monitoring because it is one of the most labile coagulation factors and is therefore a sensitive marker of changes to FFP induced by inappropriate processing/handling. Immediately after being thawed, standard FFP must have at least 0. 7 iu/ml of FVIII in at least 75% of units. Other details of the quality monitoring required, such as residual levels of red cells, platelets and leucocytes are available elsewhere (http: //www. transfusionguidelines. org. uk/red-book). Once frozen, FFP may be stored for up to 36 months at ≤25°C. Typical values for plasma are given in Table 1. Group O: 0·53 (0·52–0·53 iu/ml) Non-O: 0·71 (63–84) 106 (iu/unit) >75% of units >0·50 iu/ml FVIII >75% of units >140 mg/unit fibrinogen >70 iu/unit FVIII >75% of units >700 mg/unit fibrinogen >350 iu/unit FVIII >75% of units >140 mg/unit fibrinogen >50 iu/unit FVIII 75% of units >700 mg/unit fibrinogen >250 iu/unit FVIII Cryoprecipitate is manufactured by slowly thawing FFP overnight at 4°C. This precipitates out cryoproteins: FVIII, von Willebrand factor (VWF), FXIII, fibronectin and fibrinogen. After centrifugation, the cryoproteins are resuspended in a reduced volume of plasma (20–60 ml). The cryoprecipitate specification requires that 75% of packs contain at least 140 mg of fibrinogen and 70 iu of FVIII. UK Blood Transfusion Services (UKBTS) also produce pooled cryoprecipitate prepared from five single donations; the specification is five times that of a single cryoprecipitate unit (i. e. 700 mg fibrinogen and 350 iu FVIII) in a typical volume of 200–280 ml. Cryoprecipitate should be stored at a core temperature of ≤−25°C for a maximum of 36 months. Typical values for cryoprecipitate are given in Table 1. Due to natural variation in coagulation factors levels between donors, there is wide variation in FVIII and fibrinogen levels between units. There is no current clinical indication for cryoprecipitate-depleted plasma (the supernatant left after cryoprecipitate has been removed from plasma) in the UK; this product is no longer produced by the UKBTS. Pathogen inactivated (PI) plasma is indicated for all individuals born after 1 January 1996. The residual risk of a unit of plasma being infectious for known viruses that are tested for is very low (Table 2). There are now three systems that are licensed in Europe for the pathogen inactivation of units of plasma within Blood centres: methylene blue (Theraflex), amotosalen (Intercept) and riboflavin (Mirasol). Of these, currently methylene blue is available in the UK. These systems are based on the addition of a photosensitiser to plasma followed by exposure to visible or ultraviolet (UV) light, and then removal of the photosensitiser (except for Mirasol). A pooled solvent-detergent treated plasma (SDFFP), Octaplas LG, which also includes a prion reduction step, is available in the UK from Octapharma AG (Lachen, Switzerland). Key features of these components are given in Table 2. Available in UK? PLASMA HIV 1 in 15·5 milliona HBV 1 in 2·1 milliona HCV 1 in 95·8 milliona 1% TNBP 1% Triton X-100 1 μmol/l MB+ visible light 30 min 150 μmol/l amotosalen + UVA light 4 min 50 μmol/l riboflavin+ UV 4–10 min YES 4 log) reduction of enveloped viruses, but activity against non-enveloped viruses (hepatitis A virus, parvovirus B19 and hepatitis E virus) are more variable. For this reason, plasma used as a source of SDFFP supplied in the UK is tested for the latter viruses. When frozen, FFP packs become relatively brittle and must be handled with care. Vulnerable parts of the pack include the stumps of the entry lines, which can break off if knocked. All UKBTS provide frozen plasma in a vacuum-packed outer container so that the plasma pack itself does not come into direct contact with thawing devices. Because of the potential for pinholes and cracks in the plastic that may not be visible, it is imperative that procedures for thawing FFP are designed to minimise the risk of bacterial contamination. Once thawed, the primary pack should be removed from the over-wrap bag and examined for leaks or damage. Damaged packs should not be used. If there is any unexpected appearance such as flocculation or discolouration, or apparent leaks, packs should be discarded, or referred for further opinion. There are several methods available to thaw plasma. Those that do not directly expose units to water are recommended to reduce the risk of bacterial contamination. Whatever method is used to thaw plasma, the procedure to follow, cleaning and maintenance schedules should be described by a specific standard operating procedure relevant to the method employed. Methods that thaw plasma using dry heat with agitation are available and in use in the UK. Dry ovens (temperature-controlled fan-assisted incubators) may have a lower potential for contaminating FFP packs with microbes, although they are usually of limited capacity. Although these can defrost FFP in 2–3 min, they have the disadvantage of limited capacity. There are also concerns over the creation of 'hot spots' in the packs and the potential for parts of the pack to act as an aerial causing arcing. Previous studies have suggested that the quality of plasma once thawed is similar to that when using water bath methods (von Heymann et al, 2006; Kuta et al, 2016). The majority of water baths now used in the UK do not expose plasma to water directly, but rather the