Blood Transfusion

The new SoHO Regulation. What should the blood system expect?

Simonetta Pupella — 2024-09-30

On the 13^th of June 2024, the “Regulation (EU) 2024/1938 of the European Parliament and of the Council on standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC” of came into force it shall apply from 7 August 2027. The new act represents the final results of a long and, demanding work of negotiation between European Commission, Member States and the Council with the final aim to have only one high level act regulating all the Substances of Human Origin (SoHO) and, legally binding in its entirety for the Member States (MS). The principles and standards set in the Regulation combine the need to strength the mutual recognition of the oversight activities among MS and, the capacity of the SoHO system to deal with the innovation in the field facilitating the connection with competent authorities, professionals and final users of the SoHO preparations.

Inclusion of cryoprecipitate, pathogen-reduced, in the who model lists of essential medicines for adults and children: a call for action

Jay Epstein — 2024-01-31

This is a commentary on the recent listing of cryoprecipitate pathogen-reduced on the WHO Model List of Essential Medicines

Genomic characterisation of clinically significant blood group variants in Aboriginal Australians

Sudhir Jadhao — 2024-03-11

Background - Hematological disorders are often treated with blood transfusions. Many blood group antigens and variants are population-specific, and for patients with rare blood types, extensive donor screening is required to find suitable matches for transfusion. There is a scarcity of knowledge regarding blood group variants in Aboriginal Australian populations, despite a higher need for transfusion due to the higher prevalence of renal diseases and anaemia.

Materials and methods - In this study, we applied next-generation sequencing and analysis to 245 samples obtained from Aboriginal Australians from South-East Queensland, to predict antigen phenotypes for 36 blood group systems.

Results - We report potential weak antigens in blood group systems RH, FY and JR that have potential clinical implications in transfusion and pregnancy settings. These include partial DIII type 4, weak D type 33, and Del RHD (IVS2-2delA). The rare Rh phenotypes D+ C+ E+ c− e+ and D+ C+ E+ c+ e− were also detected.

Discussion - The comprehensive analyses of blood group genetic variant profiles identified in this study will provide insight and an opportunity to improve Aboriginal health by aiding in the identification of appropriate blood products for population-specific transfusion needs.

Development and evaluation of trigger tools to identify pediatric blood management errors

Swaminathan Kandaswamy — 2024-03-27

Background - Pediatric patient blood management (PBM) programs require continuous surveillance of errors and near misses. However, most PBM programs rely on passive surveillance methods. Our objective was to develop and evaluate a set of automated trigger tools for active surveillance of pediatric PBM errors.

Materials and methods - We used the Rand-UCLA method with an expert panel of pediatric transfusion medicine specialists to identify and prioritize candidate trigger tools for all transfused blood products. We then iteratively developed automated queries of electronic health record (EHR) data for the highest priority triggers. Two physicians manually reviewed a subset of cases meeting trigger tool criteria and estimated each trigger tool’s positive predictive value (PPV). We then estimated the rate of PBM errors, whether they reached the patient, and adverse events for each trigger tool across four years in a single pediatric health system.

Results - We identified 28 potential triggers for pediatric PBM errors and developed 5 automated trigger tools (positive patient identification, missing irradiation, unwashed products despite prior anaphylaxis, transfusion lasting >4 hours, over-transfusion by volume). The PPV for ordering errors ranged from 38-100%. The most frequently detected near miss event reaching patients was first transfusions without positive patient identification (estimate 303, 95% CI: 288-318 per year). The only adverse events detected were from over-transfusions by volume, including 4 adverse events detected on manual review that had not been reported in passive surveillance systems.

Discussion - It is feasible to automatically detect pediatric PBM errors using existing data captured in the EHR that enable active surveillance systems. Over-transfusions may be one of the most frequent causes of harm in the pediatric environment.

Assessment of metabolic and hemostatic profile of apheresis platelet concentrates: does the storage medium play a role?

