Perseverance and collaboration: How a new clinical trial aims to determine whether sex matters when matching blood products to patients

As the Principal Investigator for the SexMatters trial described in this blog, Dr. Mickey Zeller is an Associate Professor in the Department of Medicine at McMaster University. She is also a Medical Officer at Canadian Blood Services. 

Around 2018, Dr. Mickey Zeller's grandmother asked her a question that she couldn’t fully answer at the time. It’s a question that Dr. Zeller continues to keep top-of-mind in her roles as an Associate Professor at McMaster University and a Medical Officer at Canadian Blood Services. Having sustained a pelvic fracture at the age of 94, she asked her granddaughter, “If I need a blood transfusion, could it come from a man... and if it does, would that be safe?”. As Dr. Zeller describes, “I looked at her and, in that moment, I said, ‘Grandma, no one knows! But it’s on my list to find out!’.” 

In fact, questions about whether selecting products based on the sex of donor and recipient could improve outcomes following blood transfusions have been around for years. However, there is not yet been enough evidence to definitively answer whether this strategy would help optimize hospital and blood operator practices.

After much perseverance, collaboration with researchers across Canadian Blood Services’ extended research network, and a successful bid for CIHR funding, a research team led by Dr. Zeller is embarking on a new research journey they hope will finally provide the evidence to answer questions about whether sex matters in red blood cell transfusion.

What will the study focus on and why is it needed?

When a patient requires a transfusion of red blood cells (RBCs), the matching of product to patient is based on compatibility testing that looks at whether the blood is group A, B, AB or O, whether it is Rh positive or negative, and what other antibodies are present. Canadian Blood Services’ Rare Blood Program also helps ensure patients with specific combinations of antigens – proteins that appear on the surface of red blood cells – can be matched with appropriate blood components. Laboratory studies on donor factors such as age and sex have looked at their impact on characteristics of RBCs in terms of hematocrit, cell volume, hemoglobin content, and deformability – that is, the flexibility or “squeeze-ability” of the cells. However, currently available evidence has not demonstrated a need for red blood cells for transfusion to be matched based on the sex of either donor or recipient. 

The principal research question being posed by this study is: In adults admitted to the ICU who require RBC transfusions, do donor-recipient sex-matched RBC transfusions result in improved 30-day mortality compared with sex-mismatched RBC transfusions? Answering this question has a large potential for impact because of the substantial number of blood transfusions that occur throughout Canada every year.  

“If there was a risk identified [from the sex of the donor and recipient], even moving the needle a little bit to improve the matching of blood product to recipient could add another layer of safety to current practices,” Dr. Zeller explains.  

What had to happen to make this study possible?

While it seems like a basic question to remain unanswered, Dr. Zeller acknowledges the investments of energy, expertise, and funding to get the study to this point.  

“Sometimes these basic questions remain for a long time because it is challenging to get the funding and infrastructure in place to be able to answer them in a scientifically rigorous way; even if they’re basic-level questions, it’s only by investing that you are able to gather the evidence to answer the question.” Dr. Zeller says.

That’s part of the reason why Canadian Blood Services’ investments in networks like CTTG are important. The Canadian Transfusion Trials Group (CTTG) is funded by Canadian Blood Services with the aim of supporting and accelerating clinical trials that can inform best practices in transfusion medicine in Canada. CTTG reviewed and endorsed this SexMatters study and provided support through its development, making it the second RCT since CTTG’s inception to earn CIHR funding following participation in their review process.

"I had the opportunity to present to CTTG twice and receive feedback that improved this study design and my application to CIHR for its funding. Having it reviewed by people like Dr. Donald Arnold, Dr. Jeannie Callum, Dr. Nadine Shehata – people with world-recognized expertise in this area – really led to the success of this application,” Dr. Zeller says. “We were able to have really rich discussions on tough questions about study design and impact, including details like how we would account for patients that are pre-transfused entering the study.”

Says Dr. Zeller, “Each time the application went through reviews, I could present to these colleagues to essentially say, 'Here are the criticisms it has received and here’s how I’ve handled them.' And they would provide me advice and encouragement to resubmit. It is really valuable having people across the country who are cheering for you, and who are hand-in-hand with you to celebrate your success!”

“It’s an absolute privilege to do high quality research because you have to be surrounded by an incredible group of humans. Academic curiosity and commitment by those that have mentored me have enabled me to do this work. It’s out of a generosity of spirit that people have shared their expertise with me for this work, and it takes a lot of time and effort.”

Dr. Mickey Zeller, Principal Investigator for the SexMatters trial

What other research has informed this study? 

Before this study received CIHR support, the research team undertook an exploratory analysis, a systematic review and meta-analysis, and a pilot trial which took place in 2022 across five Ontario-based hospitals to establish feasibility of the randomized controlled trial. Findings of retrospective observational studies indicated potential association between sex-mismatched transfusions and mortality, but some aspects remained unclear due to low certainty of evidence, inconsistencies or contradictory subgroup analyses in the available literature.  

