Inter-unit variability and rapid depletion of 2,3-diphosphoglycerate in stored red blood cells: implications for transfusion practice in neurocritical care
This study demonstrates that 2,3-DPG levels in stored red blood cells exhibit significant inter-unit variability and rapid depletion well before the 42-day expiration, suggesting that using storage duration as a proxy for metabolic state misclassifies the actual oxygen-unloading capacity of transfused units.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
When a doctor gives a patient a blood transfusion, the goal is simple: to deliver oxygen to tissues that need it. Red blood cells act as the delivery trucks, carrying oxygen bound to a protein called hemoglobin. However, for this system to work, the hemoglobin must be willing to let go of that oxygen once it reaches the destination. A specific molecule inside the red blood cell, known as 2,3-diphosphoglycerate, acts as the release mechanism. It binds to hemoglobin and lowers its grip on oxygen, ensuring the gas is dropped off where it is needed. Without enough of this molecule, hemoglobin holds on too tightly, and the oxygen never reaches the tissues.
Blood banks store donated blood in refrigerated bags for up to six weeks before it is used. During this time, the cells are cut off from their natural environment and must survive on stored nutrients. It is a well-known fact that as blood sits in storage, it undergoes a slow decline in quality, a process scientists call the "storage lesion." The cells become more fragile, the fluid around them becomes more acidic, and the crucial release molecule, 2,3-diphosphoglycerate, begins to disappear. For years, researchers have debated whether the age of the blood bag matters for the patient. Some studies suggest that fresher blood is better, while others find no difference. A major reason for this confusion has been the assumption that all bags of the same age are identical. If a bag is ten days old, it is assumed to have the same metabolic state as any other ten-day-old bag. This study challenges that assumption by looking directly at the chemical reality inside the bags.
A team of researchers in Barcelona decided to look past the calendar date on the blood bag and examine the actual chemical state of the cells inside. They collected twenty-four units of leukodepleted packed red blood cells, which are standard blood products with white blood cells removed. These units were prepared from healthy donors and stored in a solution containing saline, adenine, glucose, and mannitol. The team did not just check the blood once; they sampled the same bags repeatedly over a period of six weeks, starting from the third day of storage and continuing until the fortieth-second day. To get the most accurate picture possible, they used a highly sensitive technique called liquid chromatography–mass spectrometry. This method allows scientists to weigh and count specific molecules with extreme precision, far better than older testing methods. They measured the amount of the oxygen-release molecule and the acidity of the fluid in each bag at every checkpoint.
The results revealed a surprising truth about the blood supply. On the very first day they tested the bags, the third day of storage, the units were not all the same. The amount of the oxygen-release molecule varied wildly from one bag to another. In some bags, the level was nearly zero, while in others, it was still high, nearly twenty times higher than the lowest ones. This means that two bags of blood with the exact same age could have completely different abilities to deliver oxygen. However, this difference did not last long. As the days passed, the levels in every single bag began to drop rapidly. By the seventh day, the average amount of the molecule had fallen to less than a third of what it was at the start. By the fourteenth day, it had dropped by more than ninety percent. After seventeen days, the molecule was so low in most bags that the equipment could no longer detect it.
At the same time, the researchers tracked the acidity of the blood. They found that the fluid became steadily more acidic every day, dropping from a neutral level to a significantly acidic state by the end of the six-week period. The data showed a clear link: as the blood became more acidic, the oxygen-release molecule disappeared. The acidification of the storage fluid seems to be the primary driver that shuts down the production of the molecule and speeds up its breakdown. This rapid depletion happens long before the blood reaches its official expiration date of forty-two days.
The study argues that the current way we classify blood as "fresh" or "old" based solely on the number of days it has been stored is misleading. A bag labeled as "old" might have been depleted of its oxygen-release capability weeks ago, but a bag labeled as "young" might have already lost most of it if it started with a low level. The researchers suggest that the focus should not be on changing transfusion policies to use only the newest bags, but rather on improving the storage solutions themselves. They point out that previous experiments have shown that adding certain substances to the storage fluid, or controlling the acidity, could potentially keep the oxygen-release molecule alive for longer. By fixing the environment inside the bag, it may be possible to keep the blood functional for its entire shelf life, ensuring that every unit given to a patient is capable of delivering oxygen effectively, regardless of how many days have passed since donation.
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