Rik Tonino

For a large part based on the published article: “Toward personalized transfusion strategies: The emerging role of wearable biosensors in chronic anaemia management” R.P.B. Tonino,1,2,3 M.R. Schipperus,4 and J.J. Zwaginga1,2 1 Leiden University Medical Center, Leiden, The Netherlands 2 TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands 3 Groene Hart Ziekenhuis, Gouda, The Netherlands 4 Sanquin Blood Supply, Amsterdam, The Netherlands Introduction Throughout this thesis, we have tried to answer several pressing questions: what are the effects of haemoglobin modulation? Is there a causal relationship between Hb level and physiological or patient-reported outcomes? How can we measure these outcomes effectively and accurately? And how should we interpret these measurements to inform and optimize transfusion or donation strategies? As Bram Stoker, author of Dracula, might have put it: “The blood is the life” – but how much life is actually in the blood? Here we summarize our findings and reflect upon their implications. Chapter 2 Haemoglobin modulation affects physiology and patient-reported outcomes in anaemic and non-anaemic subjects: An umbrella review Background and context Both low and high haemoglobin concentrations are known to affect physiological performance and quality of life. Yet, despite decades of research, uncertainty remains regarding how Hb modulation through interventions such as transfusion, phlebotomy, iron supplementation or erythropoiesis-stimulating therapy, or even altitude exposure, translates into measurable physiological and patient-reported outcomes. Existing clinical thresholds for transfusion or target Hb levels often rely on arbitrary or disease-specific conventions rather than on integrative physiological evidence. To address this gap, we conducted an umbrella review synthesizing evidence from published systematic reviews and meta-analyses that evaluated the relationship between Hb modulation and both physiological and subjective outcomes in adults with and without anaemia. The goal was to determine whether changes in Hb concentration are consistently associated with improvements in measurable function and perceived well-being across populations and interventions. Study summary and findings A systematic search across six databases up to April 2022 identified 33 systematic reviews, comprising diverse populations (anaemic, non-anaemic, and polycythaemic) and interventions aimed at modulating Hb levels. Eligible reviews reported at least one physiological endpoint (e.g., VO2max, heart rate, exercise capacity) or a patient-reported outcome (e.g., fatigue, dyspnoea, Quality of Life). Quality assessment using AMSTAR-2 revealed that only 7 reviews were rated as high quality, whereas 24 were judged critically low, highlighting substantial methodological limitations within the available literature. Across the included reviews, increases in Hb concentration were generally associated with improvements in both physiological measures and patient-reported outcome measures. These benefits were, as might be expected, most pronounced among individuals with low baseline Hb levels, where modest Hb increases translated into gains in functional capacity and perceived vitality. For example, in chronic kidney disease, raising Hb toward 12 g/dL (7.5 mmol/L) was consistently linked to enhanced exercise tolerance, improved fatigue and quality-of-life scores. Evidence regarding the effects of supraphysiologic Hb increases or intentional Hb reduction (e.g., phlebotomy, haemodilution) was limited and heterogeneous. Overall, we concluded that Hb modulation exerts measurable physiological and patient-perceived effects, but the strength and consistency of evidence are constrained by the quality and heterogeneity of existing studies. Critical analysis This umbrella review provides the first comprehensive synthesis of evidence linking Hb modulation to physiological and subjective outcomes across a spectrum of populations and interventions. We employed a transparent search strategy, adhered to PRISMA guidelines, and used a formal quality appraisal tool. By combining data from multiple disease contexts, the study successfully highlights overarching physiological patterns that transcend individual disorders. However, several limitations temper the interpretative value of its findings. The predominance of low-quality reviews underscores the fragility of the evidence. Considerable heterogeneity–in populations, interventions, endpoints, and analytic methods–prevents reliable quantitative pooling or inference about causality. Another limitation lies in the indirectness of umbrella-level evidence: overlapping primary studies across reviews may have inflated perceived consistency, while publication bias on expected results could favour the latter. Moreover, the review focuses on associations rather than mechanistic pathways, leaving uncertain whether observed improvements are directly mediated by Hb change or by concurrent physiological and/or behavioural/psychological