{"id":26920,"date":"2026-09-15T15:12:09","date_gmt":"2026-09-15T13:12:09","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/rik-tonino\/"},"modified":"2026-10-31T11:32:35","modified_gmt":"2026-10-31T10:32:35","slug":"rik-tonino","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/rik-tonino\/","title":{"rendered":"Rik Tonino"},"content":{"rendered":"","protected":false},"featured_media":26921,"template":"","meta":{"_acf_changed":false},"university_us_portfolio":[22],"class_list":["post-26920","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","university_us_portfolio-universiteit-leiden"],"acf":{"main_text":"","naam_van_het_proefschift":"Remote monitoring in chronic anaemia Towards personalized transfusion strategies","samenvatting":"Bloed speelt een cruciale rol in het menselijk lichaam. Hemoglobine in rode bloedcellen \nzorgt voor het transport van zuurstof naar alle organen en weefsels. Wanneer het \nhemoglobinegehalte te laag is, zoals bij bloedarmoede, kan dit leiden tot klachten \nzoals vermoeidheid, kortademigheid en een verminderde kwaliteit van leven. Een \nveelgebruikte behandeling is het geven van bloedtransfusies. Tegelijkertijd brengen \ntransfusies ook risico\u2019s en kosten met zich mee, wat het belangrijk maakt om zorgvuldig \naf te wegen wanneer en hoeveel bloedtransfusies gegeven worden. \n\nIn de afgelopen decennia is een terughoudend transfusiebeleid de standaard \ngeworden. Dit beleid is grotendeels gebaseerd op onderzoek bij acuut zieke pati\u00ebnten, \nwaarin is aangetoond dat lagere hemoglobinegrenzen veilig zijn als gekeken wordt \nnaar harde uitkomsten zoals overleving en complicaties. Voor pati\u00ebnten met chronische \nbloedarmoede is echter minder duidelijk wat de optimale strategie is. Bij deze groep \nspelen klachten en kwaliteit van leven een grote rol, wat de vraag oproept of streven \nnaar een hoger hemoglobinegehalte mogelijk meer voordelen dan nadelen geeft. \n\nHet doel van dit proefschrift is om beter te begrijpen hoe veranderingen in hemoglobine \nhet lichaam en de kwaliteit van leven be\u00efnvloeden, en hoe deze kennis kan bijdragen \naan een meer gepersonaliseerde benadering in de transfusiegeneeskunde. \n\nIn hoofdstuk 2 vatten we eerder verrichte onderzoeken samen, waarmee we laten zien \ndat veranderingen in het hemoglobinegehalte invloed hebben op zowel lichamelijke \nfuncties als door pati\u00ebnten gerapporteerde uitkomsten, zoals vermoeidheid en kwaliteit \nvan leven. Op basis van bestaande studies blijkt dat een stijging van het hemoglobine \ndoorgaans leidt tot verbetering van deze uitkomsten, vooral bij lagere uitgangswaarden. \nTegelijkertijd wordt duidelijk dat er grote kennislacunes bestaan en dat veel studies van \nbeperkte kwaliteit zijn. \n\nIn hoofdstuk 3 onderzoeken we hoe artsen in de praktijk omgaan met transfusies bij \npati\u00ebnten die langdurig afhankelijk zijn van rode bloedcellen. We laten zien dat er \naanzienlijke variatie bestaat in de gekozen transfusiegrenzen en behandeldoelen, en \nop basis van welke pati\u00ebntkenmerken deze beslissingen worden genomen. Dit wijst \nmogelijk op een gebrek aan eenduidige richtlijnen voor deze pati\u00ebntengroep, maar kan \nook een uiting van de heterogeniteit van de pati\u00ebntengroep. \n\nIn hoofdstukken 4 en 5 richten we ons op nieuwe manieren om het effect van \nbloedarmoede en transfusies te meten. We onderzoeken de haalbaarheid van het \ngebruik van draagbare sensoren (wearables) om pati\u00ebnten op afstand te monitoren. \nDeze technologie maakt het mogelijk om continu gegevens te verzamelen over \nbijvoorbeeld hartslag, ademhaling en lichamelijke activiteit. De resultaten laten zien dat \ndeze vorm van monitoring uitvoerbaar is en potentieel waardevolle inzichten kan geven \nin de fysiologische effecten van transfusies. \n\nIn hoofdstuk 6 bestuderen we het omgekeerde van transfusie: het verwijderen van \nbloed door middel van een aderlating \u2013 bij zowel gezonde bloeddonoren als pati\u00ebnten \nmet polycythaemia vera, een ziekte die een te hoog hemoglobinegehalte geeft. We \nlaten zien dat een aderlating leidt tot meetbare veranderingen in hartslag \u2013 vooral bij \neen normaal hemoglobinegehalte \u2013 wat inzicht geeft in hoe het lichaam reageert op \nveranderingen in zuurstoftransportcapaciteit.\n\nIn hoofdstuk 7 onderzoeken we of het effect van een bloedtransfusie afhankelijk is van \nde hoeveelheid toegediende rode bloedcellen. In een gerandomiseerde studie laten we \nzien dat er aanwijzingen zijn voor een dosis-effectrelatie, waarbij grotere hoeveelheden \nbloed mogelijk leiden tot grotere verbeteringen in fysiologische en door pati\u00ebnten \ngerapporteerde uitkomsten. Dit ondersteunt onze hypothese dat transfusies beter \nafgestemd kunnen worden op de individuele behoefte van de pati\u00ebnt.\n\nIn hoofdstuk 8 bespreken we de belangrijkste bevindingen van dit proefschrift en \nplaatsen we deze in een breder perspectief. Het uiteindelijke doel van een transfusie is \nhet verbeteren van zuurstofvoorziening in weefsels en het daarmee verhogen van de \nkwaliteit van leven, maar deze effecten worden slechts gedeeltelijk weerspiegeld door \nhet hemoglobinegehalte. Dit proefschrift laat zien dat een meer gepersonaliseerde \nbenadering van transfusiegeneeskunde tot betere zorg kan leiden. Hierbij moeten niet \nalleen laboratoriumwaarden, maar ook fysiologische metingen en de ervaringen van \nde pati\u00ebnt worden meegenomen. Nieuwe technologie\u00ebn, zoals wearables en eHealth toepassingen, bieden mogelijkheden om deze gegevens continu op een objectieve \nmanier te verzamelen. \n\nDeze ontwikkelingen kunnen er in de toekomst voor zorgen dat beter bepaald kan \nworden wanneer een transfusie nodig is en wat de optimale hoeveelheid is voor een \nindividuele pati\u00ebnt. Dit kan leiden tot zorg die niet alleen veiliger en effici\u00ebnter is, maar \nvooral beter aansluit bij de behoeften en kwaliteit van leven van de pati\u00ebnt.","summary":"For a large part based on the published article: \n\u201cToward personalized transfusion strategies: The emerging role of \nwearable