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National Clinical Guideline Centre (UK). Blood Transfusion. London: National Institute for Health and Care Excellence (NICE); 2015 Nov. (NICE Guideline, No. 24.)
Cryoprecipitate is prepared from the cryoglobulin fraction obtained by thawing fresh frozen plasma. After removal of the supernatant, the precipitate, containing Factor VIII:C, von Willebrand factor (VWF), fibrinogen, fibronectin and factor XIII is refrozen in approximately 30 ml of plasma. This can be stored at -25°C or below for up to 36 months. After thawing, it should be infused as soon as possible though it can be stored at ambient temperature for up to 4 hours. The UK specification is a minimum of 140 mg of fibrinogen for each cryoprecipitate unit. Cryoprecipitate is used as a source of fibrinogen in acquired hypofibrinogenaemia, which may be seen, for example, with major haemorrhage or disseminated intravascular coagulation. Fibrinogen concentrate is available in the UK but only licensed for use in congenital hypofibrinogenaemia. Cryoprecipitate must not be used for replacement of coagulation factors in inherited conditions such as haemophilia or von Willebrand's disease, since specific factor concentrates are available.
16.1. Review question: What is the clinical- and cost-effectiveness of transfusions of cryoprecipitate to treat and prevent bleeding?
For full details see review protocol in Appendix C.
Table 119PICO characteristics of review questions
| Population |
|
|---|---|
| Intervention(s) |
|
| Comparison(s) | All thresholds compared with one another |
| Outcomes | Critical outcomes:
|
| Study design |
|
16.2. Review question: What is the clinical- and cost-effectiveness of different target levels of post-transfusion haemostasis tests with the use of cryoprecipitate for prophylactic transfusions?
For full details see review protocol in Appendix C.
Table 120PICO characteristics of review question
| Population |
|
|---|---|
| Intervention(s) |
|
| Comparison(s) |
|
| Outcomes | Critical outcomes:
|
| Study design |
|
16.3. Clinical evidence
We searched for systematic reviews, randomised controlled trials and observational studies addressing the two clinical questions: ‘What is the clinical- and cost-effectiveness of transfusions of cryoprecipitate to treat and prevent bleeding?’ and ‘What is the clinical- and cost-effectiveness of different target levels of post-transfusion haemostasis tests with the use of cryoprecipitate for prophylactic transfusions?’
We did not identify any study entirely meeting our protocol criteria. However, we identified a large observational study assessing the efficacy of cryoprecipitate in patients with major trauma,134 which we have included in our evidence review (indirect population). We also identified a small prospective cohort study (n=13) which assessed the efficacy of cryoprecipitate use in treating bleeding in patients undergoing cardiac surgery; 180 however, we did not include this study in our review as this did not meet our protocol criteria of including cohort studies with more than 1000 patients.
In our search, we also identified a Cochrane review which assessed the benefits and harms of fibrinogen concentrate.331 This Cochrane review assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients. But we did not consider inclusion of this Cochrane review in our evidence review as fibrinogen concentrate was not included as one of the blood products to be covered in our scope.
Evidence from the included studies is summarised in the modified GRADE clinical evidence profile below (Table 121). See also the study selection flow chart in Appendix E, study evidence tables in Appendix H, forest plots in Appendix K, and excluded studies list in Appendix P.
Table 121
Summary of studies included in the review.
Table 122
Modified GRADE profile: Cryoprecipitate versus no cryoprecipitate.
16.4. Economic evidence
Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
Unit costs
Relevant unit costs are provided in Appendix N to aid consideration of cost-effectiveness.
16.5. Evidence statements
Clinical
One large prospective cohort study assessed the efficacy of cryoprecipitate in patients with major trauma. The evidence showed mortality (all-cause) at 30 days and number of RBC units transfused (24 hours) to be higher in patients receiving cryoprecipitate transfusion compared with patients not receiving cryoprecipitate transfusion. The evidence was of very low quality.