Eleni Petrou — 2024-07-30

Background - The impact of pathogen reduction technology (PRT) on metabolic and haemostatic profile of treated platelets remains a subject of debate. Platelets Additive Solutions (PASs) are suggested as more appropriate storage medium compared to plasma. To investigate this in terms of zero heterogeneity PRT-treated and control apheresis platelet concentrates (PCs), collected from the same donors and stored in PAS and plasma respectively, were analyzed.

Materials and methods - In the first arm of the study six double dose-apheresis PCs were produced, split and stored in plasma, while in the second arm six split double dose-apheresis PCs from the same donors, were produced and stored in PAS. Control and PRT-treated PCs resulted in both arms. Metabolic and haemostatic markers were evaluated in all the examined groups on days 1, 3 and 5.

Results - A time dependent increased metabolism both in PAS and plasma-stored PCs was evident in PRT-treated PCs. However, the metabolic profile was better preserved in PCs stored in PAS, as higher pH (6.8 vs 6.5, p=0.007) and lower lactate levels (12.6 vs 17.8 mmol/L, p=0.009) were documented in PRT-treated PAS-PCs compared to plasma-PCs, on day 5. A time dependent decreased hemostatic capacity regardless the storage medium was evident in PRT-treated PCs, (PAS-PCs MCF, p=0.004 and plasma-PCs MCF, p=0.007). Similar results were obtained in control PCs.

Discussion - The use of PAS preserves the metabolic profile of PCs more adequately compared to plasma but has no effect on the haemostatic profile. The clinical relevance of these findings needs further investigation.

Blood transfusion-associated anaphylaxis in perioperative- and non-perioperative patients in Western Norway 2002-2021

Bjarte Erikstein — 2024-05-15

Background - Anaphylaxis after blood transfusion is a feared complication accounting for severe morbidity. A retrospective study was performed at Haukeland University Hospital, Bergen, Norway, to investigate the rate and features of transfusion-associated anaphylaxis (TAA) occurring between 2002-2021.

Materials and methods - Identified cases of TAA were studied by an immunologist and an allergist to extract information about general characteristics, amplifying factors, co-morbidity, treatment, and treatment responses. TAA was reported as perioperative or non-perioperative.

Results - We identified 29 cases of TAA: 13 perioperative and 16 non-perioperative. Allergic transfusion reaction had an incidence rate of 34/100,000 transfusions and TAA a rate of 7/100,000 transfusions. The incidence of allergic reactions and TAA increased 2.6- and 6.4-fold during the study period. The first perioperative TAA was discovered 12 years into the study period but was equally frequent as non-perioperative transfusion-associated anaphylaxis in the last five years of the study period. 52% of the TAA cases had relevant co-morbidity and 100% of them had amplifying factors. Although only 38% of the non-perioperative patients received epinephrine as treatment, 94% of them had a good treatment response to their total treatment regimen. Poorer treatment response was observed with higher age, more cardiovascular- and respiratory disease, higher use of amplifying and sedating medications and a higher severity score.

Discussion - Our findings indicate that TAA, especially in the perioperative setting, is underdiagnosed. The increased incidence of TAA in our study is temporally related to the introduction of a national hemovigilance program, introduction of standardized laboratory testing for anaphylaxis and increased multidisciplinary focus on the condition. In conclusion, increased awareness of TAA, and especially in the perioperative setting, is needed. A multidisciplinary approach is necessary to improve identification and reporting of TAA.

In vitro regenerative effects of a pooled pathogen-reduced lyophilized human cord blood platelet lysate for wound healing applications

Marianna Buscemi — 2024-09-16

Background - Cord blood platelets, easily obtained from blood units not suitable for haematopoietic stem cell transplantation, represent an abundant source of growth factors for use in wound healing. Although several protocols have been described for platelet lysate production, no standard manufacturing protocol is available. The use of pooled cord blood platelets could thus facilitate standardization. In this study, the effect of varying concentrations (up to 20%) of a pooled pathogen-reduced lyophilized cord blood platelet lysate (PRL-CBPL) was investigated in different cell types involved in the wound healing process. The effect of heparin addition was also evaluated. In parallel, a comparison was performed with a single donor cord blood platelet lysate (SD-CBPL).