biosensors in chronic anaemia management\u201d\n\nR.P.B. Tonino,1,2,3 M.R. Schipperus,4 and J.J. Zwaginga1,2\n1 Leiden University Medical Center, Leiden, The Netherlands \n2 TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands \n3 Groene Hart Ziekenhuis, Gouda, The Netherlands \n4 Sanquin Blood Supply, Amsterdam, The Netherlands\n\nIntroduction \nThroughout this thesis, we have tried to answer several pressing questions: what \nare the effects of haemoglobin modulation? Is there a causal relationship between \nHb level and physiological or patient-reported outcomes? How can we measure \nthese outcomes effectively and accurately? And how should we interpret these \nmeasurements to inform and optimize transfusion or donation strategies? \n\nAs Bram Stoker, author of Dracula, might have put it: \u201cThe blood is the life\u201d \u2013 but how \nmuch life is actually in the blood? Here we summarize our findings and reflect upon \ntheir implications.\n\nChapter 2\nHaemoglobin modulation affects physiology and patient-reported outcomes in \nanaemic and non-anaemic subjects: An umbrella review\n\nBackground and context\nBoth low and high haemoglobin concentrations are known to affect physiological \nperformance and quality of life. Yet, despite decades of research, uncertainty remains \nregarding how Hb modulation through interventions such as transfusion, phlebotomy, \niron supplementation or erythropoiesis-stimulating therapy, or even altitude \nexposure, translates into measurable physiological and patient-reported outcomes. \nExisting clinical thresholds for transfusion or target Hb levels often rely on arbitrary or \ndisease-specific conventions rather than on integrative physiological evidence.\n\nTo address this gap, we conducted an umbrella review synthesizing evidence from \npublished systematic reviews and meta-analyses that evaluated the relationship \nbetween Hb modulation and both physiological and subjective outcomes in adults \nwith and without anaemia. The goal was to determine whether changes in Hb \nconcentration are consistently associated with improvements in measurable function \nand perceived well-being across populations and interventions.\n\nStudy summary and findings\nA systematic search across six databases up to April 2022 identified 33 systematic \nreviews, comprising diverse populations (anaemic, non-anaemic, and polycythaemic) \nand interventions aimed at modulating Hb levels. Eligible reviews reported at \nleast one physiological endpoint (e.g., VO2max, heart rate, exercise capacity) or a \npatient-reported outcome (e.g., fatigue, dyspnoea, Quality of Life).\n\nQuality assessment using AMSTAR-2 revealed that only 7 reviews were rated as high \nquality, whereas 24 were judged critically low, highlighting substantial methodological \nlimitations within the available literature.\n\nAcross the included reviews, increases in Hb concentration were generally associated \nwith improvements in both physiological measures and patient-reported outcome \nmeasures. These benefits were, as might be expected, most pronounced among \nindividuals with low baseline Hb levels, where modest Hb increases translated into \ngains in functional capacity and perceived vitality. For example, in chronic kidney \ndisease, raising Hb toward 12 g\/dL (7.5 mmol\/L) was consistently linked to enhanced \nexercise tolerance, improved fatigue and quality-of-life scores. Evidence regarding \nthe effects of supraphysiologic Hb increases or intentional Hb reduction (e.g., \nphlebotomy, haemodilution) was limited and heterogeneous. \n\nOverall, we concluded that Hb modulation exerts measurable physiological and \npatient-perceived effects, but the strength and consistency of evidence are constrained \nby the quality and heterogeneity of existing studies.\n\nCritical analysis\nThis umbrella review provides the first comprehensive synthesis of evidence linking Hb \nmodulation to physiological and subjective outcomes across a spectrum of populations \nand interventions. We employed a transparent search strategy, adhered to PRISMA \nguidelines, and used a formal quality appraisal tool. By combining data from multiple \ndisease contexts, the study successfully highlights overarching physiological patterns \nthat transcend individual disorders.\n\nHowever, several limitations temper the interpretative value of its findings. The \npredominance of low-quality reviews underscores the fragility of the evidence. \nConsiderable heterogeneity\u2013in populations, interventions, endpoints, and analytic \nmethods\u2013prevents reliable quantitative pooling or inference about causality. \n\nAnother limitation lies in the indirectness of umbrella-level evidence: overlapping \nprimary studies across reviews may have inflated perceived consistency, while \npublication bias on expected results could favour the latter. Moreover, the review \nfocuses on associations rather than mechanistic pathways, leaving uncertain whether \nobserved improvements are directly mediated by Hb change or by concurrent \nphysiological and\/or behavioural\/psychological changes.\n\nDespite these limitations, the review\u2019s findings reinforce the clinical observation that \nraising Hb from sub-physiologic to near-normal levels can enhance both functional \nand subjective outcomes, whereas there is no evidence regarding Hb elevation above \nphysiologic norms. \n\nFuture studies should emphasize standardized physiological metrics, incorporate \ndigital or wearable monitoring for objective continuous assessment, and integrate \npatient-reported outcome measures to better capture the multidimensional impact \nof Hb modulation. Rigorous randomized trials and high-quality systematic reviews are \nneeded to clarify optimal targets and balance benefit against risk.