No evidence was identified for the critical outcomes such as bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections, quality of life, serious adverse events, adverse events related to transfusion, or for the important outcomes such as number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital.
Economic
No relevant economic evaluations were identified.
16.6. Recommendations and link to evidence
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (for example, pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life, serious adverse events and adverse events related to transfusion as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade-off between clinical benefits and harms | No direct evidence relating to the use of cryoprecipitate transfusion at any specific fibrinogen level was identified for this recommendation. There was indirect evidence (indirect population) from one large multicentre prospective cohort study which compared the efficacy of cryoprecipitate administration in patients with major trauma.134 The study reported that mortality at 30 days appeared to be higher in patients receiving cryoprecipitate transfusion compared with patients not receiving cryoprecipitate transfusions and the number of units of RBC transfused appeared to be higher in patients receiving cryoprecipitate transfusion compared with patients not receiving cryoprecipitate transfusion. Although the study reported adverse events associated with the use of cryoprecipitate, the GDG noted that it had a high risk of bias and the findings are likely to be specific to the trauma population and agreed that these cannot be extrapolated to this review population as the population was too indirect. Major trauma is excluded from the scope of this guidance - for guidance specific to this topic, follow the recommendations in NICE's guideline on Major trauma, currently in development. The GDG discussed that, despite the lack of evidence, cryoprecipitate should be considered for the treatment of acquired fibrinogen deficiency when there is active bleeding. The potential benefit of reducing bleeding and preventing further deterioration is likely to outweigh the risk of adverse effects of transfusion. In many such clinical settings there may be other multiple clotting factor deficiencies and accordingly initial treatment with FFP should be given. Whilst FFP does contain fibrinogen, the volume needed to be transfused per adult dose is relatively large (at least 15 ml/kg plasma). Cryoprecipitate contains fibrinogen in a more concentrated form with a lower total volume transfused per dose. Accordingly, in patients needing fibrinogen replacement, in particular if on-going low fibrinogen levels after FFP transfusion or where fibrinogen levels are dropping rapidly, cryoprecipitate therapy is indicated. The risks of cryoprecipitate therapy are as those stated earlier in relation to potential adverse events of transfusing blood and components. The donor exposure depends on the component transfused. Accordingly, each unit of red cells exposes the patient to one donor per red cell unit transfused, FFP to approximately 4 to 6 donors per adult dose (of 4 to 6 units FFP), but the standard adult cryoprecipitate dose of 10 units (in 2 pools of 5 units each in the UK) results in a donor exposure of 10 donors per adult dose. Cryoprecipitate delivers a high dose of fibrinogen in a small fluid volume, compared with therapeutic doses of FFP, so the GDG agreed that cryoprecipitate may be considered as initial treatment when fibrinogen replacement in a small volume is desirable for example to minimise the risk of TACO. The GDG noted that cryoprecipitate transfusion may reduce the risk of transfusion-associated circulatory overload (TACO) compared to FFP transfusion. There was no specific evidence available for the indications for cryoprecipitate transfusion in the paediatric population. The GDG agreed that the same recommendations should apply for children as for adults in the absence of evidence that indications for cryoprecipitate in children with bleeding and low fibrinogen are different compared to adults. However, there are specific recommendations for dosage and type of component for children (see recommendation number Error! eference source not found..). This recommendation was based on the indirect evidence and consensus expert opinion of the GDG members. |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for cryoprecipitate were identified. The cost of cryoprecipitate was considered by the GDG. Pooled cryoprecipitate costs £181 per pool in England and North Wales, where one pool of cryoprecipitate is derived from 5 units of donated blood.219 For patients born on or after 1st January 1996, methylene blue cryoprecipitate is required. The cost of methylene blue cryoprecipitate-pooled (non-UK sourced) is £1,080 per pool where one pool of methylene blue cryoprecipitate is derived from 6 units of donated blood. It was noted that this figure does not include all costs associated with a transfusion such as staff time, disposables, and storage, wastage and laboratory tests. No direct estimates for the additional cost of transfusing cryoprecipitate were identified. