The field of haemovigilance continues to develop, building on more than forty years of international experience. This review considers the current scope and activities of haemovigilance around the world and explores aspects of preparation for the advent of new blood products and alternative therapies to transfusion; new tools for data acquisition (including patient- and donor-reported outcomes, and data from ‘wearables’) and the analysis and communication of haemovigilance results.

# Introduction

Haemovigilance broadly refers to systematic surveillance efforts to reduce harm from blood donation and transfusion. The International Haemovigilance Network (IHN) describes haemovigilance as “a set of surveillance procedures covering the whole transfusion chain (from the collection of blood and its components to the follow-up of recipients), intended to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of labile blood products and to prevent their occurrence or recurrence” [1].

Building on more than forty years of experience, the field of haemovigilance continues to develop [2]. Major focus areas include improving systems to minimise human errors and their consequences, and focusing on best practice to understand and share approaches for success. There are also new concepts and new expectations about what needs to be done, and how this can be achieved, and new tools to help us. The purpose of this review is to explore developments in haemovigilance that should be highlighted today so that the haemovigilance community can prepare for the future. Under the broad headings below we explore some of the key concepts and challenges.

# How will we forecast the future?

Most haemovigilance systems have no formal forecasting mechanism for future activities, and this is something that could be considered further by all established and developing systems. Planning for the future typically occurs in a variety of ways, including through internal business processes, input from steering committees or equivalent advisory groups, feedback from participating institutions and stakeholder meetings, and ‘horizon scanning’ of the external environment. How this information is processed and managed is highly variable. Haemovigilance programs are generally well linked with blood sector activities in their own countries, and frequently internationally as well. In this way, awareness of, and contributions to, developments in blood policy, regulation, changes in clinical practice, blood manufacturing and new research can signal the way ahead for haemovigilance.

The haemovigilance community is highly collaborative, and both formal and informal collective endeavors have been undertaken over many years, to enable coordination of both rapid and ongoing responses to various challenges (such as threats from transfusion-transmitted infections) and to learn from and support each other. For example, the European Haemovigilance Network held its first meeting of representatives from five countries in 1998; this group evolved with broader participation from within and outside Europe to become renamed in 2008 as the IHN, representing and welcoming haemovigilance programs worldwide, both established and developing. For individuals interested in haemovigilance, the Working Party on Haemovigilance of the International Society of Blood Transfusion (ISBT) is open to ISBT individual members from around the world [3]. Each serves as a useful forum for networking and learning from others’ experiences and sharing ideas, best practices, and resources, including new developments that may be important in future haemovigilance. The World Health Organization (WHO) has also played an important role in supporting policy development and improved practice in member states, through Aides-Mémoire and guidance documents on haemovigilance [4,5] and other relevant areas of practice directed at ministries of health and national blood services, including the WHO ‘Action framework to advance universal access to safe, effective and quality-assured blood products 2020–2023′ [6]. WHO and other partners also support the NOTIFY Library, which now includes cases related to blood [7]. Recently, WHO, ISBT and IHN have collaborated on efforts to make haemovigilance tools more widely available [8,9].

# What will be the future scope of haemovigilance?

The future will reflect an evolution from the current scope of haemovigilance, which differs around the world [1]. For example, some countries, such as the United Kingdom, France, Japan, Australia and South Africa, have developed haemovigilance systems focused on patients receiving conventional labile blood components such as red cells, platelets, plasma and cryoprecipitate. Others, such as Germany and New Zealand, have taken a broader view, capturing also the use of fractionated plasma products, such as immunoglobulins and coagulation factors, whereas elsewhere plasma products are regulated separately as pharmaceuticals, and captured in dedicated pharmacovigilance systems. Some countries, such as the Netherlands, Canada, and the United States have included haemovigilance into a broad ‘biovigilance’ approach, incorporating blood along with cellular therapies, tissues, organs, human milk and other ‘substances of human origin’ or ‘medical products of human origin’. Donor vigilance is recognized as a vital component of haemovigilance, in order to protect donor health and wellbeing and serves as part of national public health programs, including surveillance of emerging infectious threats to the blood supply, from ‘vein to vein’.