\n\nChapter 3\nClinical practice for outpatients that are chronically red cell dependent: A survey in \nthe Netherlands \n\nBackground and context\nFor patients that are chronically transfusion-dependent, evidence guiding optimal \ntransfusion triggers, unit numbers and intervals in non-acute settings is scarce. In \nthe absence of robust data, clinical decisions regarding maintenance transfusion \nregimens are often empirical and institution specific. We therefore designed a survey \nto characterize current outpatient transfusion practices in the Netherlands, focusing \non three key dimensions: pre-transfusion haemoglobin thresholds, number of RBC \nunits per transfusion episode, and interval between transfusions. We further sought \nto identify patient- and haematologist-specific factors influencing these decisions.\n\nStudy summary and findings\nBetween June and October 2020 we administered a web-based 44-question survey \nto members of the Dutch Haematology Association. Fifty physicians responded \n(response rate ~30%) representing both academic and community hospitals. The \nresponses revealed a very wide variation in transfusion strategies. Reported median \npre-transfusion Hb threshold was 8.0 g\/dL (5.0 mmol\/L), but individual thresholds \nranged from 6.4 to 9.6 g\/dL (4.0\u20136.0 mmol\/L). Most centres transfused 1\u20132 RBC units per \nepisode (range 0\u20133 units) at intervals of 2\u20134 weeks, though reported intervals ranged \nfrom 1 to 12 weeks. Physicians reported that the clinical factors most strongly influencing \ntransfusion strategy were the presence of angina pectoris, cardiac failure, and dyspnoea. \nAmong subjective considerations, quality of life and patients\u2019 self-sustainability were \nregarded as most relevant. In contrast, fatigue, cognitive status, emotional state, and \nvital parameters were considered to have less influence on transfusion decisions. We \nconcluded that while individualization may account for some variation in practice, the \nwide heterogeneity observed underscores the necessity for randomized controlled \ntrials to inform evidence-based guidelines on the management of chronic transfu sion-dependent patients, including the identification of key clinical parameters.\n\nCritical analysis\nThis survey addresses a significant gap in transfusion medicine by providing insights \ninto real-world practices for the management of chronically transfused outpatients. \nIts strength lies in providing a quantitative snapshot of the diversity of practice across \nDutch haematologists and in highlighting the absence of consensus thresholds in a \nroutine care setting. The inclusion of both unit number and interval data, along with \nthreshold values, adds practical relevance for clinicians and guidelines.\n\nNevertheless, the study has several limitations. As a self-report survey, it reflects \nreported practice rather than verified transfusion records, opening the possibility \nof recall bias or social desirability bias. The relatively low response rate (30%) and \npossible non-response bias may reduce generalisability. Importantly, the study does \nnot correlate transfusion strategies with clinical outcomes (such as symptom relief, \nquality of life improvement or iron overload). Consequently, the variation observed \ncannot be judged as beneficial, neutral or harmful. Differences in patient populations \n(diagnosis, comorbidity, transfusion burden) across centres may explain much of the \nheterogeneity yet cannot be delineated fully from the survey design. \n\nNonetheless, the findings have important implications. The documented variation \nhints at potential under- or over-transfusion in some patient groups and underscores \nthe need for prospective comparative studies. From a clinical perspective, this survey \ninvites transfusion services to reflect on their local thresholds and intervals relative \nto peer practice and to consider monitoring of patient outcome\u2013both objective and \nsubjective\u2013and resource utilisation. For guideline developers, the work emphasises \nan urgent need to incorporate maintenance transfusion strategies into the broader \nframework of patient blood management that mostly deals with perioperative \nsituations.\n\nThis survey of outpatient RBC transfusion practice in the Netherlands demonstrates \nconsiderable heterogeneity in thresholds, unit numbers and intervals for chronically \ntransfused patients. While individualised care remains appropriate, the extent of \nvariation and lack of outcome data highlight a pressing need for prospective research \nand evidence-based guidelines. Until such data emerge, clinicians are encouraged \nto monitor not only Hb levels but also patient-centred outcomes to ensure optimal \npractice.\n\nChapter 4\nRemote patient monitoring in adults receiving transfusion or infusion for \nhaematological disorders using the VitalPatch\u00ae and AccelerateIQTM monitoring \nsystem: Quantitative feasibility study \n\nBackground and context\nPatients with hematologic disorders receiving treatments such as red blood cell \ntransfusions, chemotherapy, or immunotherapy are vulnerable to infusion-related \ncomplications, often signalled by changes in vital signs. Traditionally, symptom \nmonitoring post-treatment is patient-reported, which can delay the detection of \nadverse events. Wearable biosensors\u2013already validated and used in cardiology \npractice\u2013in this line offer a solution. These devices enable continuous, real-time \nmonitoring of physiological parameters beyond the clinic or in less supervised (such as \nhome-) transfusion settings. This feasibility study explored whether integrating such \ntechnology into outpatient care is acceptable and practical.\n\nStudy summary and findings\nIn this quantitative feasibility study, twelve adult patients with hematologic \nconditions\u2013including multiple myeloma, myelodysplastic syndrome, and non-Hodgkin \nlymphoma\u2013were enrolled to wear the VitalPatch\u00ae biosensor for a period of 12 days \naround a planned infusion or transfusion. Patients received red blood cell transfusions \n(n = 4), intravenous proteasome inhibitors (n = 4), or immunotherapy (n = 4). The \nmajority of participants (83%) were aged 60 years or older.