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Transfusion. 2016 Oct;56(10):2571-2583. doi: 10.1111/trf.13745. Epub 2016 Aug 9.

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

Author information

1
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. tak77@pitt.edu.
2
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. tak77@pitt.edu.
3
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
5
Canadian Blood Services, Centre for Innovation, Edmonton, Alberta, Canada.
6
Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
7
Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington.
8
Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, Washington.
9
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

BACKGROUND:

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. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established.

STUDY DESIGN AND METHODS:

We 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.

RESULTS:

An 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.

CONCLUSION:

Our 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.

PMID:
27507802
PMCID:
PMC5065383
DOI:
10.1111/trf.13745
[Indexed for MEDLINE]
Free PMC Article

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