Materials and methods - The effect of PRL-CBPL on the viability and proliferation of different cell lines (L929 mouse fibroblasts and HaCaT keratinocytes) and human primary cells (fibroblasts-NHDF, coronary artery smooth muscle cells-HCASMC and coronary artery endothelial cells-HCAEC), on HaCaT migration and the chemotactic effect on human monocytes (THP-1) was evaluated.

Results - PRL-CBPL showed a lower PDGF-AB amount compared to SD-CBPL. Differing concentrations of both CBPL were necessary to influence cell viability and proliferation. 3% was the optimal concentration for L929 and HaCaT as well as for NHDF and HCASMC, while HCAEC required 10%. The effect of added heparin was more evident on SD-CBPL and in particular on NHDF and HCASMC proliferation. Keratinocyte scratch closure was obtained with 3 and 5% PRL-CBPL and SD-CBPL respectively. Both CBPLs caused an increase in the number of migrated THP-1 monocytes in a concentration-dependent manner up to 20% with a higher monocyte migration for SD-CBPL with respect to PRL-CBPL and in cells treated with heparin.

Discussion - The data obtained suggest that PRL-CBPL is an effective standardized alternative to SD-CBPL.

Ten years of a neonatal screening program for hemoglobinopathies in Friuli-Venezia Giulia: first regional experience in Italy

Epifania Rita Testa — 2023-11-30

Background - Hemoglobinopathies are the commonest genetic defect worldwide (7% of the world’s population has at least one hemoglobin mutation). Although prenatal screening for hemoglobinopathies is not obligatory during pregnancy in Italy, it is offered to women by the Italian National Health Service in the pre-conception phase. The screening of newborns is a valid alternative, and has been adopted in various European countries, albeit in a piecemeal fashion. Neonatal screening has the advantage of providing early diagnosis of a hemoglobinopathy. Here we report the findings from the experience with neonatal screening in Friuli-Venezia Giulia since 2010.

Materials and methods - The hemoglobinopathy screening project in Friuli-Venezia Giulia, a Region in north Italy, began in November 2010. High-performance liquid chromatography was performed on dried blood spot samples collected by obstetric nurses from neonates within 5-8 days after birth.

Results - From 2010 to 2019, 11,956 newborns were screened, and abnormal hemoglobin was found in 519 of them (4.34%): the variants identified included HbS, HbC, HbD, HbE and HbX. More specifically, the HbS variant was observed in 347 (2.9%) newborns and the homozygous pattern was identified in 24 (0.2%) cases. The screening also detected two cases of β-thalassemia major.

Discussion - We report our experience of 10 years of screening newborns for hemoglobinopathies in Friuli-Venezia Giulia, in which 7.7% of people come from malaria-endemic areas. Increased mobility and migratory flows bringing in hemoglobinopathy carriers from endemic areas have led to an increase in mutations in non-malarial countries, with a current incidence of around 4% in the newborns we tested. This means that hemoglobinopathies can be described as a rare condition. Our data show that incidence rates are comparable to those of other inherited disorders such as phenylketonuria, thereby justifying the inclusion of the test for hemoglobinopathies into screening programs for rare diseases.

Identification of the novel c.300C>G variation on the ABO*A1.02 allele associated with an AweakB phenotype

Yuqing Shen — 2024-02-28

Background - Variants of the ABO gene that can lead to the malfunctioning of ABO glycosyltransferase (GT) and consequently result in weakened ABO phenotype. In this study, we investigated the mechanism behind the emergence of the A_weakB phenotype associated with this novel weak ABO subgroup allele.

Materials and methods - The ABO phenotyping and genotyping were performed by serological studies and direct DNA sequencing of ABO gene. The total glycosyltransferase transfer capacity in serum was examined, and the flow cytometry was applied to detect the A antigen on the red blood cells. The role of the novel mutation was evaluated by 3D model, predicting protein structure and stability changes.