changes. Despite these limitations, the review’s findings reinforce the clinical observation that raising Hb from sub-physiologic to near-normal levels can enhance both functional and subjective outcomes, whereas there is no evidence regarding Hb elevation above physiologic norms. Future studies should emphasize standardized physiological metrics, incorporate digital or wearable monitoring for objective continuous assessment, and integrate patient-reported outcome measures to better capture the multidimensional impact of Hb modulation. Rigorous randomized trials and high-quality systematic reviews are needed to clarify optimal targets and balance benefit against risk. Chapter 3 Clinical practice for outpatients that are chronically red cell dependent: A survey in the Netherlands Background and context For patients that are chronically transfusion-dependent, evidence guiding optimal transfusion triggers, unit numbers and intervals in non-acute settings is scarce. In the absence of robust data, clinical decisions regarding maintenance transfusion regimens are often empirical and institution specific. We therefore designed a survey to characterize current outpatient transfusion practices in the Netherlands, focusing on three key dimensions: pre-transfusion haemoglobin thresholds, number of RBC units per transfusion episode, and interval between transfusions. We further sought to identify patient- and haematologist-specific factors influencing these decisions. Study summary and findings Between June and October 2020 we administered a web-based 44-question survey to members of the Dutch Haematology Association. Fifty physicians responded (response rate ~30%) representing both academic and community hospitals. The responses revealed a very wide variation in transfusion strategies. Reported median pre-transfusion Hb threshold was 8.0 g/dL (5.0 mmol/L), but individual thresholds ranged from 6.4 to 9.6 g/dL (4.0–6.0 mmol/L). Most centres transfused 1–2 RBC units per episode (range 0–3 units) at intervals of 2–4 weeks, though reported intervals ranged from 1 to 12 weeks. Physicians reported that the clinical factors most strongly influencing transfusion strategy were the presence of angina pectoris, cardiac failure, and dyspnoea. Among subjective considerations, quality of life and patients’ self-sustainability were regarded as most relevant. In contrast, fatigue, cognitive status, emotional state, and vital parameters were considered to have less influence on transfusion decisions. We concluded that while individualization may account for some variation in practice, the wide heterogeneity observed underscores the necessity for randomized controlled trials to inform evidence-based guidelines on the management of chronic transfu sion-dependent patients, including the identification of key clinical parameters. Critical analysis This survey addresses a significant gap in transfusion medicine by providing insights into real-world practices for the management of chronically transfused outpatients. Its strength lies in providing a quantitative snapshot of the diversity of practice across Dutch haematologists and in highlighting the absence of consensus thresholds in a routine care setting. The inclusion of both unit number and interval data, along with threshold values, adds practical relevance for clinicians and guidelines. Nevertheless, the study has several limitations. As a self-report survey, it reflects reported practice rather than verified transfusion records, opening the possibility of recall bias or social desirability bias. The relatively low response rate (30%) and possible non-response bias may reduce generalisability. Importantly, the study does not correlate transfusion strategies with clinical outcomes (such as symptom relief, quality of life improvement or iron overload). Consequently, the variation observed cannot be judged as beneficial, neutral or harmful. Differences in patient populations (diagnosis, comorbidity, transfusion burden) across centres may explain much of the heterogeneity yet cannot be delineated fully from the survey design. Nonetheless, the findings have important implications. The documented variation hints at potential under- or over-transfusion in some patient groups and underscores the need for prospective comparative studies. From a clinical perspective, this survey invites transfusion services to reflect on their local thresholds and intervals relative to peer practice and to consider monitoring of patient outcome–both objective and subjective–and resource utilisation. For guideline developers, the work emphasises an urgent need to incorporate maintenance transfusion strategies into the broader framework of patient blood management that mostly deals with perioperative situations. This survey of outpatient RBC transfusion practice in the Netherlands demonstrates considerable heterogeneity in thresholds, unit numbers and intervals for chronically transfused patients. While individualised care remains appropriate, the extent of variation and lack of outcome data