Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach
Lieberman L, Greinacher A, Murphy MF, Bussel J, Bakchoul T, Corke S, Kjaer M, Kjeldsen-Kragh J, Bertrand G, Oepkes D, et al
British journal of haematology. 2019
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.
Postnatal intervention for the treatment of FNAIT: a systematic review
Baker JM, Shehata N, Bussel J, Murphy MF, Greinacher A, Bakchoul T, Massey E, Lieberman L, Landry D, Tanael S, et al
Journal of perinatology : official journal of the California Perinatal Association. 2019
OBJECTIVE Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with life-threatening bleeding. This systematic review of postnatal management of FNAIT examined transfusion of human platelet antigen (HPA) selected or unselected platelets, and/or IVIg on platelet increments, hemorrhage and mortality. STUDY DESIGN MEDLINE, EMBASE and Cochrane searches were conducted until 11 May 2018. RESULT Of 754 neonates, 382 received platelet transfusions (51%). HPA-selected platelets resulted in higher platelet increments and longer response times than HPA-unselected platelets. However, unselected platelets generally led to sufficient platelet increments to 30 x 10(9)/L, a level above which intracranial hemorrhage or other life-threatening bleeding rarely occurred. Platelet increments were not improved with the addition of IVIg to platelet transfusion. CONCLUSION Overall, HPA-selected platelet transfusions were more effective than HPA-unselected platelets but unselected platelets were often effective enough to achieve clinical goals. Available studies do not clearly demonstrate a benefit for addition of IVIg to platelet transfusion.
Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference
Mueller MM, Van Remoortel H, Meybohm P, Aranko K, Aubron C, Burger R, Carson JL, Cichutek K, De Buck E, Devine D, et al
Importance: Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. Objective: To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. Evidence Review: The scientific committee developed 17 Population/Intervention/Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018. Findings: From 17607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23143 patients and 82 observational studies with more than 4 million patients, were analyzed. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. Conclusions and Relevance: The 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.
Transfusion-associated circulatory overload-a systematic review of diagnostic biomarkers
Klanderman RB, Bosboom JJ, Migdady Y, Veelo DP, Geerts BF, Murphy MF, Vlaar APJ
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BACKGROUND Transfusion-associated circulatory overload (TACO) is the leading cause of transfusion-related major morbidity and mortality. Diagnosing TACO is difficult because there are no pathognomonic signs and symptoms. TACO biomarkers may aid in diagnosis, decrease time to treatment, and differentiate from other causes of posttransfusion dyspnea such a transfusion-related acute lung injury. STUDY DESIGN AND METHODS A systematic review of literature was performed in EMBASE, PubMed, the TRIP Database, and the Cochrane Library, from inception to June 2018. All articles discussing diagnostic markers for TACO were included. Non-English articles or conference abstracts were excluded. RESULTS Twenty articles discussing biomarkers for TACO were included. The majority investigated B-type natriuretic peptide (BNP) and the N-terminal prohormone cleavage fragment of BNP (NT-proBNP), markers of hydrostatic pressure that can be determined within 1 hour. The data indicate that a post/pretransfusion NT-proBNP ratio > 1.5 can aid in the diagnosis of TACO. Posttransfusion levels of BNP less than 300 or NT-proBNP less than 2000 pg/mL, drawn within 24 hours of the reaction, make TACO unlikely. Cut-off levels that exclude TACO are currently unclear. In critically ill patients, the specificity of natriuretic peptides for circulatory overload is poor. Other biomarkers, such as cytokine profiles, cannot discriminate between TACO and transfusion-related acute lung injury. CONCLUSION Currently, BNP and NT-proBNP are the primary diagnostic biomarkers researched for TACO. An NT-proBNP ratio greater than 1.5 is supportive of TACO, and low levels of BNP or NT-proBNP can exclude TACO. However, they are unreliable in critically ill patients. Other biomarkers, including cytokines and pulmonary edema fluid-to-serum protein ratio have not yet been sufficiently investigated for clinical use.
Pathogen-reduced platelets for the prevention of bleeding
Estcourt LJ, Malouf R, Hopewell S, Trivella M, Doree C, Stanworth SJ, Murphy MF
The Cochrane Database of Systematic Reviews. 2017;((7)):CD009072.