\n\nThe VitalPatch\u00ae system\u2013capable of measuring heart rate, respiration rate, skin \ntemperature, activity, heart rate variability and position\u2013was generally well tolerated, \nwith minimal interference in daily activities. Patient-reported outcomes were collected \nat baseline, day 1, day 5, and day 8 after application of the patch. Data indicated that \nwearing the device had minimal impact on the patient's life. Ease of use, influence on \nsleep, impact on follow-up of health, or discomfort with continuous monitoring did \nnot change between baseline and day 8. Patients reported low levels of discomfort, \nalthough a 20% increase in skin irritation was reported, particularly when applying \na second patch. Both patients and nurses rated the wearability and usability of the \ndevice positively. Nurses also reported that the sensor was easy to apply and provided \nreliable measurements.\n\nIn this study we concluded that remote physiological monitoring using wearable \nbiosensors is feasible and acceptable among adult patients receiving outpatient \ntransfusions or infusions. These findings support the potential for broader \nimplementation of such technologies to improve patient safety and data collection in \nhaematology care.\n\nCritical analysis\nWhile this feasibility study highlights the potential of wearable biosensors like the \nVitalPatch\u00ae to enhance outpatient monitoring in haematology, its limitations constrain \nthe broader implications of its findings. The small sample size (n = 12), short duration \nof monitoring (12 days), and observational design restrict generalizability and preclude \nconclusions about clinical efficacy or long-term outcomes.\n\nThe study shows that continuous monitoring is technically feasible and generally well \naccepted by patients and healthcare staff. However, the absence of a control group \nor direct linkage between recorded physiological changes and clinical actions limits \nits ability to demonstrate tangible clinical benefit. Although not a goal of the study, \nno adverse events or treatment modifications were reported in response to biosensor \ndata. Therefore, impact on clinical decision-making has yet to be formally evaluated.\n\nFurthermore, while usability ratings were favourable, participant recruitment from a \nsingle centre introduces potential selection bias. A more practical challenge is the \nbattery life of 4 days, while mild skin irritation in some patients also raises concerns \nabout long-term tolerability, especially in older adults with sensitive skin.\n\nBroader implementation challenges\u2013such as data interpretation, workflow integration, \nand costs\u2013remain unexplored. Nevertheless, the study does support continued \nuse and development of remote biosensor monitoring as part of a shift toward \npersonalized, proactive care in haematology. \n\nUnpublished exploratory observations beyond the study scope\nAlthough not part of the study\u2019s predefined objectives, we conducted exploratory \nanalyses of the physiological data collected via the VitalPatch\u00ae. Notably, post-transfusion \nmeasurements revealed patterns that appeared physiologically relevant and clinically \nintriguing (Fig. 1). These preliminary findings prompted further interest in the potential \nrole of wearable biosensors in monitoring transfusion responses, ultimately serving as \nthe impetus for the subsequent pilot study.\n\nChapter 5\nRemote monitoring of vital and activity parameters in chronic transfusion-dependent \npatients: A feasibility pilot using wearable biosensors \n\nBackground and context\nThis study aimed to assess the feasibility of using wearable biosensors and web-based \nassessments to monitor vital signs, activity levels, and cognitive function in transfusi on-dependent patients with myelodysplastic syndrome or thalassemia.\n\nStudy summary and findings\nIn this follow-up pilot study, five patients who regularly receive transfusions were \nmonitored starting 7 days before transfusion up until the following transfusion. The \nmonitoring tools included the AccelerateIQTM platform leveraging the VitalPatch\u00ae\nbiosensor, the Withings Steel HR smartwatch, and web-based cognitive and quality \nof life assessments. Data collection was successful, with the AccelerateIQTM platform \nyielding 97.8% high-quality usable data and the Withings Steel HR providing 98.9% \nhigh-quality usable data. Post-transfusion assessments indicated a significant decrease \nin heart rate and an improvement in sustained attention, suggesting a positive \nphysiological and cognitive response to transfusion. However, measures of physical \nactivity and self-reported quality of life did not show significant changes following \ntransfusion.\n\nCritical analysis\nThis feasibility study demonstrates the potential of integrating wearable biosensors \nand digital assessments into the care of transfusion-dependent patients. The high \nquality and usability of the collected data indicate that such technologies can be \neffectively employed in this patient population. The observed improvements in \nheart rate and cognitive function post-transfusion provide preliminary evidence that \nobjective physiological and cognitive metrics may serve as valuable indicators of \ntransfusion efficacy. \n\nBesides the small sample size, the lack of significant changes in physical activity \nand quality of life measures may be due to the short\u2013one single transfusion cycle\u2013\nmonitoring period. Moreover, patient-related factors such as age, frailty, comorbidities, \nand individual circumstances substantially affect these parameters. \n\nMoreover, reliance on heart rate alone is likely insufficient to support algorithm-driven \ndecision-making in transfusion care. More nuanced physiological markers such \nas heart rate variability, or yet-to-be-identified proxies of transfusion need\u2013like a \ngradually declining condition\u2013will likely be necessary to develop robust, clinically \nrelevant algorithms.