highlight a pressing need for prospective research and evidence-based guidelines. Until such data emerge, clinicians are encouraged to monitor not only Hb levels but also patient-centred outcomes to ensure optimal practice. Chapter 4 Remote patient monitoring in adults receiving transfusion or infusion for haematological disorders using the VitalPatch® and AccelerateIQTM monitoring system: Quantitative feasibility study Background and context Patients with hematologic disorders receiving treatments such as red blood cell transfusions, chemotherapy, or immunotherapy are vulnerable to infusion-related complications, often signalled by changes in vital signs. Traditionally, symptom monitoring post-treatment is patient-reported, which can delay the detection of adverse events. Wearable biosensors–already validated and used in cardiology practice–in this line offer a solution. These devices enable continuous, real-time monitoring of physiological parameters beyond the clinic or in less supervised (such as home-) transfusion settings. This feasibility study explored whether integrating such technology into outpatient care is acceptable and practical. Study summary and findings In this quantitative feasibility study, twelve adult patients with hematologic conditions–including multiple myeloma, myelodysplastic syndrome, and non-Hodgkin lymphoma–were enrolled to wear the VitalPatch® biosensor for a period of 12 days around a planned infusion or transfusion. Patients received red blood cell transfusions (n = 4), intravenous proteasome inhibitors (n = 4), or immunotherapy (n = 4). The majority of participants (83%) were aged 60 years or older. The VitalPatch® system–capable of measuring heart rate, respiration rate, skin temperature, activity, heart rate variability and position–was generally well tolerated, with minimal interference in daily activities. Patient-reported outcomes were collected at baseline, day 1, day 5, and day 8 after application of the patch. Data indicated that wearing the device had minimal impact on the patient's life. Ease of use, influence on sleep, impact on follow-up of health, or discomfort with continuous monitoring did not change between baseline and day 8. Patients reported low levels of discomfort, although a 20% increase in skin irritation was reported, particularly when applying a second patch. Both patients and nurses rated the wearability and usability of the device positively. Nurses also reported that the sensor was easy to apply and provided reliable measurements. In this study we concluded that remote physiological monitoring using wearable biosensors is feasible and acceptable among adult patients receiving outpatient transfusions or infusions. These findings support the potential for broader implementation of such technologies to improve patient safety and data collection in haematology care. Critical analysis While this feasibility study highlights the potential of wearable biosensors like the VitalPatch® to enhance outpatient monitoring in haematology, its limitations constrain the broader implications of its findings. The small sample size (n = 12), short duration of monitoring (12 days), and observational design restrict generalizability and preclude conclusions about clinical efficacy or long-term outcomes. The study shows that continuous monitoring is technically feasible and generally well accepted by patients and healthcare staff. However, the absence of a control group or direct linkage between recorded physiological changes and clinical actions limits its ability to demonstrate tangible clinical benefit. Although not a goal of the study, no adverse events or treatment modifications were reported in response to biosensor data. Therefore, impact on clinical decision-making has yet to be formally evaluated. Furthermore, while usability ratings were favourable, participant recruitment from a single centre introduces potential selection bias. A more practical challenge is the battery life of 4 days, while mild skin irritation in some patients also raises concerns about long-term tolerability, especially in older adults with sensitive skin. Broader implementation challenges–such as data interpretation, workflow integration, and costs–remain unexplored. Nevertheless, the study does support continued use and development of remote biosensor monitoring as part of a shift toward personalized, proactive care in haematology. Unpublished exploratory observations beyond the study scope Although not part of the study’s predefined objectives, we conducted exploratory analyses of the physiological data collected via the VitalPatch®. Notably, post-transfusion measurements revealed patterns that appeared physiologically relevant and clinically intriguing (Fig. 1). These preliminary findings prompted further interest in the potential role of wearable biosensors in monitoring transfusion responses, ultimately serving as the impetus for the subsequent pilot study. Chapter 5 Remote monitoring of vital and activity parameters in chronic transfusion-dependent patients: A