BACKGROUND Platelet transfusions are used to prevent and treat bleeding in people who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of viral, bacterial, or protozoal contamination of platelets remains. There is also an ongoing risk from newly emerging blood transfusion-transmitted infections for which laboratory tests may not be available at the time of initial outbreak.One solution to reduce the risk of blood transfusion-transmitted infections from platelet transfusion is photochemical pathogen reduction, in which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. This process might offer additional benefits, including platelet shelf-life extension, and negate the requirement for gamma-irradiation of platelets. Although current pathogen-reduction technologies have been proven to reduce pathogen load in platelet concentrates, a number of published clinical studies have raised concerns about the effectiveness of pathogen-reduced platelets for post-transfusion platelet count recovery and the prevention of bleeding when compared with standard platelets.This is an update of a Cochrane review first published in 2013. OBJECTIVES To assess the effectiveness of pathogen-reduced platelets for the prevention of bleeding in people of any age requiring platelet transfusions. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 9), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 24 October 2016. SELECTION CRITERIA We included RCTs comparing the transfusion of pathogen-reduced platelets with standard platelets, or comparing different types of pathogen-reduced platelets. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures expected by Cochrane. MAIN RESULTS We identified five new trials in this update of the review. A total of 15 trials were eligible for inclusion in this review, 12 completed trials (2075 participants) and three ongoing trials. Ten of the 12 completed trials were included in the original review. We did not identify any RCTs comparing the transfusion of one type of pathogen-reduced platelets with another.Nine trials compared Intercept(R) pathogen-reduced platelets to standard platelets, two trials compared Mirasol(R) pathogen-reduced platelets to standard platelets; and one trial compared both pathogen-reduced platelets types to standard platelets. Three RCTs were randomised cross-over trials, and nine were parallel-group trials. Of the 2075 participants enrolled in the trials, 1981 participants received at least one platelet transfusion (1662 participants in Intercept(R) platelet trials and 319 in Mirasol(R) platelet trials).One trial included children requiring cardiac surgery (16 participants) or adults requiring a liver transplant (28 participants). All of the other participants were thrombocytopenic individuals who had a haematological or oncological diagnosis. Eight trials included only adults.Four of the included studies were at low risk of bias in every domain, while the remaining eight included studies had some threats to validity.Overall, the quality of the evidence was low to high across different outcomes according to GRADE methodology.We are very uncertain as to whether pathogen-reduced platelets increase the risk of any bleeding (World Health Organization (WHO) Grade 1 to 4) (5 trials, 1085 participants; fixed-effect risk ratio (RR) 1.09, 95% confidence interval (CI) 1.02 to 1.15; I2 = 59%, random-effect RR 1.14, 95% CI 0.93 to 1.38; I2 = 59%; low-quality evidence).There was no evidence of a difference between pathogen-reduced platelets and standard platelets in the incidence of clinically significant bleeding complications (WHO Grade 2 or higher) (5 trials, 1392 participants; RR 1.10, 95% CI 0.97 to 1.25; I2 = 0%; moderate-quality evidence), and there
Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review
Winkelhorst D, Murphy MF, Greinacher A, Shehata N, Bakchoul T, Massey E, Baker J, Lieberman L, Tanael S, Hume H, et al
Several strategies can be used to manage fetal or neonatal alloimmune thrombocytopenia (FNAIT) in subsequent pregnancies. Serial fetal blood sampling (FBS) and intrauterine platelet transfusions (IUPT), and weekly maternal intravenous immunoglobulin infusion (IVIG), with or without additional corticosteroid therapy are common options, but the optimal management has not been determined. The aim of this systematic review was to assess antenatal treatment strategies for FNAIT. Four randomized controlled trials and twenty-two non-randomized studies were included. Pooling of results was not possible due to considerable heterogeneity. Most studies found comparable outcomes regarding the occurrence of intracranial hemorrhage, regardless of antenatal management strategy applied; FBS, IUPT or IVIG with/without corticosteroids. There is no consistent evidence for the value of adding steroids to IVIG. Fetal blood sampling or intrauterine platelet transfusion resulted in a relatively high complication rate, consisting mainly of preterm emergency cesarean section, 11% per treated pregnancy in all studies combined. Overall, non-invasive management in pregnant mothers who have had a previous neonate with FNAIT is effective without the relatively high rate of adverse outcomes seen with invasive strategies. This systematic review suggests that first line antenatal management in FNAIT is weekly IVIG administration, with or without the addition of corticosteroids.
