Transfusion topics trending at Lifeblood in May

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Each month, we look forward to bringing you what we're talking about at Lifeblood - and a commentary of these published articles of interest by one of our transfusion experts, Katie Havelberg.

Re-introducing whole blood for transfusion: considerations for blood providers

This review addresses the re-introduction of whole blood for transfusion and the associated issues, such as re-evaluation of haemolysins, storage conditions and shelf life; the requirement for leucocyte depletion/ pathogen reduction; and inventory management. Additionally, it calls for research to define the optimal whole blood product and the indications for its use.

There is a resurgence of interest amongst clinicians for the use of whole blood (WB) in the treatment of haemorrhagic shock, primarily for the treatment of traumatic haemorrhage especially in the pre-hospital setting and remote locations where the availability of blood components may be limited. Its use is still under debate, partly because of a lack of data demonstrating a clear clinical benefit compared with component therapy, and partly due to logistical and operational considerations in supplying it.

Its use is becoming more prevalent. In Norway, whole blood has been introduced in two air ambulance services. In the USA, The University of Pittsburgh Medical Center has been using low titre group O cold-stored whole blood (CSWB) for several years for all male and females who are >50 years old and who are hypotensive from traumatic haemorrhage, an approach for which the clinical safety and feasibility have been well documented. At the Mayo Clinic, which services a large area with scarce population, WB has been introduced in the pre-hospital setting through availability in air ambulances. Royal Caribbean Cruise Lines has developed a programme for remote whole blood transfusions where during a 36-month period, 37 severely bleeding individuals were transfused with a mortality of 13%. In New Zealand, the Auckland Rescue Helicopter and land-based rapid response vehicle carry one or two units of leucoreduced group O negative CSWB for pre­hospital resuscitation.

WB preparations are diverse, meaning data on one product type might not extrapolate to another.  Variables in the collection, processing and storage of WB can influence the biological composition, quality and safety of the final product. There is no consensus on terminology to describe or label WB products in terms of these variables, especially storage temperature and platelet content.

Cold storage of WB units is a balance between maintaining sufficient quality while minimising risks associated with storage lesions and potential microbial growth. The combined effect of cold temperature and length of storage on the platelet and plasma constituents in the WB unit have not been extensively investigated.

The risk of transfusion transmissible infectious diseases (TTID) is likely to be less than that for separate blood components because a WB unit is from a single donor. The selection of male donors, women who have never been pregnant, or women who have tested negative to histocompatibility antibodies since their most recent pregnancy would be necessary to limit the risk of transfusion-related acute lung injury (TRALI) due to inadvertent transfusion of donor derived anti-histocompatibility antibodies.

The purpose of this review from members of the Biomedical for Excellence for Safer Transfusion (BEST) Collaborative is to describe the practical issues and considerations related to the 're-introduction' of WB for blood providers. The reviewers note there are still unresolved questions related to the optimal preparation and storage of whole blood, and the advantages of cold-stored whole blood versus component therapy. Studies are needed to understand the clinical and logistical benefits that WB may bring compared to component therapy, to define what patient populations might most benefit, and to define the maximal number of units that might safely be transfused before switching to component therapy. Recent observational studies suggest a benefit of whole blood, but there is a need for well-designed randomised trials to address these questions.

Hervig TA et al. Re-introducing whole blood for transfusion: considerations for blood providers. Vox Sanguinis 2021; 116 (2): 167-174


Rh disease prevention: the European perspective

This article provides an overview on the management of Rh disease prevention in European countries, using data gathered from an online survey on guidelines and biological testing and sent out to 15 expert laboratories.

The survey contained 56 questions to assess management of Rh disease prevention. Questions included the existence of national guidelines, the type of anti-Rh(D) immunoglobulins used, foetal RHD genotyping, newborn Rh phenotyping, diagnosis and quantification of feto-maternal haemorrhages, antepartum and postpartum immunoprophylaxis, assessment of the prevention efficacy, differentiation between passive and immune anti-Rh(D) in the maternal blood, follow-up of errors or omissions of the prophylaxis, and overall impact of the prevention policy.

Experts from 13 countries responded. Guidelines on anti-Rh(D) prophylaxis are similar regarding the major aspects of RH disease prevention- indication and timing of anti-Rh(D) administration, as well as indication of foetal RHD genotyping. Different anti-Rh(D) preparations are used, and the dosing may differ depending on gestational age. Other controversial issues include:

(1) Timing of foetal RHD genotyping;

(2) Indication of tests performed to quantitate feto-maternal haemorrhage prior to anti-Rh(D) administration; and

(3) If there is a remaining indication for newborn Rhesus phenotyping.