feasibility pilot using wearable biosensors Background and context This study aimed to assess the feasibility of using wearable biosensors and web-based assessments to monitor vital signs, activity levels, and cognitive function in transfusi on-dependent patients with myelodysplastic syndrome or thalassemia. Study summary and findings In this follow-up pilot study, five patients who regularly receive transfusions were monitored starting 7 days before transfusion up until the following transfusion. The monitoring tools included the AccelerateIQTM platform leveraging the VitalPatch® biosensor, the Withings Steel HR smartwatch, and web-based cognitive and quality of life assessments. Data collection was successful, with the AccelerateIQTM platform yielding 97.8% high-quality usable data and the Withings Steel HR providing 98.9% high-quality usable data. Post-transfusion assessments indicated a significant decrease in heart rate and an improvement in sustained attention, suggesting a positive physiological and cognitive response to transfusion. However, measures of physical activity and self-reported quality of life did not show significant changes following transfusion. Critical analysis This feasibility study demonstrates the potential of integrating wearable biosensors and digital assessments into the care of transfusion-dependent patients. The high quality and usability of the collected data indicate that such technologies can be effectively employed in this patient population. The observed improvements in heart rate and cognitive function post-transfusion provide preliminary evidence that objective physiological and cognitive metrics may serve as valuable indicators of transfusion efficacy. Besides the small sample size, the lack of significant changes in physical activity and quality of life measures may be due to the short–one single transfusion cycle– monitoring period. Moreover, patient-related factors such as age, frailty, comorbidities, and individual circumstances substantially affect these parameters. Moreover, reliance on heart rate alone is likely insufficient to support algorithm-driven decision-making in transfusion care. More nuanced physiological markers such as heart rate variability, or yet-to-be-identified proxies of transfusion need–like a gradually declining condition–will likely be necessary to develop robust, clinically relevant algorithms. Future research should explore the integration of wearable biosensor data into clinical decision-making processes. Such studies could assess whether continuous monitoring can lead to more personalized transfusion schedules, improved patient outcomes, and enhanced quality of life. Furthermore, evaluating the cost-effectiveness and patient adherence to long-term use of wearable devices will be essential for widespread implementation. Chapter 6 Heart rate changes after phlebotomy in polycythaemia vera and healthy donors: An observational case-crossover pilot study Background and context While low Hb is linked to fatigue and reduced quality of life, excessive levels–as seen in polycythaemia vera (PV)–can increase blood viscosity, potentially also compromising oxygen delivery. Despite this, the physiological effects of modest Hb reduction in non-anaemic individuals or in PV patients undergoing phlebotomy remain poorly studied. This pilot aimed to explore whether small decreases in Hb levels elicit measurable physiological responses, and whether consumer-grade biosensors can detect them. Study summary and findings The study involved six healthy blood donors and five PV patients who were regularly monitored via smartwatches for one week before and after phlebotomy. Among healthy donors, a significant increase in heart rate post-phlebotomy was observed, particularly during daytime hours, with gradual normalization. PV patients showed no consistent change in heart rate. Activity levels rose briefly in healthy donors but declined post-phlebotomy in PV patients, with modest recovery. Quality-of-life scores showed minimal change in both groups. Critical analysis The study effectively illustrates that even small Hb reductions can provoke measurable physiological changes in healthy individuals, notably increased heart rate. However, the small, homogeneous sample–especially the all-female healthy donor group–limits generalizability. The short follow-up period may not capture long-term changes, and the observed variations in step count and quality-of-life scores may reflect natural fluctuations more than true physiological shifts. The consistently high (100%) quality of life score in the healthy donor group indicates a limitation of the EQ-5D-5L questionnaire, where the ceiling effect prevents variation in responses. Notably, PV patients exhibited greater physiological stability, suggesting that either a slightly higher baseline Hb might reduce the impact of phlebotomy, or possibly adaptation to chronic phlebotomy–no newly diagnosed PV patients with much higher Hb values were investigated. The study underscores the potential of wearable