unit is placed in a pocket around which a water-based solution circulates. When using a water bath, it is essential to place the FFP pack in a vacuum-sealed over-wrap to protect it from bacterial contamination. Water baths used for thawing FFP must only be used for this purpose. All maintenance should be documented and logged. The average time for thawing FFP or cryoprecipitate in water baths is 20 min. Scant data exist in relation to the ideal temperature for thawing of plasma. Data that do exist suggest that temperatures close to 37°C may be optimal, because cryoprecipitate will form when thawed closer to 4°C, and thawing at higher temperatures might affect the viability of plasma proteins. The current recommendation is that plasma be thawed at 33–37°C (http: //www. transfusionguidelines. org. uk/document-library/supporting-papers). However, methods of thawing plasma at higher temperatures, e. g. 45°C, are available, which might improve the speed of thawing. Data on the effect of thawing plasma at 45°C or higher are lacking. It is important that alternative thawing temperatures be validated for all components, and for their maximal post-thaw shelf-life. For SDFFP, the manufacturer's instruction on thawing should be followed. Once thawed, standard FFP may be stored at +4 ± 2°C in an approved temperature-controlled blood storage refrigerator before administration to a patient as long as the infusion is completed within 24 h of thawing. Pre-thawed plasma can also be stored at +4 ± 2°C for up to 120 h for use only in patients who develop unexpected major bleeding (e. g. following trauma). This extended storage of pre-thawed FFP for patients with unexpected major haemorrhage was recommended to enable rapid provision of FFP for these patients where delay would be detrimental while also limiting FFP wastage. Data from NHSBT show that with the exception of protein C, all clotting factors decrease between 24 and 120 h after thawing. Most FVIII loss occurs within the first 24 h following thawing, after which the rate of loss decreases. For other clotting factors, the loss of activity is more linear once thawed. However, with the exception of FVIII, mean levels remain above 70% at 120 h (http: //www. transfusionguidelines. org. uk/document-library/supporting-papers). To minimise the risk of bacterial growth during extended storage of thawed plasma (>24 h), thawing methods that do not directly expose primary plasma packs to water must be used, and time out of controlled storage must be kept to a minimum. Pre-thawed FFP that is out of a controlled temperature environment (+4 ± 2°C), can be accepted back into temperature-controlled storage if this occurs on one occasion only of less than 30 min. Transfusion of FFP should be completed within 4 h of issue out of a controlled temperature environment. At present, there is a lack of evidence relating to how long thawed plasma can safely remain out of controlled temperature storage. This recommendation is based on current practice in other countries and expert opinion, extrapolated from evidence on red cell storage with the aim of minimising FFP wastage, while also ensuring safety of the component for recipients. The recommendation may change in the future as a result of research carried out on FFP storage and bacterial growth. Once thawed, MBFFP may be stored at +4 ± 2°C in an approved temperature-controlled blood refrigerator before administration to the patient, as long as the infusion is completed within 24 h of thawing. The post-thaw shelf-life of this component was reviewed in 2016 and was not extended further (http: //www. transfusionguidelines. org. uk/document-library/supporting-papers), as the coagulation factor content of PI plasma is reduced compared to standard FFP, and some studies have shown an increase in coagulation activation with extended storage of thawed MBFFP (Thiele et al, 2016). There are no trials that have assessed the efficacy of MBFFP versus standard FFP. SDFFP is a licensed medicinal product and therefore its shelf-life following thawing should be governed by the manufacturer (Octapharma). Once thawed, cryoprecipitate must not be refrozen and should be used immediately. If delay is unavoidable, the component should be stored at ambient temperature and used within 4 h. NHSBT have assessed the haemostatic properties of thawed cryoprecipitate beyond 4 h (up to 72 h), and have demonstrated that these are stable i. e. fibrinogen, FXIII, rotational thromboelastometry (ROTEM®) and thrombin generation (Green et al, 2016). However, the potential risk of bacterial contamination arising from storing cryoprecipitate at ambient temperature will need to be assessed before the shelf life of thawed cryoprecipitate can be extended beyond 4 h. Patients who are likely to receive multiple units of FFP should be considered for vaccination against hepatitis A and B (HAV, HBV), and patients who are likely to receive large or repeated doses of FFP should receive pathogen-reduced plasma. Such patients include those with congenital factor deficiencies for whom no pathogen-reduced concentrate is available, and patients undergoing intensive plasma exchange, e. g. for thrombotic thrombocytopenic purpura (TTP). In order to avoid the risk of ABO-associated haemolysis in recipients, plasma of donors with identical ABO blood group to the recipient should be used as the