\n\nFuture research should explore the integration of wearable biosensor data into clinical \ndecision-making processes. Such studies could assess whether continuous monitoring \ncan lead to more personalized transfusion schedules, improved patient outcomes, and \nenhanced quality of life. Furthermore, evaluating the cost-effectiveness and patient \nadherence to long-term use of wearable devices will be essential for widespread \nimplementation.\n\nChapter 6\nHeart rate changes after phlebotomy in polycythaemia vera and healthy donors: \nAn observational case-crossover pilot study \n\nBackground and context\nWhile low Hb is linked to fatigue and reduced quality of life, excessive levels\u2013as seen in \npolycythaemia vera (PV)\u2013can increase blood viscosity, potentially also compromising \noxygen delivery. Despite this, the physiological effects of modest Hb reduction in \nnon-anaemic individuals or in PV patients undergoing phlebotomy remain poorly \nstudied. This pilot aimed to explore whether small decreases in Hb levels elicit \nmeasurable physiological responses, and whether consumer-grade biosensors can \ndetect them.\n\nStudy summary and findings\nThe study involved six healthy blood donors and five PV patients who were regularly \nmonitored via smartwatches for one week before and after phlebotomy. Among \nhealthy donors, a significant increase in heart rate post-phlebotomy was observed, \nparticularly during daytime hours, with gradual normalization. PV patients showed \nno consistent change in heart rate. Activity levels rose briefly in healthy donors but \ndeclined post-phlebotomy in PV patients, with modest recovery. Quality-of-life scores \nshowed minimal change in both groups. \n\nCritical analysis\nThe study effectively illustrates that even small Hb reductions can provoke measurable \nphysiological changes in healthy individuals, notably increased heart rate. However, \nthe small, homogeneous sample\u2013especially the all-female healthy donor group\u2013limits \ngeneralizability. The short follow-up period may not capture long-term changes, and \nthe observed variations in step count and quality-of-life scores may reflect natural \nfluctuations more than true physiological shifts. The consistently high (100%) quality \nof life score in the healthy donor group indicates a limitation of the EQ-5D-5L \nquestionnaire, where the ceiling effect prevents variation in responses.\n\nNotably, PV patients exhibited greater physiological stability, suggesting that either \na slightly higher baseline Hb might reduce the impact of phlebotomy, or possibly \nadaptation to chronic phlebotomy\u2013no newly diagnosed PV patients with much \nhigher Hb values were investigated. The study underscores the potential of wearable \ndevices for passive physiological monitoring in diverse clinical settings. The findings \nsuggest that even subtle changes in normal haemoglobin levels can be detected by a \nsmartwatch, making it an intriguing technique. However, given the very small sample \nsize, this pilot study should be viewed as an initial signal pointing toward the potential \nfor larger-scale investigations.\n\nChapter 7\nHeart rate changes in chronically red cell transfusion-dependent patients: a dose dependent effect of red cell transfusion\u2013A randomized crossover trial, interim analysis\n\nBackground and context\nAs a follow-up to earlier pilot studies, we are currently conducting the REMOTE-2 \nstudy\u2013a multicentre, randomized, within-subject crossover trial in outpatient clinics. \nThe study investigates the physiological and patient-reported effects of varying red \nblood cell transfusion strategies in adults with chronic transfusion dependence due \nto myelodysplastic syndromes, myeloproliferative neoplasms, or overlap conditions. \nEach participant receives their standard-of-care transfusion regimen, followed by \ntwo intensified regimens: one with one additional red blood cell unit (SoC+1), and \none with two additional units (SoC+2). The primary objective is to assess the effect \nof increasing transfusion-modulated Hb on heart rate using wearable biosensors. \nSecondary objectives include evaluating changes in physical activity, quality of life, \nand cognitive function. Heart rate and activity were continuously monitored with a \nwrist-worn biosensor; QoL, fatigue, and cognition were assessed at predefined time \npoints before and after transfusion. Due to slow enrolment, an interim analysis of the \nfirst 12 participants was undertaken to provide early insights and determine whether \ncontinuation of the study remained justified.\n\nSummary and results\nAn increase in haemoglobin level was followed by a dose-dependent reduction in heart \nrate. SoC transfusions yielded a small non-significant decrease, whereas SoC+1 and \nSoC+2 resulted in progressively larger reductions. Heart rate reductions persisted into \nthe late post-transfusion phase following SoC+1 and SoC+2. Daily step count showed \nwide inter- and intra-individual variability with no consistent differences between \nregimens, and no temporal pattern suggestive of transfusion-related improvement. \n\nNor were any statistically significant cognitive effects of transfusion volume observed. \nHowever, descriptive patterns suggested small, inconsistent improvements in \nplanning, working memory strategy, and sustained attention\u2013most apparent in the \nSoC+2 regimen. Whether these reflect transfusion effects or practice\/familiarity \neffects is uncertain.\n\nQoL and fatigue scores did not show statistically significant improvements. \nNevertheless, trends were compatible with short-term benefit: reduced physical \nburden and fatigue at the early post-transfusion visit following SoC+1 and SoC+2, \nwith some persistence of improvement in the SoC+2 regimen. These findings mirror \nearlier small trials suggesting better symptom control under more liberal transfusion \nstrategies.[1,2]\n\nOverall, the interim data suggest that higher transfusion volumes reduce heart rate in \na dose-dependent manner, with non-significant but clinically plausible trends toward \nimproved patient-reported outcomes.