In the future, will we see a trend to this broader scope (biovigilance approach), or more splitting into niche areas for detailed examination focused solely on blood products? There are some advantages to highly focused activities, including less risk of ‘dilution’ of effort and ability to engage experts with deep knowledge in the field. On the other hand, potential advantages to broader-based efforts include harmonization of efforts across areas facing common threats, and the ability to use standardized terminologies, common definitions, platforms, regulatory approaches, and project resources – including staff with expertise in the field – for greater efficiency.

Crucially, the scope of haemovigilance in any setting depends on a number of factors, including the health system, blood program and regulatory framework in which the haemovigilance program operates. It is recognized that there is no ‘one size fits all’ haemovigilance system for all settings, and that a haemovigilance program must work in the context of each country; furthermore, optimal arrangements may change over time as health systems evolve. These are all important considerations, for planning of resources, and for continuity and development of the program. Haemovigilance also links directly with other blood safety activities, and aligns with transfusion education and training, clinical audit and patient blood management (for example, in messages around clinical decision-making, avoidance of unnecessary transfusions, and use of alternatives to transfusion) so some resources such as administrative support and education may be able to be applied broadly across multiple programs.

Some relevant datasets are not currently well integrated into haemovigilance reporting, such as data from clinical trials of new therapeutics, and data held by industry (e.g., manufacturers of drugs, other therapeutics and devices) until these products reach routine clinical use; this is explored below. Furthermore, in many cases, data on cell salvage, long-term adverse consequences of transfusion, or on out-of-hospital transfusions (for example, subcutaneous immunoglobulin therapy managed by patients at home) are not readily captured by current haemovigilance programs. Importantly, health economics analyses of the impact of changes in blood product manufacturing or transfusion practice are largely lacking but are increasingly being incorporated into clinical trials and clinical quality registries, and so some of these may be incorporated into routine evaluations of practice in the future to help understand the true costs of transfusion to the community.

# New blood products and transfusion processes

Blood products continue to evolve, and an increasingly broad range of modified and refined products can be anticipated in the future. It is likely that these will include manufactured (‘lab-grown’ and genetically modified) blood components and diverse cellular therapies. Some of these will undoubtedly provide great benefit to patients (for example, more targeted and highly standardized products, not limited by donor-to-donor variation) but may carry new hazards which may require both short- and long-term monitoring. Haemovigilance will play an important role in monitoring both the safety and potentially the clinical effectiveness of manufacturing process changes, such as the current worldwide transition to the use of blood bags with non-diethylhexyl phthalate (DEHP) plasticiser.

Concurrently, new therapeutics that are alternatives to transfusion, or which may reduce the demand for transfusion in patients who have historically been heavily transfused, are also becoming available. These include, for example, gene therapies, and other targeted treatments to ameliorate anaemia or its consequences for patients with haemoglobinopathies [10,11] and myelodysplasia [12] who currently require long-term red cell support, or complement-directed and antibody therapies to treat autoimmune haemolytic anaemia [13,14]. New agents such as thrombopoietin receptor agonists to manage thrombocytopenia offer hope for patients with bone marrow failure syndromes such as aplastic anaemia, many of whom are currently dependent on frequent platelet transfusions [15].

Involving haemovigilance representatives in the planning and implementation of new products will help ensure that appropriate surveillance and feedback mechanisms are in place when needed.

# Who needs to be involved in haemovigilance, and what skills and experience will they need?

People are involved in haemovigilance at every step, as donors, patients, staff members, and professional or community representatives providing vital community perspectives on risks and consequences, and how current systems may be improved. In fact, at present, haemovigilance systems largely depend on people in a range of settings, such as hospitals or blood centres, identifying reportable donation, manufacturing or transfusion-related events, taking steps to report and analyse them, and to provide expert commentary and feedback to people at participating sites. Haemovigilance professionals have a broad range of skills and experience, including in clinical incident review, data management and analysis, communications and reporting; however, already, and increasingly in the future, our staff will need new skills in data collection, linkage, and analysis, and to use new communication tools, as described in the following section.