first choice. In an emergency, if the patient's blood group is unknown, ABO non-identical plasma is acceptable if it has 'low-titre' anti-A or anti-B activity. Group O FFP should only be given to group O patients (Table 3). For more details on plasma group for MBFFP, to the guideline et al, 2016). The risk of following FFP transfusion was reviewed in 2004 by UKBTS FFP and cryoprecipitate contain only a of red cell after FFP thawing would be to be in This that following administration of plasma to an is very to (http: //www. transfusionguidelines. org. uk/document-library/supporting-papers). There are three of cell and (Table there is no on plasma blood group following and most clinical practice on current of of ABO The of and recipient blood groups are important when the plasma group for as as ABO and of plasma for patients undergoing is given in Table For patients who of plasma should be by the group at the As for there is no on plasma blood group following and most of the clinical on the of the of ABO and the of when of the is et al, This section will only the use of FFP prior to interventions in patients who have abnormal clotting For the use of FFP in bleeding or for the of coagulation in patients prior to surgery or invasive procedures to the relevant British Society for Haematology (BSH) et al, et al, The UK FFP audit in 2009 showed that of patients FFP in the of clinical bleeding (Stanworth et al, of these patients it prior to invasive procedures for or of time (i. e. or (i. e. mean transfusion of FFP only in or no of or (Stanworth et al, 2011a). The use of FFP prior to procedure in patients with abnormal clotting tests is not by good quality and several systematic observational have that an abnormal or does not bleeding et al, A and of bleeding, and of the bleeding with or other invasive procedure et al, are more important than clotting tests when a procedure is likely to be with For patients with a of bleeding, to a for further is as standard coagulation tests may be there is very evidence to the of use of FFP any clinical in abnormal clotting tests or bleeding (Stanworth et al, All these that there is a need for clinical studies to evaluate the efficacy and safety of FFP in patients with abnormal clotting who are undergoing a to of FFP Other clotting such as or have been shown to be in blood transfusion and during cardiac surgery for bleeding patients et al, et However, their in bleeding in patients with abnormal or time or monitoring the of FFP prior to invasive procedure or surgery, The of wide variation in the of FFP administered first to to (Stanworth et al, A trial early for patients with an of who were to undergo an invasive and patients to receive FFP or no FFP The a where coagulation factors, thrombin and thromboelastometry (ROTEM®) were before and after FFP transfusion at the FFP transfusion had only a effect on coagulation as although levels of and were thrombin was and factors levels were et al, by et compared standard doses of FFP versus higher doses in patients and a such that from patients in the higher group had significantly higher in and levels compared to the standard Although doses of FFP might improve standard tests of coagulation et al, higher doses of blood components will be with further Many published studies the use of plasma are and to in tests with clinical outcomes et al, 2012). In of the practice of plasma transfusion as prophylaxis in patients before invasive procedures to have clinical there is currently evidence to an evidence based recommendation on the for use of FFP prior to invasive procedures in patients with abnormal clotting For of major bleeding the recommended for FFP is to 20 et al, There are data on use of cryoprecipitate in in the UK and have that cryoprecipitate is being administered for use et al, et al, 2012). Cryoprecipitate can be considered in patients because of low fibrinogen 1 for interventions at risk of bleeding, or in If cryoprecipitate is administered in such a a of will increase fibrinogen in an adult by approximately 1 et al, However, there is evidence to the of fibrinogen at which cryoprecipitate transfusion is or the of cryoprecipitate for prophylaxis in patients before invasive procedures. administration of FFP during the of patients with major blood loss may to FFP and cryoprecipitate should not be used for volume in patients who are not coagulation tests in patients are most a result of the such as or in may therefore from of with major blood to of in the of bleeding (Stanworth et al, of do not bleeding risk in a patient and are due to deficiency, or the of coagulation factor a In a controlled trial FFP with no FFP in patients with an of there was no in the of bleeding between the groups et al, A of intensive patients undergoing demonstrated no in bleeding between patients with of or These patients also had thromboelastometry carried out with being within the in all one et al, Patients with have abnormal coagulation studies and may of an studies where coagulation are described in et al, No data exist to practice in patients with a in or A examined patients with according to patients had component prior to of which were in the group and were in the The described bleeding with one of haemorrhage in group and found that FFP transfusion was not in the et al, Many patients in who are have in of the This should be with or FFP is not