devices for passive physiological monitoring in diverse clinical settings. The findings suggest that even subtle changes in normal haemoglobin levels can be detected by a smartwatch, making it an intriguing technique. However, given the very small sample size, this pilot study should be viewed as an initial signal pointing toward the potential for larger-scale investigations. Chapter 7 Heart rate changes in chronically red cell transfusion-dependent patients: a dose dependent effect of red cell transfusion–A randomized crossover trial, interim analysis Background and context As a follow-up to earlier pilot studies, we are currently conducting the REMOTE-2 study–a multicentre, randomized, within-subject crossover trial in outpatient clinics. The study investigates the physiological and patient-reported effects of varying red blood cell transfusion strategies in adults with chronic transfusion dependence due to myelodysplastic syndromes, myeloproliferative neoplasms, or overlap conditions. Each participant receives their standard-of-care transfusion regimen, followed by two intensified regimens: one with one additional red blood cell unit (SoC+1), and one with two additional units (SoC+2). The primary objective is to assess the effect of increasing transfusion-modulated Hb on heart rate using wearable biosensors. Secondary objectives include evaluating changes in physical activity, quality of life, and cognitive function. Heart rate and activity were continuously monitored with a wrist-worn biosensor; QoL, fatigue, and cognition were assessed at predefined time points before and after transfusion. Due to slow enrolment, an interim analysis of the first 12 participants was undertaken to provide early insights and determine whether continuation of the study remained justified. Summary and results An increase in haemoglobin level was followed by a dose-dependent reduction in heart rate. SoC transfusions yielded a small non-significant decrease, whereas SoC+1 and SoC+2 resulted in progressively larger reductions. Heart rate reductions persisted into the late post-transfusion phase following SoC+1 and SoC+2. Daily step count showed wide inter- and intra-individual variability with no consistent differences between regimens, and no temporal pattern suggestive of transfusion-related improvement. Nor were any statistically significant cognitive effects of transfusion volume observed. However, descriptive patterns suggested small, inconsistent improvements in planning, working memory strategy, and sustained attention–most apparent in the SoC+2 regimen. Whether these reflect transfusion effects or practice/familiarity effects is uncertain. QoL and fatigue scores did not show statistically significant improvements. Nevertheless, trends were compatible with short-term benefit: reduced physical burden and fatigue at the early post-transfusion visit following SoC+1 and SoC+2, with some persistence of improvement in the SoC+2 regimen. These findings mirror earlier small trials suggesting better symptom control under more liberal transfusion strategies.[1,2] Overall, the interim data suggest that higher transfusion volumes reduce heart rate in a dose-dependent manner, with non-significant but clinically plausible trends toward improved patient-reported outcomes. Critical analysis This interim analysis provides an early contribution to a field with limited empirical evidence, addressing the clinically relevant question of whether higher haemoglobin targets in chronically transfusion-dependent patients yield measurable physiological or patient-reported benefits. The most compelling finding is a dose-dependent reduction in heart rate with higher transfusion volumes, supporting the hypothesis that increased haemoglobin decreases cardiopulmonary compensation and enhances physiological reserve. This effect remained significant after conservative statistical correction, reinforcing its validity and demonstrating the sensitivity of wearable biosensors to detect subtle, clinically meaningful changes. Interpretation is constrained by the small sample size, which limits power for secondary outcomes and may obscure effects on quality of life, cognition, or activity. High variability in step counts and self-reported measures further reduces sensitivity, while cognitive results may be confounded by practice effects, and remote CANTAB testing may be less reliable in older populations.