Solving the Puzzle of Transfusion-Related Immune Reactions

March 13, 2018

Now that physicians have the “how” of blood transfusions mastered, they are starting to explore the “what” — and they’re learning that the effects of sharing human blood may be even more far-reaching and complex than previously imagined.

With the initial safety challenges addressed and the technical barriers of donor blood storage and cleaning improved, critical care physicians and hematologists can examine the nitty gritty of the procedure: why do some patients fare better than others after a blood transfusion, when all else remains relatively constant? And even more importantly, could some of our transfusion practices do more harm than good?

Waking Up to a New Puzzle

The history of blood transfusion has in numerous respects been a successful one. Long used for patients with severe blood loss or blood disorders, transfusions have saved many lives.

But periodically, the world is reminded of the imperfections of medical care. After surviving multiple revelations that blood contains more than just red blood cells — such as proteins, blood types and pathogens including HIV — this life-saving clinical practice may face yet another speed bump: the concept of transfusion-related immunomodulation.

“Problems with safety have improved vastly over the past century, but like anything else, we’re not 100 percent there,” says Jennifer Muszynski, MD, principal investigator in the Center for Clinical and Translational Research and a physician on the critical care team at Nationwide Children’s Hospital. “Now, outside of patients who are bleeding to death and need a transfusion right away, we have to ask ourselves, ‘Will giving a blood transfusion help, not affect you at all, or eventually even be harmful?’”

Spurred by observations in the 1970s and 80s that organ transplant patients who had received blood transfusions experienced less organ rejection, likely due to immune suppression, Dr. Muszynski and her research team joined a growing community of physician-scientists investigating the potential impact of blood products on patient immune health, systemic inflammation and outcomes.

“In the case of an organ transplant, immunosuppression could be beneficial,” Dr. Muszynski explains. “But if you’re a patient who needs a functioning immune response to combat infection, that potential effect is not a great thing.”

Initial research following the organ-transplant observations attributed an immunosuppressive effect to the white blood cells remaining in donor blood. Now, most red blood cell products in the U.S. are processed in a way that removes white blood cells, yet studies indicate transfusion-related immunomodulation may still happen. Some patients — no one knows exactly how to predict who — do just fine, while others may end up with severe immune dysregulation, sepsis, organ failure or systemic complications.

Sorting Through the Pieces

Dr. Muszynski and her colleagues at Nationwide Children’s and elsewhere have been searching for the underlying cause of immunosuppression following transfusion.

“We’re really starting to put some pieces together around what components in that bag of blood may have immunologic effects in the recipient and what those effects are,” Dr. Muszynski says. “Our work in the lab suggests that no single factor will capture the whole picture.”

Instead, Dr. Muszyinski believes that a complex system of factors come into play, as demonstrated by her publications exploring the various roles of monocytes, red blood cell supernatants, microvesicles, protein-bound RNA, blood storage time, pre-transfusion immune health, and the conceptualization and measurement of innate immune suppression.

Download the illustration as PDF here: Transfusion-Related Immunomodulation

In particular, her focus on the spectrum of immune suppression and inflammation in critically ill children highlights a concept called the “multi-hit phenomenon” In patients with otherwise good health, some researchers believe a blood transfusion — even one with blood containing potential immune-suppressing components — may be inconsequential in terms of immune suppression. But for patients who have already experienced multiple health threats, or hits, such as septic shock and organ failure, a blood transfusion may be the proverbial straw that breaks the camel’s back.

“If we add blood products with components that can cause inflammation and immunosuppression in different balances, you have the potential for blood to impact both sides of that equation,” Dr. Muszynski says. “We need to figure out to what degree blood products impact that balance, and how transfusion compares to all of the other things happening in their underlying illness.”

In light of evidence that found little benefit from transfusions in the treatment of mild anemia in certain populations, many intensive care units have shifted to a more restrictive approach to blood transfusions. However, some patient groups, including those with acute or septic shock, still receive transfusions liberally in many hospitals.

“There may be a benefit of transfusing children with septic shock, but it is a population where we don’t know the best strategy yet,” Dr. Muszynski says. “Those patients already have a lot of ‘hits’ to their system, so they may also be the patients who face the most potential harm from transfusions.”

Dr. Muszynski and her colleagues have an ongoing observational study to examine the impact of transfusion among children with septic shock. They hope to better delineate which groups of patients experience a benefit and which do not, with the goal of planning a trial to confirm where transfusion will be helpful rather than harmful.

Putting Together the Full Picture

As her laboratory and observational clinical studies continue, Dr. Muszynski is busy spreading the word about transfusion-related immunomodulation. Her reviews published this year in the journal Transfusion and last year in the Journal of Trauma and Acute Care Surgery describe and explore the current understanding of the potential impact of transfusion and trauma on immune suppression and patient outcomes.

As more scientists and physicians become aware of this phenomenon, Dr. Muszynski hopes transfusion policies will start to converge on more restrictive and evidence-based approaches when merited.

“We want to know — for specific patient populations and even down to the specific patient — if they get a blood transfusion, will it help or potentially harm them?” Dr. Muszynski says. “That’s the ultimate question behind all of this research, and we need clinical trials to uncover the answers.”

Dr. Muszynski and her colleagues at Nationwide Children’s have the advantage of working with a multicenter, multidisciplinary group called the Pediatric Critical Care Blood Research Network (Blood Net). Researchers at more than 80 participating centers in the United States, Canada, Australia and Europe focus on pediatric critical care blood research, searching for the individual pieces in the world of transfusion-related immunomodulation and how they fit together into one complete puzzle.

“Taking a systems-based approach is going to be necessary to capture the importance of transfusion within the entire system of illness, immunosuppression and inflammation,” Dr. Muszynski says. “It’s going to take a team of people to find the individual pieces and how they fit together into one complete puzzle.”



  1. Shah S, Spinella PC, Muszynski JA. Immunologic effects of trauma and transfusion. Journal of Trauma and Acute Care Surgery. 2017 Jun;82(6S Suppl 1):S50-S56.
  2. Remy KE, Hall MW, Cholette J, Juffermans NP, Nicol K, Doctor A, Blumberg N, Spinella PC, Norris PJ, Dahmer MK, Muszynski JA. Mechanisms of red blood cell transfusion-related immunomodulation. Transfusion. 2018 Jan. [E-pub ahead of print.]

 Image credits: Nationwide Children’s Hospital