Much previous research involving Canadian Blood Services researchers has also supported the need for this randomized controlled trial. This includes: 

• research undertaken in the lab of Canadian Blood Services Senior Scientist, Dr. Jason Acker, which has investigated impacts of various factors (including age and sex) on red blood cell storage and other factors of quality;  
• the iTADs clinical trial (short for “An innovative Trial Assessing Donor Sex on Recipient Mortality") undertaken by Canadian Blood Services Adjunct Scientist Dr. Dean Fergusson and colleagues that signalled there may be increased risks with blood from younger, female donors; 
• as well as research by Canadian Blood Services Adjunct Scientists Nancy Heddle and Dr. Donald Arnold at McMaster University’s Michael G. DeGroote Centre for Transfusion Research (formerly known as the McMaster Centre for Transfusion Research) which was supported through Canadian Blood Services’ Transfusion Medicine Research Program Support Award.  

Earlier publications involving these and other researchers have also investigated the impact that blood donor age and sex have on outcomes for transfusion recipients, summarized evidence related to sex-matched versus mismatched transfusions and mortality, and the biological mechanisms implicated in adverse outcomes of sex-mismatched transfusions. There is still room for more investigation to build on this previously completed research, and that aligns with Canadian Blood Services' emphasis on the importance of research that spans the continuum from bench-to-bedside to continuously improve our processes, products and services. As Dr. Zeller describes: “There are biological studies and retrospective data, but we only have one existing RCT. There’s a real importance to pursue a prospective, RCT so we can look forward as opposed to looking back.”

“As every blood donor is unique, the challenge we have is to understand which donor-specific factors can be better matched to improve patient outcomes.  Differences in the biology of blood cells from male and female blood donors are well defined, but what we do not understand is if these differences affect health outcomes in transfused patients.  This is very important question that the SexMatters clinical trial is proposing to address.”

Dr. Jason Acker, Co-Investigator in the SexMatters trial

How will the study work and why the focus on transfusions in the ICU?  

Focusing on transfusions in the ICU is a significant distinguishing feature of this study. The iTADS trial was completed as a multicentre, double-blind trial, but it looked at mortality rates across the whole hospital. This new trial will look at transfusions received by patients in the intensive care unit (ICU) specifically. 

“In the hospital, we know that mortality rate is much higher in a transfused ICU patient compared to a patient in another part of the hospital,” Dr. Zeller says. “We’ve chosen to focus this study on the sickest population of patients – those in the ICU – with the idea that any impact will be seen most prominently in this group. The analysis will include consideration to dosage so we can adjust for the specific number of units transfused to each patient.” 

The study is also designed so that participants will not know whether a blood transfusion is matched or mismatched based on the sex of donor or recipient – a method used to prevent potential bias in the trial. 

“At the hospital, you always get a list with each shipment of blood product that says what units you have received from the blood operator”, Dr. Zeller explains. “As part of this study’s protocol, participating hospitals will see an additional colour-coding noted on this inventory, and this is what will be used when it comes time for us to do our analysis.”  

Who could benefit from this knowledge and what are the next steps?  

Dr. Zeller is glad to have Canadian Blood Services involved in this research, acknowledging that changing policy related to matching of blood products would be a significant change for hospitals and blood suppliers, requiring strong evidence from RCTs like this one.  

“This study will help to inform health-care professionals who prescribe and administer blood products, along with patients, donors, and the blood operator, too. One of the important questions if it does turn out to have a significant difference is ‘Then what?’ We already divide our inventory by group (ABO) and by Rh status (+/-). Would the need to be matching by sex further impact inventory? We don’t know yet, but that’s why it’s important to have the blood supplier involved,” Dr. Zeller says. 

The study will require a total sample size of approximately 11,000 patients across an expected nine hospital sites in Ontario.  

“We’ve designed this study to be very efficient; it’s got components of what would be considered a pragmatic study design,” Dr. Zeller says. “In terms of the products, Canadian Blood Services does not have to provide anything different than they already do for this study (other than the colour-coded markers) and we will use electronic capture to pull data, so we don’t need to collect study information at bedside. These were processes leveraged from the earlier iTADS study as the iTADS research team was very supportive of us learning from what they did.”  

“Whether transfusions should be matched for donor sex is a question that has been percolating in people’s minds for many years. Dr. Zeller has had the courage and perseverance to tackle this important question, which could have important policy implications.  I’m excited for Dr. Zeller to embark on this journey and advance knowledge on best transfusion practices.”  

Dr. Donald Arnold, Co-Director of CTTG and Co-Investigator in the SexMatters trial 

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Through discovery, development and applied research, Canadian Blood Services drives world-class innovation in blood transfusion, cellular therapy and transplantation—bringing clarity and insight to an increasingly complex healthcare future. Our dedicated research team and extended network of partners engage in exploratory and applied research to create new knowledge, inform and enhance best practices, contribute to the development of new services and technologies, and build capacity through training and collaboration. Find out more about our research impact.   

The opinions reflected in this post are those of the author and do not necessarily reflect the opinions of Canadian Blood Services nor do they reflect the views of Health Canada or any other funding agency.