Molecular Mechanisms of Transfusion-Associated Immunomodulation and Its Impact in the Critically Ill

Allogeneic blood transfusion is frequently performed in critically ill patients, but accumulating evidence demonstrates that it is not a biologically neutral intervention. Transfusion-associated immunomodulation (TRIM) encompasses the immunological effects of transfusion, ranging from immune suppression to proinflammatory activation and cancer recurrence, with potential impact on morbidity and mortality in the intensive care unit. We conducted a narrative review of recent experimental and clinical evidence on TRIM to describe the molecular pathways involved. We reviewed, randomized trials, metaanalyses, and large observational cohorts to evaluate the clinical relevance of TRIM in critically ill populations. TRIM arises from multiple converging mechanisms. These pathways alter innate and adaptive immunity, leading to increased risk of healthcare-associated infections, transfusion-related acute lung injury, acute kidney injury, multiorgan dysfunction, prolonged length of stay, and cancer recurrence in surgical patients. Blood-sparing strategies, including patient blood management (PBM), mitigate exposure. The impact of storage duration and novel processing technologies remains unclear. There is still a gap in research that needs to be addressed. Transfusion-associated immunomodulation (TRIM) is a phenomenon in which donor leukocytes, extracellular vesicles, microparticles, bioactive lipids, and cytokines interact with the host immune system to produce a spectrum of immunological effects. In critically ill patients, the immune system is already fragile, and these mechanisms predispose patients to infections, pulmonary complications, organ dysfunction, prolonged recovery, and even cancer recurrence. Although TRIM cannot currently be diagnosed through a single biomarker or clinical test, its existence is strongly supported by mechanistic studies and consistent clinical associations between transfusion exposure and adverse outcomes.