Using a scenario approach to assess for the current and future demand of immunoglobulins: An interview and literature study from The Netherlands.

OBJECTIVES: To explore the current and future demand of immunoglobulins globally and specifically for the Netherlands by assessing: (I) which specialties contribute to current demand, (II) new areas of medical need, (III) which transformational factors may impact demand and to what effect, by using a scenario approach. BACKGROUND: As immunoglobulin demand continues to increase globally, there is concern of increasing shortages and questions of whether and how future demand will continue based on medical need. METHODS/MATERIALS: In line with scenario principles, a scoping review of Pubmed, Web of Science, Embase and Cochrane and grey literature was conducted. Semi-structured interviews with subject matter experts were held. The results of the review and interviews were analysed for major themes. RESULTS: The scoping review resulted in 97 articles, 74 regarding clinical uses, and 23 regarding organisational and other themes. Fifteen clinical and non-clinical experts were interviewed. I) Neurology, immunology, and haematology were specialties that contribute most to current demand. II) Regarding potential new areas of medical need, the literature review resulted in more indications than the interviews, for example, post-renal transplants. III) Four groups of key transformational factors were found: factors that could increase immunoglobulin demand (e.g., EMA revisions), decrease demand (e.g., replacement products, Dutch Transfer Act 2021), factors that remain to be seen how it impacts demand (e.g., further evidence), and miscellaneous factors (e.g., supply-related). CONCLUSION: Having identified the specialties and relevant transformational factors that affect immunoglobulin demand, more research is needed on what clinical or organisational strategies would be effective in controlling demand in general for the Netherlands and abroad. Other blood establishments may also use a scenario approach to increase preparedness for future (un)expected developments.

Not a crystal ball: Mapping opportunities and threats for the future demand of red blood cells in the Netherlands using a scenario approach.

BACKGROUND: As Western blood transfusion practices are changing, there is interest and need in anticipating the future demand of blood products and how a blood establishment can actively prepare for various long-term developments. This article provides an overview of how a scenario approach was used to prioritize key categories of drivers for the future demand of red blood cells and the organizational implications thereof for Sanquin, the Dutch national blood establishment. STUDY DESIGN AND METHODS: Based on previously identified drivers from interviews and a literature review (Step 1), we conducted scenario sessions and a survey to rank a list of drivers ("themes") with its related opportunities and threats (Step 2), to identify mitigating measures per theme through focus groups (Step 3). RESULTS: In Step 2, 10 themes were found that were classified in terms of importance and uncertainty. These were plotted on a two-dimensional graph with an ellipse to indicate the interquartile ranges per theme. Experts rated the top three most important themes to be the blood supply organization, precision medicine, and red blood cell replacements. In Step 3, focus groups identified specific mitigating measures per theme. These measures had parallel ideas, such as the need for an innovative mentality, internal and external communication and collaboration, and building Sanquin's reputation and trust with the public. CONCLUSION: Having identified the most important themes with suggestions for mitigating measures, Sanquin can take steps to become adaptive and proactive. Other blood establishments may also use a scenario approach to create contextualized long-term strategies.

Putting the spotlight on donation-related risks and donor safety - are we succeeding in protecting donors?

BACKGROUND AND OBJECTIVE: The European consortium project TRANSPOSE (TRANSfusion and transplantation: PrOtection and SElection of donors) aimed to assess and evaluate the risks to donors of Substances of Human Origin (SoHO), and to identify gaps between current donor vigilance systems and perceived risks. MATERIALS AND METHODS: National and local data from participating organizations on serious and non-serious adverse reactions in donors were collected from 2014 to 2017. Following this, a survey was performed among participants to identify risks not included in the data sets. Finally, participants rated the risks according to severity, level of evidence and prevalence. RESULTS: Significant discrepancies between anticipated donor risks and the collected data were found. Furthermore, many participants reported that national data on adverse reactions in donors of stem cells, gametes, embryos and tissues were not routinely collected and/or available. CONCLUSIONS: These findings indicate that there is a need to further develop and standardize donor vigilance in Europe and to include long-term risks to donors, which are currently underreported, ensuring donor health and securing the future supply of SoHO.

Validation of a standardized donor health questionnaire across substances of human origin.

