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

Transfusion - Tập 56 Số 10 - Trang 2571-2583 - 2016
Tamir Kanias1,2, Derek Sinchar2, David O. Osei-Hwedieh2, Jeffrey Baust2, Andrew Jordan3,4, James C. Zimring5,6,7, Hayley R. Waterman5, Karen S. de Wolski5, Jason P. Acker3,4, Mark T. Gladwin1,2
1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
2Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
3Canadian Blood Services, Centre for Innovation, Edmonton, Alberta, Canada
4Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
5Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington
6Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington.
7Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, Washington

Tóm tắt

BACKGROUNDRed 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. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established.STUDY DESIGN AND METHODSWe studied sex differences in storage or stress‐induced hemolysis in RBC units from the United States and Canada in 22 inbred mouse strains and in patients with sickle cell disease (SCD) using measures of hemolysis in 315 patients who had homozygous SS hemoglobin from the Walk‐PHASST cohort. A mouse model also was used to evaluate posttransfusion recovery of stored RBCs, and gonadectomy was used to determine the mechanisms related to sex hormones.RESULTSAn analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis compared with females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in patients with SCD. The sex difference is intrinsic to the RBC and is not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and posttransfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress.CONCLUSIONOur findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and SCD and establishing a role for donor genetic variables in the viability of stored RBCs and in human hemolytic diseases.

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Transfusion

Tập 56 Số 10

2571-2583

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