Optimal dose, timing and ratio of blood products in massive transfusion: results from a systematic review
McQuilten ZK, Crighton G, Brunskill S, Morison JK, Richter TH, Waters N, Murphy MF, Wood EM
Transfusion Medicine Reviews. 2017;32((1):):6-15
Optimal dose, timing and ratio to red blood cells (RBC) of blood component therapy (fresh frozen plasma [FFP], platelets, cryoprecipitate or fibrinogen concentrate) to reduce morbidity and mortality in critically bleeding patients requiring massive transfusion is unknown. We performed a systematic review for randomized controlled trials (RCT) in MEDLINE, The Cochrane Library, Embase, CINAHL, PubMed the Transfusion Evidence Library and using multiple clinical trials registries to 21 February 2017. Sixteen RCTs were identified: six completed (five in adult trauma patients, one pediatric burn patients) and ten ongoing trials. Of the completed trials: three were feasibility trials, comparing a FFP, platelets and RBC ratio of 1:1:1 to laboratory-guided transfusion practice [n=69], early cryoprecipitate compared to standard practice [n=41], and early fibrinogen concentrate compared to placebo [n=45]; one trial compared the effect of FFP, platelets and RBC ratio of 1:1:1 with 1:1:2 on 24-hour and 30-day mortality [n=680]; one compared whole blood to blood component therapy on 24-hour blood use [n=107]; one compared a FFP to RBC ratio of 1:1 with 1:4 [n=16]. Data from two trials were pooled in a meta-analysis for 28-day mortality because the transfusion ratios achieved were similar. Results from these two trials suggest higher transfusion ratios were associated with transfusion of more FFP and platelets without evidence of significant difference with respect to mortality or morbidity. On the limited evidence available, there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion.
Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support
Estcourt LJ, Malouf R, Trivella M, Fergusson DA, Hopewell S, Murphy MF
The Cochrane Database of Systematic Reviews. 2017;((1)):CD011305.
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BACKGROUND Many people diagnosed with haematological malignancies experience anaemia, and red blood cell (RBC) transfusion plays an essential supportive role in their management. Different strategies have been developed for RBC transfusions. A restrictive transfusion strategy seeks to maintain a lower haemoglobin level (usually between 70 g/L to 90 g/L) with a trigger for transfusion when the haemoglobin drops below 70 g/L), whereas a liberal transfusion strategy aims to maintain a higher haemoglobin (usually between 100 g/L to 120 g/L, with a threshold for transfusion when haemoglobin drops below 100 g/L). In people undergoing surgery or who have been admitted to intensive care a restrictive transfusion strategy has been shown to be safe and in some cases safer than a liberal transfusion strategy. However, it is not known whether it is safe in people with haematological malignancies. OBJECTIVES To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT). SEARCH METHODS We searched for randomised controlled trials (RCTs) and non-randomised trials (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 6), and 10 other databases (including four trial registries) to 15 June 2016. We also searched grey literature and contacted experts in transfusion for additional trials. There was no restriction on language, date or publication status. SELECTION CRITERIA We included RCTs and prospective NRS that evaluated a restrictive compared with a liberal RBC transfusion strategy in children or adults with malignant haematological disorders or undergoing HSCT. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures expected by Cochrane. MAIN RESULTS We identified six studies eligible for inclusion in this review; five RCTs and one NRS. Three completed RCTs (156 participants), one completed NRS (84 participants), and two ongoing RCTs. We identified one additional RCT awaiting classification. The completed studies were conducted between 1997 and 2015 and had a mean follow-up from 31 days to 2 years. One study included children receiving a HSCT (six participants), the other three studies only included adults: 218 participants with acute leukaemia receiving chemotherapy, and 16 with a haematological malignancy receiving a HSCT. The restrictive strategies varied from 70 g/L to 90 g/L. The liberal strategies also varied from 80 g/L to 120 g/L.Based on the GRADE rating methodology the overall quality of the included studies was very low to low across different outcomes. None of the included studies were free from bias for all 'Risk of bias' domains. One of the three RCTs was discontinued early for safety concerns after recruiting only six children, all three participants in the liberal group developed veno-occlusive disease (VOD). Evidence from RCTsA restrictive RBC transfusion policy may make little or no difference to: the number of participants who died within 100 days (two trials, 95 participants (RR: 0.25, 95% CI 0.02 to 2.69, low-quality evidence); the number of participants who experienced any bleeding (two studies, 149 participants; RR:0.93, 95% CI 0.73 to 1.18, low-quality evidence), or clinically significant bleeding (two studies, 149 participants, RR: 1.03, 95% CI 0.75 to 1.43, low-quality evidence); the number of participants who required RBC transfusions (three trials; 155 participants: RR: 0.97, 95% CI 0.90 to 1.05, low-quality evidence); or the length of hospital stay (restrictive median 35.5 days (interquartile range (IQR): 31.2 to 43.8); liberal 36 days (IQR: 29.2 to 44), low-quality evidence).We are uncertain whether the restrictive RBC transfusion strategy: decreases quality of life (one trial, 89 participants, fatigue score: restrictive median 4.8 (IQR 4 to 5.2); liberal m
Children or adults with malignant haematological disorders treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (6 studies).