Haemovigilance also needs links with, and visibility of, the broader health sector: Understanding how donor centres and health services (both hospital- and community-based) function (now and in the future), and how people think and behave, is critical for improving transfusion practice and reducing risks and errors by designing new health systems with these ‘human factors’ in mind. Likewise, understanding the pathophysiology of transfusion reactions and the potential impact of changes in manufacturing requires and benefits from links with blood services and research. Many insights vital to haemovigilance have come from other industry sectors, such as aviation safety [16], so connections with experts in diverse fields will continue to be highly valuable.

# We will have new tools for both practice and vigilance

Haemovigilance programs in the future will need to be able to use new tools, and to capture, analyse and interpret data from new sources and communicate this to a wide audience. Examples already available include:

Wearables: Clinical practice is rapidly evolving, with a great deal of care formerly provided in the hospital now delivered in the community, including some transfusion and transplantation services. In many countries, the COVID-19 pandemic greatly accelerated the pace of this transition. A vast array of new tools is already available for monitoring donor, product and patient safety remotely, but most have not yet been widely or routinely applied to haemovigilance. One example is the use of wearables to capture vital signs and overall wellbeing, which are increasingly being used in everyday life (via ‘smart watches’, and Bluetooth devices for monitoring heart rate, oxygen and glucose levels) and in clinical settings, both hospital-based and ‘hospital-in-the-home’ environments. Many current challenges, such as how to reliably capture, interpret, integrate, validate, store and respond to data from these devices are rapidly being overcome. It is likely that these will become important tools for future on-site and remote monitoring of blood donors and transfused patients – including to determine whether, and when, a patient may need a transfusion at all, as well as to understand the clinical consequences of that transfusion.

Linked datasets, and tools for searching, extracting and analysing information: New resources include artificial intelligence (AI) tools, which will greatly enhance opportunities to capture data from large, routinely collected datasets, such as those used by primary care, hospital and primary care electronic medical records, clinical audits, pathology and pharmaceutical systems, health insurance, and blood centres. These AI tools should greatly reduce reliance on individual manual data entry and reporting, save time and effort, and provide greater access and reliability – helping us move from ‘volume-based’ work to ‘value-based' work [17]. As these datasets are increasingly integrated and accessible to authorized users, the size of the dataset available for haemovigilance will increase in size and complexity. With access to these resources, we will be in a good position to conduct data-driven haemovigilance and research, where mining of large datasets can identify patterns and outcomes [18]. This may be especially helpful in detecting rare events, as has been used in related vigilance settings [19]. These data can also be used to develop models for risk prediction but must be carefully constructed to be complete, fit for purpose, and to avoid bias. The ‘big data’ approach will also enable data-driven development of hypotheses for future research and action [20]. It is acknowledged that in many countries elements of the health systems are not yet well integrated, but there is hope for the future: many low- and middle-income countries were able to bypass the need for paper-based haemovigilance reporting and manual data extraction and analysis (which was the starting point and experience of most countries where haemovigilance systems were established decades ago) and proceed to direct implementation of electronic systems [21–23]; and now as new health systems are developed in these settings, new data systems will develop alongside them with greater functionality at lower cost. As haemovigilance is evolving so should (and will) the regulatory approach, and the regulatory framework should help embrace new technology capabilities, facilitate collaboration and information sharing nationally and internationally.

Donor- and patient-reported outcomes data: To complement device and health system data, we will likely increasingly see patient-reported outcomes (PROs) being incorporated into research, clinical practice and haemovigilance. In addition to the formal quality-of-life tools widely used in clinical trials, and which may be either general or disease/context-specific, patient-reported outcome measures (PROMs) are recognized as very valuable to understand a person’s experience. So far, there have been relatively few PRO data available from blood donation or transfusion settings [24,25], and few specific tools exist for this purpose; however, we can expect rapid development in this area. Incorporating PROs into haemovigilance practice will provide many opportunities for understanding donor and patient experiences and providing data on delayed adverse events (which are currently poorly captured). In this regard we should also be mindful to be inclusive in our approach, so that there is access for a diversity of patients’ and donors’ voices and opportunities for meaningful input, and that we design haemovigilance systems that do not leave anyone behind, including those without or with limited access to new technologies.