\n\nCritical analysis\nThis interim analysis provides an early contribution to a field with limited empirical \nevidence, addressing the clinically relevant question of whether higher haemoglobin \ntargets in chronically transfusion-dependent patients yield measurable physiological \nor patient-reported benefits. \n\nThe most compelling finding is a dose-dependent reduction in heart rate with \nhigher transfusion volumes, supporting the hypothesis that increased haemoglobin \ndecreases cardiopulmonary compensation and enhances physiological reserve. This \neffect remained significant after conservative statistical correction, reinforcing its \nvalidity and demonstrating the sensitivity of wearable biosensors to detect subtle, \nclinically meaningful changes.\n\nInterpretation is constrained by the small sample size, which limits power for \nsecondary outcomes and may obscure effects on quality of life, cognition, or activity. \nHigh variability in step counts and self-reported measures further reduces sensitivity, \nwhile cognitive results may be confounded by practice effects, and remote CANTAB \ntesting may be less reliable in older populations.[3] Additionally, adjustments to \nSoC transfusion volumes to avoid excessive unit numbers introduce complexity in \ninterpreting comparisons. For patients with a three-unit SoC\u2013where a SoC + 2 strategy \nwould result in five units and increase the risk of transfusion-associated circulatory \noverload\u2013the SoC dose was reduced to two units, yielding SoC, SoC + 1, and \nSoC + 2 regimens of two, three, and four units. This also shifts the SoC comparator in \nthis crossover design, as it no longer matches patients\u2019 usual baseline dose.\n\nThe absence so far of clear improvements in activity or QoL does not preclude \nclinical benefit, as chronic anaemia may require sustained haemoglobin elevation for \nfunctional gains on physical or mental fitness to emerge, and current instruments may \nlack sensitivity to short-term changes. Minimizing haemoglobin fluctuations, rather \nthan achieving transient post-transfusion peaks\u2013may ultimately prove more relevant \nto patient well-being. More frequent transfusions preferably at home in this respect \nshould be investigated with wearables additionally monitoring potential transfusion \nreactions\/side effects. \n\nOverall, this interim analysis provides preliminary evidence supporting the biological \nplausibility of benefit from more liberal transfusion strategies in chronic anaemia. Higher \ntransfusion volumes consistently reduced heart rate in chronically anaemic, transfu sion-dependent patients, suggesting heart rate may serve as a useful intermediate \nmarker of transfusion effect, with early signals also hinting at potential improvements \nin symptoms and cognitive function. The study further demonstrates the feasibility of \nintegrating wearable technology into transfusion trials. While these findings require \nconfirmation in larger, fully powered cohorts, they support continued investigation of \nindividualized, outcome-oriented transfusion strategies beyond traditional restrictive \nthresholds, including evaluation of whether sustained Hb elevation translates into \nmeaningful gains in function, cognition, or quality of life and how such benefits \nbalance against risks such as iron overload.\n\nOther currently running trials\nAnother transfusion study incorporating biosensor technology is REDDS: Study 2.[4] \nThis investigation compares patients\u2019 standard transfusion regimens with a fixed weekly \ntransfusion schedule to investigate the effect of reduced Hb fluctuations. In addition \nto assessing health-related quality of life (HRQoL), the study employs accelerometry \nto objectively measure patient activity levels throughout the study period. Lastly, the \nOURA feasibility pilot study, using a finger ring based biosensor, will assess whether \npatients with myelodysplastic syndromes (MDS) can maintain Oura ring use for more \nthan 70% of the time over a three-month period. Secondary exploratory analyses \nwill examine correlations between wearable-derived physiological parameters and \ntransfusion dates and self-rated physical functioning.[5]\n\nCurrent applications of biosensors in other fields\nWhile a focused approach is essential to advancing transfusion-related biosensor \ndevelopment, insights from other fields can inform and accelerate progress. A \nleading example is the use of hybrid closed-loop systems in diabetes management,[6] \nwhich integrate continuous glucose monitoring with algorithm-driven insulin delivery \nand remote data sharing, exemplifying the potential of biosensor-guided therapy. \n\nThis model has also spurred interest in wearable biosensors for neuropsychiatric \napplications, including the detection of stress-related biochemical markers.\n[7] In wound care, biosensors are employed to monitor parameters such as pH, \ntemperature, moisture, and inflammatory biomarkers, enabling timely intervention \nand improved healing outcomes.[8] Similarly, cardiovascular research utilizes \nbiosensors in flexible comfortable formats (patches textiles, contact lenses, \ntattoos) to continuously track vital heart-related signals, moving beyond simple \nmeasurements such as heart rate, toward integrated cardiovascular health \ntools\u2013an approach that may also inform transfusion monitoring strategies.[9]\n\nGeneral discussion \nTransfusion research has traditionally focused on broad clinical outcomes such \nas survival and hospital length of stay\u2013primarily in patient groups with acute \nanaemia\u2013leading to the conclusion that a restrictive transfusion strategy is generally \npreferable\u2013an approach informed by the scarcity and cost of blood products as well \nas the undeniable, sometimes severe, adverse effects associated with transfusion. Yet \nfor patients with chronic, transfusion-dependent anaemia, quality of life and objective \nmeasures of functional well-being should be integral considerations. These patients\u2019 \nphysical and psychological states are shaped by highly individual and timing-specific \nfactors, and emerging technologies such as wearable devices may offer continuous, \npatient-centred assessment that could support more personalized transfusion care.