recommended for of deficiency in such patients in the of of coagulation factors (except FVIII) as liver in and liver of coagulation tests and is with a that this increased bleeding Observational studies have demonstrated that the in clotting times is not of bleeding risk in these in the of such as haemorrhage et al, while some liver patients have some bleeding have a with the same This is primarily because of the levels of are in the same as the clotting factor no to bleeding risk in a of patients on intensive care. A fibrinogen level and a of were the most important of bleeding et al, 2016). The of bleeding and bleeding to invasive procedures in patients with liver are low et al, 2016). However, there is clinical practice in the use of FFP and cryoprecipitate for prophylaxis in patients with liver et al, 2016). Transfusion of FFP in liver may not in coagulation and evidence that transfusion can the risk of bleeding is et al, Transfusion of blood components has a potential for due to in in patients with et al, The risk factors for haemorrhage in liver are increased and rather than in factors to the bleeding FFP is transfused in patients bleeding from to volume which may increase the rate further increase in There is no good evidence that transfusion of FFP or cryoprecipitate reduces or is of any clinical in patients with and there is in published on its for and et al, The most on haemorrhage from the for the of liver against the use of FFP and the of in this et al, FFP is also administered prior to liver However, liver patients at increased risk of bleeding are likely to be by of the procedure itself e. g. liver the not rather than by prior administration of blood et al, and liver do not the use of FFP or cryoprecipitate for low risk such as for the of the FFP is the only currently available for deficiency and deficiency of and FVIII. It may also be in other coagulation in the of where a more specific is or if the is et al, For further details on and of of of major bleeding, and the use of plasma in and to the relevant BSH et al, et al, et al, et al, et al, et al, et al, 2016). In MBFFP was in 2012 due to an increased of compared to other plasma components 2011). of to MBFFP from Of Transfusion data has not demonstrated a increase in transfusion and or when compared to standard FFP Blood Transfusion Services and 2012). MBFFP to be used in the UK and other with no concerns safety et al, of plasma showed a reduction in all and in when SDFFP with standard FFP but there was no in the of or et al, 2016). Cryoprecipitate has similar to FFP for and It has also been in of et al, from the countries in the UK at a time when they had to a of plasma the UK countries have now to plasma for and are as those within 24 h of transfusion and are the most following FFP transfusion. of in the UK remain stable at It occurs usually within the first and the of is The use of and in this is not based on Other may during transfusion or after Review by component that are very with FFP but and and are more likely with FFP than any other blood A deficiency, although in the is in this et al, From to only patients who after FFP were shown to have deficiency with in the recipient is to be a major factor to et al, 2011). of have while there has been of transfusion in to over in et al, of within 24 h of transfusion that do not the for or are as There is some evidence that patients with are more to 2016). reduction for in 2003 with a to plasma of FFP in the UK from have reduced from a of 36 in 2003 to in to have also reduced to between and with in the period et al, 2016). However, are and the is not The components in are now red or platelets with no with FFP since In and patients after cryoprecipitate plasma from donors, all with recommended that cryoprecipitate should also be from donors as is the for FFP et al, and this has now been into practice in the UK. is now the most cause of and major to since but other may with similar and that although patients are may at any age and with of components et al, Patients should be assessed for risk factors prior to these include cardiac evidence of and low use of a prior to blood transfusion of patients to assess the risk of et al, of by blood components is In the 20 of there have been with plasma with FFP hepatitis E one and one HIV in and one from cryoprecipitate in et al, 2016). from plasma components have not been There have been no of the and in this is to be and at the time of to the the BSH the any for the content of this All members of the group with all with the exception of plasma where there was no The to for in the literature for with all relevant for the ABO for the Octapharma and for their with in Table 2. The BSH Transfusion members at the time of this guideline were and The would to the BSH sounding and the BSH for their in this The research was by the for The BSH the during the of this All have a of to the BSH and Task which may be on The following have has from has from and for research and in relation to pathogen and has research with The following members of the group have no of to LG, and of the group will the group if any evidence available that would the strength of the in this or it The will be and removed from the BSH current website if it If are an will be published on the BSH website The is not for the content or of any supplied by the than should be to the for the