Testosterone‐dependent sex differences in red blood cell hemolysis in storage, stress, and disease

Abstract

INTRODUCTION Red blood cell (RBC) hemolysis represents an intrinsic mechanism for human vascular disease. Intravascular hemolysis releases hemoglobin and other metabolites that inhibit nitric oxide signaling and drive oxidative and inflammatory stress. While these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis including sex have not been established. MATERIALS AND METHODS We studied sex differences in storage or stress-induced hemolysis in RBC units from the US and Canada, in 22 inbred mouse strains, and in sickle cell disease using measures of hemolysis in 315 homozygous SS sickle cell patients from the Walk-PHASST cohort. We used a mouse model to evaluate post-transfusion recovery of stored RBCs, and gonadectomy to determine mechanisms related to sex hormones. RESULTS An analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis than females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in sickle cell disease. The sex difference is intrinsic to the erythrocyte and not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and post-transfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress. DISCUSSION Our findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and sickle cell disease, and establishing a role for donor genetic variables in the viability of stored erythrocytes and in human hemolytic diseases.

Quality Assessment of Established and Emerging Blood Components for Transfusion

“…Multiple groups have reported significantly lower hemolysis in units from premenopausal female donors when compared to donations from other donor populations [256, 261, 262, 265]. A number of theories have been suggested to explain this trend, based on known physiological differences between aging male and female blood donors and their circulating RBCs [261, 266, 267].…”

“…A number of theories have been suggested to explain this trend, based on known physiological differences between aging male and female blood donors and their circulating RBCs [261, 266, 267]. It has been suggested that a decrease in the surface area to cell volume ratio of circulating RBCs results in an increase in the osmotic fragility of circulating RBCs in older individuals [259].…”

Mortality after red blood cell transfusions from previously pregnant donors: complexities in the interpretation of large data

“…These data suggest a biologic mechanism affected by both gender as well as age. A recent study reported an association between male gender and increased RBC susceptibility to hemolysis in a murine model (7). These data suggest a potential mechanism given that sex-hormone levels wane with advancing age.…”

“…Post-injury hyperfibrinolysis and fibrinolysis shutdown are both associated with mortality in a U-shaped distribution (10). In addition to being young and male, the patients who die tend to have higher injury scale scores, are the recipients of more blood products and have higher rates of massive transfusion (7). In a recent prospective observational study of mortality risk factors in trauma patients, in which 88% of the trauma patients were young and male, persistent fibrinolysis shutdown and hyperfibrinolysis were both highly associated, independent risk factors for late mortality (11).…”

The effects of storage of red blood cells on the development of postoperative infections after noncardiac surgery

“…An observation, possibly related, is that blood from male donors older than 30 years or female donors older than 45 years exhibits increased susceptibility to hemolysis. 46 If confirmed, this would add to the list of potential confounders. However, in our study, RBCs from older donors were equally distributed in both groups (50/101 fresh blood group vs. 50/98 for old blood group, p 5 0.88).…”