[3] Additionally, adjustments to SoC transfusion volumes to avoid excessive unit numbers introduce complexity in interpreting comparisons. For patients with a three-unit SoC–where a SoC + 2 strategy would result in five units and increase the risk of transfusion-associated circulatory overload–the SoC dose was reduced to two units, yielding SoC, SoC + 1, and SoC + 2 regimens of two, three, and four units. This also shifts the SoC comparator in this crossover design, as it no longer matches patients’ usual baseline dose. The absence so far of clear improvements in activity or QoL does not preclude clinical benefit, as chronic anaemia may require sustained haemoglobin elevation for functional gains on physical or mental fitness to emerge, and current instruments may lack sensitivity to short-term changes. Minimizing haemoglobin fluctuations, rather than achieving transient post-transfusion peaks–may ultimately prove more relevant to patient well-being. More frequent transfusions preferably at home in this respect should be investigated with wearables additionally monitoring potential transfusion reactions/side effects. Overall, this interim analysis provides preliminary evidence supporting the biological plausibility of benefit from more liberal transfusion strategies in chronic anaemia. Higher transfusion volumes consistently reduced heart rate in chronically anaemic, transfu sion-dependent patients, suggesting heart rate may serve as a useful intermediate marker of transfusion effect, with early signals also hinting at potential improvements in symptoms and cognitive function. The study further demonstrates the feasibility of integrating wearable technology into transfusion trials. While these findings require confirmation in larger, fully powered cohorts, they support continued investigation of individualized, outcome-oriented transfusion strategies beyond traditional restrictive thresholds, including evaluation of whether sustained Hb elevation translates into meaningful gains in function, cognition, or quality of life and how such benefits balance against risks such as iron overload. Other currently running trials Another transfusion study incorporating biosensor technology is REDDS: Study 2.[4] This investigation compares patients’ standard transfusion regimens with a fixed weekly transfusion schedule to investigate the effect of reduced Hb fluctuations. In addition to assessing health-related quality of life (HRQoL), the study employs accelerometry to objectively measure patient activity levels throughout the study period. Lastly, the OURA feasibility pilot study, using a finger ring based biosensor, will assess whether patients with myelodysplastic syndromes (MDS) can maintain Oura ring use for more than 70% of the time over a three-month period. Secondary exploratory analyses will examine correlations between wearable-derived physiological parameters and transfusion dates and self-rated physical functioning.[5] Current applications of biosensors in other fields While a focused approach is essential to advancing transfusion-related biosensor development, insights from other fields can inform and accelerate progress. A leading example is the use of hybrid closed-loop systems in diabetes management,[6] which integrate continuous glucose monitoring with algorithm-driven insulin delivery and remote data sharing, exemplifying the potential of biosensor-guided therapy. This model has also spurred interest in wearable biosensors for neuropsychiatric applications, including the detection of stress-related biochemical markers. [7] In wound care, biosensors are employed to monitor parameters such as pH, temperature, moisture, and inflammatory biomarkers, enabling timely intervention and improved healing outcomes.[8] Similarly, cardiovascular research utilizes biosensors in flexible comfortable formats (patches textiles, contact lenses, tattoos) to continuously track vital heart-related signals, moving beyond simple measurements such as heart rate, toward integrated cardiovascular health tools–an approach that may also inform transfusion monitoring strategies.[9] General discussion Transfusion research has traditionally focused on broad clinical outcomes such as survival and hospital length of stay–primarily in patient groups with acute anaemia–leading to the conclusion that a restrictive transfusion strategy is generally preferable–an approach informed by the scarcity and cost of blood products as well as the undeniable, sometimes severe, adverse effects associated with transfusion. Yet for patients with chronic, transfusion-dependent anaemia, quality of life and objective measures of functional well-being should be integral considerations. These patients’ physical and psychological states are shaped by highly individual and timing-specific factors, and emerging technologies such as wearable devices may offer continuous, patient-centred assessment that could support more personalized transfusion care. Despite decades of research, uncertainty remains regarding how Hb modulation translates into measurable physiological and patient-reported outcomes. In Chapter 2, where we evaluated all available evidence from reviews, we concluded that Hb modulation exerts measurable physiological and patient-perceived effects, but the strength and consistency of evidence are constrained by the quality and heterogeneity of existing studies.[10] In clinical practice, this uncertainty is reflected in the substantial variation in transfusion thresholds, unit numbers, and intervals reported in the Netherlands, underscoring the need for prospective evidence to guide more standardized and outcome-driven transfusion policies.