\n\nDespite decades of research, uncertainty remains regarding how Hb modulation \ntranslates into measurable physiological and patient-reported outcomes. In Chapter \n2, where we evaluated all available evidence from reviews, we concluded that Hb \nmodulation exerts measurable physiological and patient-perceived effects, but the \nstrength and consistency of evidence are constrained by the quality and heterogeneity \nof existing studies.[10] \n\nIn clinical practice, this uncertainty is reflected in the substantial variation in transfusion \nthresholds, unit numbers, and intervals reported in the Netherlands, underscoring \nthe need for prospective evidence to guide more standardized and outcome-driven \ntransfusion policies.[11] \n\nDespite the well-documented impact of anaemia on functional and cognitive decline, \nmobility, and overall physical performance,[12\u201315] especially in elderly populations, \na causality behind these associations is not proven; possibly, lower haemoglobin \nconcentrations may simply indicate a more advanced disease, with consequently \npoorer QoL scores independent of the anaemia. \n\nThese unresolved uncertainties underscore the need for alternative markers to \nevaluate transfusion effects and support more individualized decisions. One approach \nexplored in the present work involved the use of wearable biosensors and web-based \nassessments.\n\nThe feasibility studies we performed indicate that biosensors are well tolerated and \ntechnically viable in outpatient settings, including among older adults.[16,17] Building \non this foundation, our interim analysis showed that transfusing more RBC units was \nassociated with a dose-dependent reduction in heart rate with the suggestion of a \nsustained effect up until the next transfusion.[18] The observed heart rate reductions \nlikely reflect an alleviation of the compensatory tachycardia characteristic of chronic \nanaemia, thereby improving physiological reserves. \n\nThese physiological changes have not yet been shown to translate into significant \nimprovements in secondary outcomes such as quality of life, fatigue, activity or \ncognitive function; an expected limitation given the sample size, though several trends \nwere suggestive. Trends towards improved cognitive performance may reflect either \nsubtle transfusion-related effects or practice-related improvement, especially given \nthe challenges older adults may face with web-based assessments. Similarly, trends \ntoward reduced fatigue and improved physical quality-of-life domains align with the \nhypothesis that higher Hb levels enhance oxygen delivery and reduce compensatory \nstrain, consistent with findings from liberal versus restrictive transfusion trials.\n[1,2] These findings, however, should be considered as hypothesis-generating and \nshould be interpreted cautiously given the small sample size and variability in patient \nresponses.\n\nIn contrast, daily step counts did not reflect transfusion effects and appear driven \nmore by individual lifestyle patterns than by Hb levels, indicating that step counts are \nunlikely to serve as reliable functional markers. More structured assessments, such \nas the 6-minute walk test, and long-term monitoring periods may more accurately \ncapture transfusion-related changes in functional capacity and a gradually changing \nlifestyle.\n\nGiven the multifactorial determinants of quality of life, it remains uncertain to what \nextent the increase in haemoglobin level alone produces clinically meaningful \nimprovements. It is plausible that reducing the amplitude of haemoglobin fluctuations, \nrather than simply increasing Hb peaks, may yield greater benefits, a hypothesis \nwarranting further investigation. The latter is the subject of the presently running \nREDDS2 study.\n\nWhile these early findings are encouraging, they require cautious interpretation. \nKey uncertainties persist regarding the reliability and interpretation of biosensor \nsignals, recommended clinical responses to alerts, and the downstream impact of \nbiosensor-guided transfusion strategies on mobility, QoL, healthcare use, and survival. \nArtificial intelligence may enhance signal fidelity by distinguishing anaemia-related \nphysiological changes from day-to-day variability in patients\u2019 activities and \ncomorbidities. Ultimately, large randomized trials with longer observation periods \ncomparing biosensor-guided strategies with current Hb-threshold-based practice \nare needed to determine their true clinical value, incorporating both short-term \nphysiological outcomes and long-term patient-centred endpoints.\n\nBefore biosensor-supported transfusion management can be implemented at scale, \nseveral practical and methodological challenges must be addressed. A key priority \nis establishing validated cut-off points and alert thresholds, as the current analyses \ndemonstrate that biosensors can reliably detect transfusion-related physiological \nchanges but do not yet define when these changes should trigger clinical action. Without \nsuch criteria, alerts may accumulate unnecessarily, increasing the likelihood of false \npositives and contributing to alert fatigue, with the risk that clinically relevant signals \nare overlooked. Additional considerations include integration with electronic health \nrecords, workflow implications for clinicians, and cost-effectiveness. Nevertheless, \nin an aging population with increasing healthcare demands, biosensor-guided \ntransfusion approaches hold considerable promise for personalizing care, optimizing \nresource use, and ultimately improving patient-centred outcomes.