BACKGROUND AND OBJECTIVES: A donor health questionnaire (DHQ) aims to ensure the safety of donors and recipients of transfusions or transplantations with blood components, plasma-derived medicinal products, tissues, haematopoietic stem cells and medically assisted reproduction (in short substances of human origin; SoHO). Currently, many different DHQs exist across countries and SoHO. TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors) developed and validated a standardized DHQ to use across countries and SoHO. We tested whether participants understand the questions and provide honest answers. METHODS: For the validation of the standardized DHQ, two demographically representative online surveys were conducted in Germany (N = 3329) and Austria (N = 3432). We surveyed whether participants understood each DHQ question and would answer the questions truthfully. We used experimental settings to test whether there is a difference between mode of administration (print vs. online), the order of the questions (subject vs. chronological order), and the positioning of the general state of health question (beginning vs. end) in the DHQ. Using regression models, we tested the DHQ's impact on participant mood after completion and on socially desirable response behaviour. RESULTS: Participants understood the DHQ questions well and would answer them honestly. Nevertheless, the data show different levels of understanding and honesty when responding. Administration mode was the only characteristic that had a significant influence on mood, with the online version resulting in a more favourable mood in comparison to the printed version. CONCLUSION: The DHQ was well understood and had a low dishonest tendency. Our findings can serve as an impulse for further research on DHQ criteria across other SoHO and countries.

How donor selection criteria can be evaluated with limited scientific evidence: lessons learned from the TRANSPOSE project.

BACKGROUND AND OBJECTIVE: Donor selection criteria (DSC) are a vital link in the chain of supply of Substances of Human Origin (SoHO) but are also subject to controversy and differences of opinion. Traditionally, DSC have been based on application of the precautionary principle. MATERIALS AND METHODS: From 2017 to 2020, TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors), a European research project, aimed to identify discrepancies between current DSC by proposing a standardized risk assessment method for all SoHO (solid organs excluded) and all levels of evidence. RESULTS: The current DSC were assessed using a modified risk assessment method based on the Alliance of Blood Operators' Risk-based decision-making framework for blood safety. It was found that with limited or diverging scientific evidence, it was difficult to reach consensus and an international standardized method for decision-making was lacking. Furthermore, participants found it hard to disregard their local guidelines when providing expert opinion, which resulted in substantial influence on the consensus-based decision-making process. CONCLUSIONS: While the field of donation-safety research is expanding rapidly, there is an urgent need to formalize the decision-making process regarding DSC. This includes the need for standardized methods to increase transparency in the international decision-making process and to ensure that this is performed consistently. Our framework provides an easy-to-implement approach for standardizing risk assessments, especially in the context of limited scientific evidence.

A predictive model for estimating the number of erythrocytapheresis or phlebotomy treatments for patients with naïve hereditary hemochromatosis.

BACKGROUND AND AIMS: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. METHODS: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 µg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. RESULTS: The linear regression model with the best predictive quality (R2  = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.

First results of a ferritin-based blood donor deferral policy in the Netherlands.

BACKGROUND: Whole blood donors are at risk of becoming iron deficient. To monitor iron stores, Sanquin implemented a new deferral policy based on ferritin levels, in addition to the traditional hemoglobin measurements. METHODS: Ferritin levels are determined in every fifth donation, as well as in all first-time donors. Donors with ferritin levels <15 ng/mL (WHO threshold) are deferred for 12 months; those ≥15 and ≤30 ng/mL for 6 months. The first results were analyzed and are presented here. RESULTS: The results show that 25% of women (N = 20151, 95% CI 24%-25%) and 1.6% of men (N = 10391, 95% CI 1.4%-1.8%) have ferritin levels ≤30 ng/mL at their first blood center visit. For repeat (non-first-time) donors, these proportions are higher: 53% of women (N = 28329, 95% CI 52%-54%) and 42% of men (N = 31089, 95% CI 41%-43%). After a 6-month deferral, in 88% of returning women (N = 3059, 95% CI 87%-89%) and 99% of returning men (N = 3736, 95% CI 98%-99%) ferritin levels were ≥15 ng/mL. After a 12-month deferral, in 74% of returning women (N = 486, 95% CI 70%-78%) and 95% of returning men (N = 479, 95% CI 94%-97%) ferritin levels increased to ≥15 ng/mL. CONCLUSION: Deferral of donors whose pre-donation ferritin levels were ≤30 ng/mL might prevent donors from returning with ferritin levels <15 ng/mL. This policy is promising to mitigate effects of repeated donations on iron stores.

[Blood safety in the Netherlands: prevention of blood-transmitted infections]. / De bloedveiligheid in Nederland.