[11] Despite the well-documented impact of anaemia on functional and cognitive decline, mobility, and overall physical performance,[12–15] especially in elderly populations, a causality behind these associations is not proven; possibly, lower haemoglobin concentrations may simply indicate a more advanced disease, with consequently poorer QoL scores independent of the anaemia. These unresolved uncertainties underscore the need for alternative markers to evaluate transfusion effects and support more individualized decisions. One approach explored in the present work involved the use of wearable biosensors and web-based assessments. The feasibility studies we performed indicate that biosensors are well tolerated and technically viable in outpatient settings, including among older adults.[16,17] Building on this foundation, our interim analysis showed that transfusing more RBC units was associated with a dose-dependent reduction in heart rate with the suggestion of a sustained effect up until the next transfusion.[18] The observed heart rate reductions likely reflect an alleviation of the compensatory tachycardia characteristic of chronic anaemia, thereby improving physiological reserves. These physiological changes have not yet been shown to translate into significant improvements in secondary outcomes such as quality of life, fatigue, activity or cognitive function; an expected limitation given the sample size, though several trends were suggestive. Trends towards improved cognitive performance may reflect either subtle transfusion-related effects or practice-related improvement, especially given the challenges older adults may face with web-based assessments. Similarly, trends toward reduced fatigue and improved physical quality-of-life domains align with the hypothesis that higher Hb levels enhance oxygen delivery and reduce compensatory strain, consistent with findings from liberal versus restrictive transfusion trials. [1,2] These findings, however, should be considered as hypothesis-generating and should be interpreted cautiously given the small sample size and variability in patient responses. In contrast, daily step counts did not reflect transfusion effects and appear driven more by individual lifestyle patterns than by Hb levels, indicating that step counts are unlikely to serve as reliable functional markers. More structured assessments, such as the 6-minute walk test, and long-term monitoring periods may more accurately capture transfusion-related changes in functional capacity and a gradually changing lifestyle. Given the multifactorial determinants of quality of life, it remains uncertain to what extent the increase in haemoglobin level alone produces clinically meaningful improvements. It is plausible that reducing the amplitude of haemoglobin fluctuations, rather than simply increasing Hb peaks, may yield greater benefits, a hypothesis warranting further investigation. The latter is the subject of the presently running REDDS2 study. While these early findings are encouraging, they require cautious interpretation. Key uncertainties persist regarding the reliability and interpretation of biosensor signals, recommended clinical responses to alerts, and the downstream impact of biosensor-guided transfusion strategies on mobility, QoL, healthcare use, and survival. Artificial intelligence may enhance signal fidelity by distinguishing anaemia-related physiological changes from day-to-day variability in patients’ activities and comorbidities. Ultimately, large randomized trials with longer observation periods comparing biosensor-guided strategies with current Hb-threshold-based practice are needed to determine their true clinical value, incorporating both short-term physiological outcomes and long-term patient-centred endpoints. Before biosensor-supported transfusion management can be implemented at scale, several practical and methodological challenges must be addressed. A key priority is establishing validated cut-off points and alert thresholds, as the current analyses demonstrate that biosensors can reliably detect transfusion-related physiological changes but do not yet define when these changes should trigger clinical action. Without such criteria, alerts may accumulate unnecessarily, increasing the likelihood of false positives and contributing to alert fatigue, with the risk that clinically relevant signals are overlooked. Additional considerations include integration with electronic health records, workflow implications for clinicians, and cost-effectiveness. Nevertheless, in an aging population with increasing healthcare demands, biosensor-guided transfusion approaches hold considerable promise for personalizing care, optimizing resource use, and ultimately improving patient-centred outcomes. Future applications of biosensors in transfusion medicine We anticipate that wearable biosensors will become increasingly integrated into transfusion medicine, particularly in the context of the ongoing shift toward decentralized and patient-centred models of care. The convergence of continuous