\n\nFuture applications of biosensors in transfusion medicine\nWe anticipate that wearable biosensors will become increasingly integrated into \ntransfusion medicine, particularly in the context of the ongoing shift toward \ndecentralized and patient-centred models of care. The convergence of continuous \nremote monitoring via cloud-connected wearable devices with personalized, \nmachine-learning\u2013driven analytics holds considerable promise for the early detection \nof anaemia-related physiological deterioration. The anticipated development \nof multimodal biosensors that can combine electric signals from the heart with \nbiomarkers from blood or tears could substantially reduce the reliance on frequent, \nroutine outpatient visits for haemoglobin monitoring, thereby alleviating the workload \nof healthcare professionals. \n\nIn parallel, the development of patient-facing smartphone applications may provide \nopportunities for disease education, therapy guidance, and even advanced care \nplanning, further supporting patient autonomy while decreasing the time and \nresources required from clinical staff. Importantly, however, attention must also be \ngiven to equitable access. Without deliberate safeguards, these technologies may \ndisproportionately benefit patients with greater resources, digital literacy, or access \nto robust healthcare systems, thereby widening existing disparities; considerations of \naffordability, usability, and inclusivity in algorithm design will therefore be essential.\n\nConsiderations for future trials\nDefinitive evaluation of biosensor-guided transfusion strategies will ultimately \nrequire a large international, multicentre trial. A pragmatic design could compare \ncurrent standard-of-care transfusion practices with an intervention arm in which \ntransfusion decisions are supported by biosensor-derived algorithms enhanced \nby machine-learning techniques. Key outcomes should include total transfusion \nrequirements, healthcare utilization and associated costs, physiological responses \ncaptured by biosensors (for example, whether algorithm-guided patients achieve \nmore sustained reductions in heart rate), patient-reported quality-of-life measures, \nand longer-term functional outcomes such as the 6-minute walk test, grip strength, \nand acute-care presentations.\n\nHowever, the feasibility of such a trial is constrained by the limited pool of eligible \npatients. As demonstrated by the slow recruitment in our own study, achieving \nadequate sample sizes would require substantial resources and extended timelines. \nExploring analogous populations\u2013such as athletes or patients with heart failure\u2013may \noffer insights into which physiological parameters best reflect functional status and \ncould help refine outcome selection for future transfusion trials.\n\nCareful consideration must also be given to the choice of biosensor. With rapid \ntechnological turnover, devices selected at trial initiation risk becoming obsolete \nby completion. Ideally, the biosensor should be wireless, capable of autonomous \ncloud-based data transfer, and require minimal patient involvement to ensure \nconsistent data capture. Questionnaires and cognitive assessments, if included, should \nbe concise and selected with care, as anaemia-related fatigue in this frail population \nmay influence performance unless this effect forms part of the research question.\n\nConclusion\nTaken together, the work presented in this thesis underscores the longstanding \nuncertainty surrounding how haemoglobin modulation translates into meaningful \nphysiological and patient-reported outcomes, and how this uncertainty continues to \nshape the wide variation observed in current transfusion practice. Across our studies, \nwe found that haemoglobin augmentation consistently reduces compensatory \ntachycardia, suggesting a tangible improvement in physiological reserve. However, \neffects on broader functional outcomes, cognition, activity, and quality of life remain \nless clear, limited both by small sample sizes and the inherent complexity of these \nmultidimensional endpoints.\n\nOur feasibility studies demonstrate that wearable biosensors and web-based \nassessments are well tolerated, technically robust, and capable of capturing \nsubtle physiological changes in chronically transfused patients. Yet their ultimate \nclinical value\u2013the extent to which biosensor-derived signals can guide transfusion \ndecisions, predict deterioration, or improve patient-centred outcomes\u2013remains to \nbe established. Addressing these questions will require larger, rigorously designed \ntrials that evaluate not only short-term physiological responses but also long-term \nimpacts on functional capacity, quality of life, iron overload, healthcare utilization, \nand survival.\n\nDespite the challenges that lie ahead, the integration of continuous monitoring with \nadvanced analytics offers a promising path toward more individualized, responsive, \nand outcome-driven transfusion care. As healthcare systems adapt to an aging \nand increasingly complex patient population, the development of physiologically \ninformed, patient-centred transfusion strategies has the potential to substantially \nenhance both clinical outcomes and quality of life for those living with chronic \nanaemia.\n\nTo borrow once more from Bram Stoker \u2013 \u201cThe blood is the life\u201d: \nThe challenge ahead is to ensure that every unit transfused not only sustains life, \nbut meaningfully enriches it.","auteur":"Rik Tonino","auteur_slug":"rik-tonino","publicatiedatum":"22 oktober 2026","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/riktonino?iframe=true","url_download_pdf":"https:\/\/ebook.proefschriftmaken.nl\/download\/f8182220-61e0-4e4f-81dc-faa6e6455ae0\/highres","url_epub":"","ordernummer":"19476","isbn":"978-94-6534-622-9","doi_nummer":"","naam_universiteit":"Universiteit Leiden","afbeeldingen":26921,"video_url":"","podcast_url":"","naam_student:":"","binnenwerk":"","universiteit":"Universiteit Leiden","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/26920","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/26921"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=26920"}],"wp:term":[{"taxonomy":"university_us_portfolio","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/university_us_portfolio?post=26920"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}