Results - The serological results revealed that the individual had an A_weakB phenotype. A novel single nucleotide variant (SNV) c.300C>G (p.F100L) based on ABO*A1.02, was detected through gene analysis, confirming the genotype of the subject as AW-var/B.01. Flow cytometric analysis of the A antigen on red blood cells demonstrated a very weak expression of A antigens in the proband, and the catalytic ability analysis indicated that the GTA had almost completely lost its ability to convert O type red blood cells into A type red blood cells. In silico analysis suggested that the SNV c.300C>G on the A1.02 might potentially decrease the stability of GTA, as indicated by the ΔΔG values -1.841. However, it was noted that the hydrogen bond structure around the 100 site did not show significant changes between the wild-type and variant GTA.

Discussion - One novel AW allele was identified and the SNV c.300C>G (p. F100L) can cause the A_weakB phenotype through reducing stability of the GTA.

Implementing Patient Blood Management in major digestive surgery: should we do more?

Marco Catarci — 2024-07-22

There is evidence of decoupling between top-down directives/guidelines and real-life data regarding the implementation of Patient Blood Management (PBM) programs in Italy. This letter suggests that bottom-up initiatives should be stimulated through the diffusion of the culture of PBM, while funding from the health authorities is needed to facilitate audit and benchmarking of the implementation process.

The SARS-CoV-2 infection rebound among patients receiving antiviral agents, convalescent plasma, or no treatment: a systematic review with meta-analysis

Ilaria Pati — 2024-05-27

Background - There is some evidence showing rebound of COVID-19 infections in patients treated with nirmatrelvir-ritonavir between 2 and 8 days following cessation of the antiviral treatment. COVID-19 rebound is not unique to patients treated with nirmatrelvir-ritonavir, but is also observed in molnupiravir recipients, in patients who did not receive any antiviral treatment and in patients who received convalescent plasma (CP).

Materials and methods - This was a systematic review with meta-analysis of clinical trials evaluating rates of virologic and clinical rebound in COVID-19 patients receiving antiviral agents, CP or no treatment. Both randomized clinical trials and controlled cohort studies were considered. The methodological quality of trials was assessed using ROB-2 and ROBIN-1 checklists, and the GRADE approach.

Results - Data were available from 16 trials. The occurrence of virologic rebound was more commonly observed among nirmatrelvir recipients than among untreated patients (relative risk [RR]=2.12; 95% confidence interval [CI]: 1.38-3.28; p=0.0007). No differences were observed in the occurrence of virologic rebound between nirmatrelvir-ritonavir and molnupiravir recipients (RR=1.01; 95% CI: 0.71-1.43). Similar rates of virologic rebounds were observed in molnupiravir recipients and untreated patients (RR=1.14; 95% CI: 0.81-1.6). One study in the pre-omicron period compared rates of virologic rebound between patients receiving standard of care with or without CP: no differences were observed between groups (RR=1.04; 95% CI: 0.55-1.99). Rates of clinical rebound were reported in seven trials, five evaluating nirmatrelvir-ritonavir and untreated patients, and two evaluating nirmatrelvir-ritonavir and molnupiravir recipients. No statistically significant differences between groups were observed. For all these comparisons, the certainty of the available evidence was graded as low or moderate.

Discussion - Virologic rebound of COVID-19 infections appears to be mild and self-limited, and was observed more commonly in nirmatrelvir-ritonavir recipients than in untreated patients, but was also observed in patients treated with molnupiravir or CP.

Recurrent disease after a matched sibling hematopoietic transplant in an aplastic anemia patient with a disease risk allele, HLA-B*40:02

Akshita Khosla — 2024-08-26

A 20-year-old female with HLA-B*40:02, considered to be one of the most studied aplastic anemia (AA) risk HLA allele, was diagnosed with severe AA. She received allogeneic hematopoietic cell transplantation (HSCT) from an HLA-matched sibling donor. Although she achieved engraftment on Day +13, blood counts started to decrease from Day +100 prior to donor chimerism decline, and she developed severe pancytopenia by Day +157 after 1^st HSCT. We considered this is a disease recurrence due to cytotoxic T lymphocytes attacking hematopoietic stem cells mediated by HLA-B*40:02. She received 2^nd HSCT from a haploidentical donor without HLA-B*40:02. She achieved engraftment on Day +13 and complete donor chimerism after 2^nd HSCT. Our experience suggested that performing a second allogeneic transplant without AA risk allele may be beneficial after a failed HSCT.