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. Based on consensus expert opinion of the GDG members, the GDG considered that, for patients with clinically significant bleeding with abnormal coagulation who have been treated with FFP and have a fibrinogen level below 1.5 g/litre, the cost of transfusing cryoprecipitate was likely to be offset by avoiding the negative costly outcomes that would result from not transfusing these patients. The potential negative outcomes include possible further bleeding leading to potentially lengthier and more complex (and costly) hospitalisation (for example, ICU), and mortality. |
| Quality of evidence | No direct evidence was identified for the use of cryoprecipitate. The quality of evidence from 1 cohort study was very low due to the indirectness of the population and risk of bias arising from selection bias related to the design of the observational study. The recommendation was based on the indirect evidence and consensus expert opinion of the GDG members. |
| Other considerations | The GDG discussed findings from studies which did not meet the protocol criteria to inform the consensus recommendation. One small prospective cohort study (n=13) assessed the efficacy of cryoprecipitate use in treating bleeding in patients undergoing cardiac surgery179 and was excluded as it did not meet our protocol criteria for inclusion of cohort studies (n<1000 patients). The study reported that fibrinogen levels (mg/dl), APTT (seconds) and INR appeared to be lower after cryoprecipitate transfusion. One Cochrane review on the use of fibrinogen concentrate331 was identified and reported the following findings, though there was considerable uncertainty with respect to all of them: Mortality and incidence of allogeneic blood transfusion appeared to be lower in patients receiving fibrinogen concentrate compared with patients not receiving it. Length of hospital stay (days) appeared to be longer in patients receiving fibrinogen concentrate compared with patients not receiving it. Adverse events such as thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis) did not appear to be different in patients receiving fibrinogen concentrate and patients not receiving it. Fibrinogen concentrate was not considered as an intervention in the scope of this guideline. The level of fibrinogen of 1.5 g/litre as a threshold for considering cryoprecipitate transfusion in bleeding patients was consensus based, and for some patients with acquired fibrinogen deficiency and bleeding that is not severe (for example, with disseminated intravascular coagulation (DIC)) a fibrinogen threshold of 1.0 g/litre may be more appropriate. The GDG also noted that methylene blue cryoprecipitate was introduced by NHSBT for treatment of children and young adults as part of the vCJD risk reduction strategy,221 and as for FFP is now provided for all patients born on or after 1st Jan 1996. Each pool of Methylene Blue contains 6 units of Cryoprecipitate. The GDG noted that there were no on-going trials of cryoprecipitate that were of interest in the guideline population defined in the review protocol. The same recommendations apply to adults and children. |
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (for example, pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life, serious adverse events and adverse events related to transfusion as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade-off between clinical benefits and harms | No evidence was identified for this recommendation. The recommendation was based on the consensus expert opinion of the GDG members. The GDG considered that cryoprecipitate may reduce the risk of bleeding and the risks of having a transfusion in patients with abnormal coagulation but there was no evidence for this. In patients who have low fibrinogen levels but are not bleeding and are not having invasive procedures or surgery with a risk of clinically significant bleeding, the GDG considered a cautious approach and recommended not offering cryoprecipitate transfusion as there is no evidence of benefit and a risk of complications of transfusion. The risks of cryoprecipitate therapy are as those stated earlier in relation to potential adverse events of transfusing blood and components. The donor exposure depends on the component transfused. Accordingly, each unit of red cells exposes the patient to one donor per red cell unit transfused, FFP to approximately 4 to 6 donors per adult dose (of 4 to 6 units FFP), but the standard adult cryoprecipitate dose of 10 units (in 2 pools of 5 units each in the UK) results in a donor exposure of 10 donors per adult dose. The GDG felt, therefore, that the overall benefit was not great enough to recommend the use of cryoprecipitate in these patients. There was