When Blood Remembers Its Sex: Toward Truly Personalized Transfusion Medicine

<b>Background</b>: Biological sex differences are well-recognized as non-negligible factors in implementing precision medicine practice. Sex chromosomes influence protein expression and signaling, and thus cellular pathways are often regulated differently. Additionally, the importance of sex as a biological variable has gained significant traction in biomedical research, including transfusion medicine. Regarding transfusion medicine, several studies reveal the role of gender in blood transfusion, blood donors' behavior towards donation, blood products' composition and storage, transfusion therapy, and possibly post-transfusion patient outcomes. <b>Methods</b>: In this review, the role of sex and gender in the whole transfusion chain (from the blood donor to the blood product and the patient) is assessed and summarized using data from observational studies, registry analyses, and randomized trials. <b>Results</b>: Female donors face higher deferral rates due to biological factors (iron deficiency, low hemoglobin, pregnancy) and sociocultural factors (caregiving responsibilities, misinformation). However, women are more likely to donate based on empathy, moral duty, or community responsibility and are more consistent in sustaining voluntary donation during crises. Men donate more frequently, typically driven by external motivators, and provide red blood cell (RBC) products with higher hemoglobin content, whereas RBCs from female donors exhibit greater metabolic stability and reduced hemolysis during storage. Plasma from multiparous women possibly contains alloantibodies associated with adverse transfusion reactions, namely transfusion-related acute lung injury (TRALI). Platelet function also varies by sex, though its possible clinical impact is still unknown. Although observational studies suggest sex-mismatched transfusions are associated with increased morbidity and mortality-particularly in transfusions from female donors to male recipients-large registries and randomized controlled trials show inconsistent or negligible effect on survival. <b>Conclusions</b>: Donor and recipient sex are emerging variables of possible clinical importance in transfusion practice. Incorporating sex-informed insights into donor recruitment, blood product handling and transfusion policies may improve safety while advancing precision medicine. Further large-scale trials are needed to elucidate the impact of sex in transfusion, identify and eliminate possible risks, and bridge the gap between biological insights and clinical practice.