Procedures for monitoring the prophylaxis efficiency and evaluating the national prevention programme also differ among countries.

Three main prophylaxis drugs used are Rhophylac (CSL Behring, 1000 and 1500 IU), Rhesonativ (Octapharma, 625 and 1250/1500 IU) and RhoGAM (Kedrion S.p.A, 1500 IU). Administration is intramuscular everywhere except Ireland & France. The overall practice is similar with a 1250 to 1500 IU dosing at 28–30 GW for routine antenatal prophylaxis and a 1000 to 1500 IU dosing for targeted antenatal prophylaxis. Some countries use a lower dose (625 IU) for targeted prophylaxis at early gestational ages. For post-delivery prevention, most use a 1250 to 1500 IU dosing.

Non-invasive foetal RHD genotyping (NIPT) is performed in all 13 countries that responded, with eight having the costs fully covered by the government or local institutions. NIPT is recommended at different gestational ages ranging from 10-27 GW. Three strategies emerged as follows:

(1) Countries that recommend NIPT as early as possible to adapt targeted antenatal prophylaxis for situations at risk of feto-maternal haemorrhage;

(2) Countries advocating NIPT during the second trimester to increase its sensitivity; and

(3) Countries that advise NIPT just before the third trimester to adapt routine antenatal prophylaxis.

The approach at delivery differs between countries with seven countries systematically performing phenotyping on the newborn’s blood, whereas four are using the foetal RHD genotype to guide postpartum anti-Rh(D) administration. Detection and quantification of feto-maternal haemorrhage (FMH) in a situation of a potentially sensitizing event are systematically performed in seven countries.

For pregnant women with a partial or non-characterized RHD variant allele, all countries adopt the same strategy, which is to consider them as Rh(D) negative patient.

Most of the survey participants have national guidelines. All recommended targeted and routine antenatal immunoprophylaxis, in accordance with the World Health Organization recommendations. The dose used in European countries is similar, between 1000 and 1500 IU.

Despite differences among countries, the Rh disease prevention policies are very efficient in Europe. HDFN cases have not completely disappeared - it therefore remains important to share best practices for continuous improvement in reducing Rh(D) alloimmunisation.

Toly-Ndour C et al. Rh disease prevention: the European perspective. Congress review. ISBT Science Series 2021; 16(1):106-118


Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis

With an aim to improve clinical outcomes by reductions in bleeding and transfusion, patient blood management (PBM) interventions include measures such as: Interventions targeting anaemia; pre surgery iron administration, perioperative cell salvage, the use of restrictive red cell transfusion thresholds, and interventions targeting bleeding; and tranexamic acid, point-of-care testing for coagulopathy. This meta-analysis assessed whether existing evidence supports the routine administration of PBM interventions during and after major surgery.

The authors performed a systematic review and network meta-analysis of randomised trials that have evaluated these five PBM interventions administered alone or in combination to patients undergoing surgery. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The primary outcomes were risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Outcomes of interest included treatment effects on transfusion and bleeding, measures of clinical effectiveness, and cost-effectiveness.

The population consisted of patients of any age undergoing surgery in the following fields: cardiovascular, neoplastic, orthopaedic, gastrointestinal, urology, organ transplantation, plastic, or maxillofacial surgery.

Some additional exclusion criteria were applied: trials with patients undergoing trauma, burns or gastrointestinal haemorrhage, gynaecological procedures, dental procedures, or critical care patients; trials that used unwashed autologous red cells in trials of cell salvage; trials comparing different drug  formulations or doses without a control group; trials without placebo or no treatment controls; and trials that did not report the pre-specified co-primary outcomes or trials that were not peer-reviewed.

Searches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion but had no statistically significant treatment effect on 30-day or hospital mortality. Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective.

PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery. However, the results of this study suggest that the adoption of restrictive transfusion thresholds in surgery patients is reasonable as it has a direct and significant cost reduction in the absence of harm.

Limitations include the pooling of studies undertaken in different cohorts and using different interventions. However, the contrast in the heterogeneity of effects across treatments and settings for bleeding and transfusion outcomes but not for effectiveness outcomes supports this approach and provides a unique perspective on the evidence for PBM. Additionally, inconsistency of outcome definitions and reporting is likely given the multiple clinical settings; however, the two primary outcomes, red cell transfusion and mortality, are resilient to detection bias.

Roman MA et al. Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis. British Journal of Anaesthesia 2021;126(1):149-156