remote monitoring via cloud-connected wearable devices with personalized, machine-learning–driven analytics holds considerable promise for the early detection of anaemia-related physiological deterioration. The anticipated development of multimodal biosensors that can combine electric signals from the heart with biomarkers from blood or tears could substantially reduce the reliance on frequent, routine outpatient visits for haemoglobin monitoring, thereby alleviating the workload of healthcare professionals. In parallel, the development of patient-facing smartphone applications may provide opportunities for disease education, therapy guidance, and even advanced care planning, further supporting patient autonomy while decreasing the time and resources required from clinical staff. Importantly, however, attention must also be given to equitable access. Without deliberate safeguards, these technologies may disproportionately benefit patients with greater resources, digital literacy, or access to robust healthcare systems, thereby widening existing disparities; considerations of affordability, usability, and inclusivity in algorithm design will therefore be essential. Considerations for future trials Definitive evaluation of biosensor-guided transfusion strategies will ultimately require a large international, multicentre trial. A pragmatic design could compare current standard-of-care transfusion practices with an intervention arm in which transfusion decisions are supported by biosensor-derived algorithms enhanced by machine-learning techniques. Key outcomes should include total transfusion requirements, healthcare utilization and associated costs, physiological responses captured by biosensors (for example, whether algorithm-guided patients achieve more sustained reductions in heart rate), patient-reported quality-of-life measures, and longer-term functional outcomes such as the 6-minute walk test, grip strength, and acute-care presentations. However, the feasibility of such a trial is constrained by the limited pool of eligible patients. As demonstrated by the slow recruitment in our own study, achieving adequate sample sizes would require substantial resources and extended timelines. Exploring analogous populations–such as athletes or patients with heart failure–may offer insights into which physiological parameters best reflect functional status and could help refine outcome selection for future transfusion trials. Careful consideration must also be given to the choice of biosensor. With rapid technological turnover, devices selected at trial initiation risk becoming obsolete by completion. Ideally, the biosensor should be wireless, capable of autonomous cloud-based data transfer, and require minimal patient involvement to ensure consistent data capture. Questionnaires and cognitive assessments, if included, should be concise and selected with care, as anaemia-related fatigue in this frail population may influence performance unless this effect forms part of the research question. Conclusion Taken together, the work presented in this thesis underscores the longstanding uncertainty surrounding how haemoglobin modulation translates into meaningful physiological and patient-reported outcomes, and how this uncertainty continues to shape the wide variation observed in current transfusion practice. Across our studies, we found that haemoglobin augmentation consistently reduces compensatory tachycardia, suggesting a tangible improvement in physiological reserve. However, effects on broader functional outcomes, cognition, activity, and quality of life remain less clear, limited both by small sample sizes and the inherent complexity of these multidimensional endpoints. Our feasibility studies demonstrate that wearable biosensors and web-based assessments are well tolerated, technically robust, and capable of capturing subtle physiological changes in chronically transfused patients. Yet their ultimate clinical value–the extent to which biosensor-derived signals can guide transfusion decisions, predict deterioration, or improve patient-centred outcomes–remains to be established. Addressing these questions will require larger, rigorously designed trials that evaluate not only short-term physiological responses but also long-term impacts on functional capacity, quality of life, iron overload, healthcare utilization, and survival. Despite the challenges that lie ahead, the integration of continuous monitoring with advanced analytics offers a promising path toward more individualized, responsive, and outcome-driven transfusion care. As healthcare systems adapt to an aging and increasingly complex patient population, the development of physiologically informed, patient-centred transfusion strategies has the potential to substantially enhance both clinical outcomes and quality of life for those living with chronic anaemia. To borrow once more from Bram Stoker – “The blood is the life”: The challenge ahead is to ensure that every unit transfused not only sustains life, but meaningfully enriches it.