no specific evidence available for the use of cryoprecipitate transfusion in the paediatric population. The GDG agreed that the same consensus recommendations should apply for children as for adults in the absence of evidence that indications for cryoprecipitate in children with bleeding and low fibrinogen are different compared to adults. However there are specific recommendations for dosage and type of component for children (see recommendation number Error! Reference source not found.. |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for cryoprecipitate were identified. The cost of cryoprecipitate was considered by the GDG. Pooled cryoprecipitate costs £181 per pool in England and North Wales, where one pool of cryoprecipitate is derived from five units of donated blood. 219 For patients born on or after 1st January 1996 methylene blue cryoprecipitate is required. The cost of methylene blue cryoprecipitate-pooled (non-UK sourced) is £1,080 per pool where one pool of methylene blue cryoprecipitate is derived from six units of donated blood. It was noted that this figure does not include all costs associated with a transfusion such as staff time, disposables, and storage, wastage and laboratory tests. No direct estimates for the additional cost of transfusing cryoprecipitate were identified. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. Based on consensus expert opinion, the GDG considered that, given the lack of evidence of benefit from cryoprecipitate transfusion in patients with abnormal coagulation and the potential infectious and immunological risks from receiving a transfusion, the cost of transfusing cryoprecipitate was not justified. |
| Quality of evidence | No evidence was identified which met the review protocol criteria. The recommendation was based on the consensus expert opinion of the GDG members. |
| Other considerations | The GDG discussed findings from studies which did not entirely meet the protocol criteria to inform the consensus recommendation. One large multicentre prospective cohort study assessed the efficacy of cryoprecipitate in patients with major trauma.134 The study reported that mortality at 30 days appeared to be higher in patients receiving cryoprecipitate transfusion compared with patients not receiving cryoprecipitate transfusions and the number of units of RBC transfused appeared to be higher in patients receiving cryoprecipitate transfusion compared with patients not receiving cryoprecipitate transfusion. Although the study reported harm associated with the use of cryoprecipitate, the GDG noted that the studies were at high risk of bias and the findings are likely to be specific to the trauma population and therefore the findings cannot be extrapolated to this review population. Major trauma is excluded from the scope of this guidance-for guidance specific to this topic, follow the recommendations in NICE's guideline on Major trauma, currently in development. Another small prospective cohort study (n=13) assessed the efficacy of cryoprecipitate use in treating bleeding in patients undergoing cardiac surgery180 and was excluded as it did not meet our protocol criteria for inclusion of cohort studies (n<1000 patients).The study reported that fibrinogen level (mg/dl) and APTT (seconds) and INR appeared to be lower after cryoprecipitate transfusion. One Cochrane review on the use of fibrinogen concentrate331 was identified and reported the following findings: Mortality and incidence of allogeneic blood transfusion appeared to be lower in patients receiving fibrinogen concentrate compared with patients not receiving concentrate. Length of hospital stay (days) appeared to be longer in patients receiving fibrinogen concentrate compared with patients not receiving concentrate. Adverse events such as thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis) did not appear to be different in patients receiving fibrinogen concentrate and patients not receiving fibrinogen concentrate. There was considerable uncertainty with respect to all the findings. Although it acts on the same pathway as fresh frozen plasma, cryoprecipitate and prothrombin complex concentrates, fibrinogen concentrate was not considered as an intervention in the scope of the guidance. The GDG also noted that methylene blue cryoprecipitate was introduced by NHSBT for treatment of children as part of the vCJD risk reduction strategy 221 and as for FFP is now provided for all patients born on or after 1st Jan 1996. Each pool of Methylene Blue contains 6 units of cryoprecipitate. The GDG noted that there were no on-going trials of cryoprecipitate in the guideline population of interest. The same recommendations apply to adults and children. |