Restrictive red blood cell (RBC) transfusion strategy.
Liberal RBC transfusion strategy.
Evidence from randomised controlled trials showed that a restrictive RBC transfusion policy may make little or no difference to: the number of participants who died within 100 days (RR: 0.25); the number of participants who experienced any bleeding (RR: 0.93), or clinically significant bleeding (RR: 1.03); the number of participants who required RBC transfusions (RR: 0.97); or the length of hospital stay. It was uncertain whether the restrictive RBC transfusion strategy: decreases quality of life, or reduces the risk of developing any serious infection (RR: 1.23).
Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials
Odutayo A, Desborough MJ, Trivella M, Stanley AJ, Doree C, Collins GS, Hopewell S, Brunskill SJ, Kahan BC, Logan RF, et al
The Lancet. Gastroenterology & Hepatology. 2017;2((5)):354-360.
BACKGROUND Acute upper gastrointestinal bleeding is a leading indication for red blood cell (RBC) transfusion worldwide, although optimal thresholds for transfusion are debated. METHODS We searched MEDLINE, Embase, CENTRAL, CINAHL, and the Transfusion Evidence Library from inception to Oct 20, 2016, for randomised controlled trials comparing restrictive and liberal RBC transfusion strategies for acute upper gastrointestinal bleeding. Main outcomes were mortality, rebleeding, ischaemic events, and mean RBC transfusion. We computed pooled estimates for each outcome by random effects meta-analysis, and individual participant data for a cluster randomised trial were re-analysed to facilitate meta-analysis. We compared treatment effects between patient subgroups, including patients with liver cirrhosis, patients with non-variceal upper gastrointestinal bleeding, and patients with ischaemic heart disease at baseline. FINDINGS We included four published and one unpublished randomised controlled trial, totalling 1965 participants. The number of RBC units transfused was lower in the restrictive transfusion group than in the liberal transfusion group (mean difference -1.73 units, 95% CI -2.36 to -1.11, p<0.0001). Restrictive transfusion was associated with lower risk of all-cause mortality (relative risk [RR] 0.65, 95% CI 0.44-0.97, p=0.03) and rebleeding overall (0.58, 0.40-0.84, p=0.004). We detected no difference in risk of ischaemic events. There were no statistically significant differences in the subgroups. INTERPRETATION These results support more widespread implementation of restrictive transfusion policies for adults with acute upper gastrointestinal bleeding. FUNDING None.
Diagnostic and therapeutic treatment modalities for acute lower gastrointestinal bleeding: a systematic review
Oakland K, Isherwood J, Lahiff C, Goldsmith P, Desborough M, Colman KS, Guy R, Uberoi R, Murphy MF, East JE, et al
Endoscopy International Open. 2017;5((10)):E959-E973.
BACKGROUND AND STUDY AIMS Investigations for lower gastrointestinal bleeding (LGIB) include flexible sigmoidoscopy, colonoscopy, computed tomographic angiography (CTA), and angiography. All may be used to direct endoscopic, radiological or surgical treatment, although their optimal use is unknown. The aims of this study were to determine the diagnostic and therapeutic yields of endoscopy, CTA, and angiography for managing LGIB, and their influence on rebleeding, transfusion, and hospital stay. PATIENTS AND METHODS A systematic search of MEDLINE, PubMed, EMBASE, and CENTRAL was undertaken to identify randomized controlled trials (RCTs) and nonrandomized studies of intervention (NRSIs) published between 2000 and 12 November 2015 in patients hospitalized with LGIB. Separate meta-analyses were conducted, presented as pooled odds (ORs) or risk ratios (RR) with 95 % confidence intervals (CIs). RESULTS Two RCTs and 13 NRSIs were included, none of which examined flexible sigmoidoscopy, or compared endotherapy with embolization, or investigated the timing of CTA or angiography. Two NRSIs (57 - 223 participants) comparing colonoscopy and CTA were of insufficient quality for synthesis but showed no difference in diagnostic yields between the two interventions. One RCT and 4 NRSIs (779 participants) compared early colonoscopy (< 24 hours) with colonoscopy performed later; meta-analysis of the NRSIs demonstrated higher diagnostic and therapeutic yields with early colonoscopy (OR 1.86, 95 %CI 1.12 to 2.86, P = 0.004 and OR 3.08, 95 %CI 1.93 to 4.90, P < 0.001, respectively) and reduced length of stay (mean difference 2.64 days, 95 %CI 1.54 to 3.73), but no difference in transfusion or rebleeding. CONCLUSIONS In LGIB there is a paucity of high-quality evidence, although the limited studies on the timing of colonoscopy suggest increased rates of diagnosis and therapy with early colonoscopy.