Amongst the various blood-safety measures to prevent blood-transmitted infections in transfusion recipients, the most important are the selection of blood donors and the testing for infections of the donations. A look-back procedure aims to inform hospitals about potentially infected blood products and to trace the relevant recipients. The opposite, reverse look-back, can also occur: following a report that a patient has an infection of which blood transfusion may be the possible source, all possibly implicated donors will be screened for the particular agent. Over the period 2007-2017, 84 look-backs were carried out by the Dutch blood product organisation Sanquin. Transmission via blood products of the human immunodeficiency virus, hepatitis C virus, human T-cell Lymphotropic virus or Treponema pallidum were not found. Look-back identified four recipients with hepatitis-B virus infection. These recipients had received a blood product from donors with an occult chronic hepatitis-B virus infection. In the Netherlands, the risks associated with transmission of infection through blood products are minimal; however, transmission may still occur, despite extensive blood-safety measures.

Ensuring HLA-matched platelet support requires an ethnic diverse donor population.

BACKGROUND: Patients refractory for platelet transfusions benefit from human leukocyte antigen (HLA)-matched platelet transfusions. Differences in ethnic background of patients and donors could hamper the availability of sufficient numbers of HLA-matched donors for all patients. We evaluated our HLA-matched donor program and explored the role of ethnic background of patients related to the number of available donors. METHODS: We performed a cohort study among consecutive patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. The number of available matched donors was determined per patient. Haplotypes were constructed from genotypes with computer software (PyPop). Based on haplotypes, HaploStats, an algorithm from the National Marrow Donor Program, was used to assess the most likely ethnic background for patients with 5 or fewer and 30 or more donors. RESULTS: HLA typing was available for 19,478 donors in September 2017. A total of 1206 patients received 12,350 HLA-matched transfusions. A median of 83 (interquartile range, 18-266) donors were available per patient. For 95 (10.3%) patients, 5 or fewer donors were available. These patients were more likely to have an African American background, whereas patients with 30 or more donors were more often from Caucasian origin, compared with Caucasian origin for patients with 30 donors. CONCLUSION: Adequate transfusion support could be guaranteed for most but not all refractory patients. More non-Caucasian donors are required to ensure the availability of HLA-matched donors for all patients in the Netherlands.

Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry.

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at clinicaltrials.gov identifier: 00600860.

Transition from fresh frozen plasma to solvent/detergent plasma in the Netherlands: comparing clinical use and transfusion reaction risks.

Plasma transfusion is indicated for replenishment of coagulative proteins to stop or prevent bleeding. In 2014, the Netherlands switched from using ~300mL fresh frozen plasma (FFP) units to using 200mL Omniplasma, a solvent/detergent treated pooled plasma (SD plasma), units. We evaluated the effect of the introduction of SD plasma on clinical plasma use, associated bleeding, and transfusion reaction incidences. Using diagnostic data from six Dutch hospitals, national blood bank data, and national hemovigilance data for 2011 to 2017, we compared the plasma/red blood cell (RBC) units ratio (f) and the mean number of plasma and RBC units transfused for FFP (~300mL) and SD plasma (200mL) for various patient groups, and calculated odds ratios comparing their associated transfusion reaction risks. Analyzing 13,910 transfusion episodes, the difference (Δf = fSD - fFFP) in mean plasma/RBC ratio (f) was negligible (Δfentire_cohort = 0.01 [95% confidence interval (CI): -0.02 - 0.05]; P=0.48). SD plasma was associated with fewer RBC units transfused per episode in gynecological (difference of mean number of units -1.66 [95% CI: -2.72, -0.61]) and aneurysm (-0.97 [-1.59, -0.35]) patients. SD plasma was further associated with fewer anaphylactic reactions than FFP (odds ratio 0.37 [0.18, 0.77; P<0.01]) while the differences for most transfusion reactions were not statistically significant. SD plasma units, despite being one third smaller in volume than FFP units, are not associated with a higher plasma/RBC ratio. SD plasma is associated with fewer anaphylactic reactions than FFP plasma/RBC units ratio.

HLA-matched platelet transfusions are effective only in refractory patients with positive HLA antibody screening.