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (for example, pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life, serious adverse events and adverse events related to transfusion as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade-off between clinical benefits and harms | No evidence was identified for use of cryoprecipitate transfusion in patients having surgery or invasive procedures with a risk of clinically significant bleeding and where there is a low fibrinogen level less than 1.0 g/litre. No evidence was identified on the use of cryoprecipitate transfusion at any specific fibrinogen level. The recommendation was based on the consensus expert opinion of the GDG members. The GDG drew on its knowledge and experience and agreed that prophylactic cryoprecipitate transfusion should be considered for patients having surgery or invasive procedures with a risk of clinically significant bleeding and abnormal coagulation test results. The lower threshold fibrinogen concentration of 1.0 g/litre (compared to 1.5 g/litre for bleeding patients) was chosen in view of the lack of evidence and as this is a commonly used dose in clinical practice. There was no specific evidence available for the use of cryoprecipitate transfusion in the paediatric population. The GDG agreed that the same consensus recommendations should apply for children as for adults in the absence of evidence that indications for cryoprecipitate in children with bleeding and low fibrinogen are different compared to adults. |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for cryoprecipitate were identified. The cost of cryoprecipitate was considered by the GDG. Pooled cryoprecipitate costs £181 per pool in England and North Wales, where one pool of cryoprecipitate is derived from five units of donated blood. 219 For patients born on or after 1st January 1996 methylene blue cryoprecipitate is required. The cost of methylene blue cryoprecipitate-pooled (non-UK sourced) is £1,080 per pool where one pool of methylene blue cryoprecipitate is derived from six units of donated blood. It was noted that these figures do not include all costs associated with a transfusion such as staff time, disposables, and storage, wastage and laboratory tests. No direct estimates for the additional cost of transfusing cryoprecipitate were identified. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. Based on consensus expert opinion, the GDG considered that for patients having surgery or invasive procedures with a risk of clinically significant bleeding and where there is a low fibrinogen level of less than 1.0 g/litre, the cost of transfusing cryoprecipitate was likely to be offset by avoiding the negative costly outcomes that would result from not transfusing these patients. The negative outcomes include possible bleeding leading to lengthier and more complex (and more costly) hospitalisation (for example, ICU) and mortality. |
| Quality of evidence | No evidence was identified which met the review protocol criteria. The recommendation was based on the consensus expert opinion of the GDG members. |
| Other considerations | The GDG agreed that as cryoprecipitate delivers a high dose of fibrinogen in a small fluid volume, relative to FFP, it may be considered as initial treatment when fibrinogen replacement in a small volume is desirable. The GDG noted that a cryoprecipitate transfusion may reduce the risk of TACO (transfusion-associated circulatory overload) more than a FFP transfusion. The GDG discussed that infectious and immunological risks with cryoprecipitate transfusion were similar to other blood products, but as cryoprecipitate is pooled (1 pool comes from 5 units of blood), this increased the risk of number of donor exposures. The GDG agreed that, although transfusion therapy with either FFP or cryoprecipitate is usually indicated if fibrinogen levels are less than 1.0 g/litre and bleeding is present, FFP transfusion should be given first instead of cryoprecipitate in order to address the multiple coagulation factor deficiencies. The same recommendations apply for adults and children. The GDG also noted that methylene blue cryoprecipitate was introduced by NHSBT for treatment of children and young adults as part of the vCJD risk reduction strategy,221 and is now provided for all patients born on or after 1st Jan 1996. Each pool of Methylene Blue cryoprecipitate contains six single units An exception to this recommendation are patients with acute promyelocytic leukaemia who have disseminated intravascular coagulation with a combination of a low fibrinogen and severe thrombocytopenia and who are at high risk of haemorrhagic complications. |
- Review question: What is the clinical- and cost-effectiveness of transfusions of cryoprecipitate to treat and prevent bleeding?
- Review question: What is the clinical- and cost-effectiveness of different target levels of post-transfusion haemostasis tests with the use of cryoprecipitate for prophylactic transfusions?
- Clinical evidence
- Economic evidence
- Evidence statements
- Recommendations and link to evidence
- Cryoprecipitate: thresholds and targets - Blood TransfusionCryoprecipitate: thresholds and targets - Blood Transfusion
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