# How will we be communicating to achieve awareness and change in the future?

Many haemovigilance programs provide annual reports to summarise data and analyses and share key findings and recommendations with a broad audience [1,21–23,26–28]. Some also provide updates via newsletters and social media, webinars and other meetings such as conferences and workshops, and some include a ‘rapid alert’ mechanism for communicating emerging threats. These activities and reports are highly valued by stakeholders but may be extremely resource-intensive to deliver. In other cases, timely and complete reporting is not presently being delivered, meaning that reporting ‘out’ to the community is well behind reporting ‘in’ (submission of data for review and analysis) and opportunities to intervene and improve are missed or delayed.

Is this how we will analyse and report data in ten years’ time, and is it enough? Some of the new tools described above will likely enable faster data collection and analysis and relieve some of the manual burden in preparing reports. We might also anticipate a greater demand from hospitals and blood centres to access and analyse their own data and compare these with other organisations’ experiences for benchmarking and practice improvement, in addition to receiving reports from a central program office. Concurrent with these developments, we are also seeing changes in the way people prefer, and expect, to receive information, such as more frequent updates, rather than waiting for a single ‘final’ report. We also need to optimize communication strategies and channels to enable greater input from donors, patients and the broader community, and ensure their voices are heard in a meaningful way. We already have the tools to do this, but they need to be more widely applied across haemovigilance, and we should incorporate measures to seek to understand how well we are communicating.

# How will we measure the impact of haemovigilance in the future?

In the ideal future state, all countries have active haemovigilance systems established, integrated and properly resourced to drive and monitor improvements in transfusion safety, and are regularly reporting results and progress [2,4,5,7]. The ultimate impact of haemovigilance is on outcomes for donors and patients, so we need to ensure these outcomes are reflected in how we structure and evaluate our haemovigilance efforts. Collecting, analysing and communicating haemovigilance data are important in and of themselves, but they are not the ultimate goals: translation of results and recommendations into policy and improved practice is essential, and in many respects and settings, these goals have not yet been met. It is not enough to count things (adverse events, reactions, and mistakes) – we need to take appropriate, timely actions and implement improvements.

How will we achieve the changes we need to make an impact on transfusion safety and improve outcomes in the future? One way is by identifying who needs to ‘be at the table’ with access to haemovigilance data and with the authority to make change happen. While every person involved in haemovigilance can make a difference, system change and improvement requires engagement and support from national blood policymakers, and senior management in hospitals and blood centres (who carry both the authority and responsibility), and clear expectations from health professionals, regulators and the community. Improving integration of haemovigilance into the wider health system will underscore vital links with clinical audit programs; with availability of information to donors, patients and families; with staff education and training programs; and will greatly assist in setting future transfusion research priorities.

Resources to help with these efforts include international haemovigilance data-sharing and benchmarking activities. To do this, we need robust, comparable haemovigilance data, and must continue the work underway on developing, validating and updating internationally harmonized haemovigilance definitions [29]. Improving access to tools and resources for all aspects of haemovigilance is the aim of the recent project supported by WHO, ISBT and IHN [8,9], and will likely be especially valuable for new and developing haemovigilance systems. International collaborations will also continue to be of great benefit to established programs, which can monitor their progress and impact over time. Incorporating a broader range of data, including health economics analyses and PROMs, alongside existing haemovigilance data, will provide valuable new perspectives and help demonstrate the need for, and impact of haemovigilance, into the future.

# Funding

The authors received no specific funding for this work.

# Author contribution

EMW wrote the first draft of the manuscript. All authors reviewed and edited the manuscript.

# Author disclaimer

This article reflects the views of the author (Barbee I. Whitaker) and should not be construed to represent FDA’s views or policies.

The authors thank the International Society of Blood Transfusion, the International Haemovigilance Network, the World Health Organization, and participants in haemovigilance programs worldwide for sharing their experiences and resources to advance this important field.