BACKGROUND: Recipients of platelet transfusions with 1-hour corrected count increments (1hCCIs) of 7.5 or less on two subsequent platelet transfusions with random platelets may benefit from human leukocyte antigen (HLA)-matched platelet concentrates. We aimed to quantify the efficacy of HLA-matched platelets concentrates expressed in 1hCCIs. METHODS: We performed a cohort study among consecutive refractory patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. We performed mixed-model linear regression comparing 1hCCIs after HLA split-antigen-matched transfusions with 1hCCIs after HLA-mismatched transfusions, adjusted for within-patient correlations. A donor-to-patient match was categorized as a split-match if all donor HLA-A and -B antigens were present in the patient as well; that is, donor and patient were HLA identical or compatible. Subgroup analyses were performed for patients with positive or negative HLA antibody screens. Finally, the additional effect of ABO mismatches on 1hCCIs was investigated. RESULTS: The 1hCCI after an HLA-matched transfusion was 14.09 (95% reference interval, 1.13-29.89). This was 1.94 (95% confidence interval [CI], 0.74-3.15) higher than 1hCCI after HLA-mismatched transfusions. In patients with negative HLA antibody screening tests, HLA matching did not affect 1hCCIs. Conditional on HLA matching, 1hCCIs decreased by 3.70 (95% CI, -5.22 to -2.18) with major ABO mismatches. CONCLUSION: Matched platelet concentrates yielded maximal 1hCCIs, whereas mismatched transfusions still resulted in adequate increments. There is no indication for HLA-matched platelets in patients with negative antibody screens.

Past, present, and future: a qualitative and literature study identifying historical trends, drivers, and transformational factors for the future demand of blood supply in the Netherlands.

BACKGROUND: As blood transfusion has evolved, there is a need to understand its historical trends and underlying drivers. Furthermore, for blood bank management to make decisions about the future, they need to consider what transformational factors (defined as developments in science, society, and technology) could significantly impact blood demand and to what effect. This study has a two-fold aim: to explore transfusion experts' perspectives regarding 1) historical trends and drivers of red blood cells (RBCs) in the past 20 years and 2) transformational factors that would impact the future demand of RBCs and to what effect. STUDY DESIGN AND METHODS: Forty-two semi-structured interviews were held with transfusion experts from the Netherlands and abroad, supplemented with a literature review of Pubmed, Google Scholar, and gray literature. RESULTS: With regard to historical trends and drivers, experts shared two main trends: decreased or increased demands for RBCs. Various drivers were reported for each trend, coupled with evidence from literature. With regard to the future, experts anticipated that RBC demands will either increase (17%), decrease (45%), decrease but stabilize (12%), or stabilize as is (7%). Various transformational factors were found to support each trend (e.g., gene therapy will reduce RBC demand), although there were factors for which experts were unsure about its effects (e.g., cultured RBCs). Seven groups of transformation factors were identified in the literature review. CONCLUSION: While the future of blood transfusion is uncertain, there are actions that blood banks may take now to prepare for potential future developments.

Apheresis causes complement deposition on red blood cells (RBCs) and RBC antigen alterations, possibly inducing enhanced clearance.

BACKGROUND: Apheresis is increasingly being applied to collect cells or plasma, even allowing the collection of multiple blood components during one procedure. Although the quality of the cellular and plasma products that are obtained by apheresis have been extensively studied and shown to be of high quality, the impact of apheresis on the red blood cells (RBCs) that are returned to the donor has not been investigated. STUDY DESIGN AND METHODS: The effect of the plasma- or plateletpheresis procedures by four different devices-MCS+ (Haemonetics), PCS2 (Haemonetics), Trima Accel (Terumo BCT), and Autopheresis-C (Auto-C, Fresenius Kabi)-on the RBCs that are returned to the donor was tested in a blinded, prospective trial in a cohort of 25 donors. RESULTS: A rheologic analysis of donor RBCs before and after plasma- or plateletpheresis showed no differences in outcome. However, a strong increase in hemolysis was found in samples from the Trima Accel devices after plateletpheresis, compared to all other machines tested. Furthermore, an increase in complement deposition on RBCs was seen after all plasmapheresis procedures (MCS+, PCS2, and Auto-C). Finally, a significant decrease in the expression of the complement-regulating protein CD59 was seen in all postapheresis samples as well as a significant decrease of the adhesion molecule CD147. CONCLUSION: The increase in complement deposition and the decrease in the expression of CD59 suggests that RBC clearance might be enhanced after return to the donor. Possible side effects due to an increase in hemolysis after Trima Accel plateletpheresis should be further investigated.

A Conceptual Framework for Optimizing Blood Matching Strategies: Balancing Patient Complications Against Total Costs Incurred.

Alloimmunization is currently the most frequent adverse blood transfusion event. Whilst completely matched donor blood would nullify the alloimmunization risk, this is practically infeasible. Current matching strategies therefore aim at matching a limited number of blood groups only, and have evolved over time by systematically including matching strategies for those blood groups for which (serious) alloimmunization complications most frequently occurred. An optimal matching strategy for controlling the risk of alloimmunization however, would balance alloimmunization complications and costs within the entire blood supply chain, whilst fulfilling all practical requirements and limitations. In this article the outline of an integrated blood management model is described and various potential challenges and prospects foreseen with the development of such a model are discussed.