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THE EFFECT OF SICKLE HEMOGLOBIN MUTATION ON RED BLOOD CELL STORAGE INTEGRITY AND POST TRANSFUSION VIABILITY

Osei-Hwedieh, David (2015) THE EFFECT OF SICKLE HEMOGLOBIN MUTATION ON RED BLOOD CELL STORAGE INTEGRITY AND POST TRANSFUSION VIABILITY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Red blood cells (RBCs) undergo progressive changes in storage, collectively referred to as the storage lesion that is associated with increases in storage and post-transfusion hemolysis. Transfusion of blood at the limits of approved storage time is associated with lower RBC post-transfusion recovery and hemolysis, which increases plasma levels of cell-free hemoglobin and iron, proposed to induce endothelial dysfunction and impair host defense, respectively. Of relevance to this study, there is noted variability among donors in the intrinsic rate of storage changes and in RBC post-transfusion recovery, suggesting that genetic determinants modulate this process. Here, I test a common genetic variable in our donor pool, sickle cell trait, present in about 8% of African Americans. Using banked human RBCs and those from a humanized transgenic sickle cell mouse, I show that sickle cell trait in both species produces storage time-dependent reductions in osmotic fragility and membrane deformability, increased storage hemolysis, and significantly reduced post-transfusion recovery in mice. Furthermore, the underlying mechanism of reduced HbAS RBC post-transfusion recovery is unrelated to macrophage uptake, reticulo-endothelial system or intravascular hemolysis, but rather by RBC intravascular sequestration in the spleen, kidney and liver. Collectively, these findings indicate that changes in HbAS RBC membrane deformability properties that are aggravated during storage lead to enhanced mechanical entrapment in tissues and rapid clearance of transfused HbAS RBCs from the circulation. These preclinical studies raise provocative questions about the use of blood from sickle cell trait individuals, particularly at the limits of approved storage.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Osei-Hwedieh, Daviddoo8@pitt.eduDOO80000-0002-7695-9643
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFreeman, Bruce A.freerad@pitt.eduFREERAD
Thesis AdvisorGladwin, Mark Tgladwinmt@upmc.eduMTG16
Committee MemberLee, Janet S.jsl26@pitt.eduJSL26
Committee MemberBinder, Robert J.rjb42@pitt.eduRJB42
Committee MemberGuillermo, Romeroggr@pitt.eduGGR
Date: 11 December 2015
Date Type: Publication
Defense Date: 2 November 2015
Approval Date: 11 December 2015
Submission Date: 11 December 2015
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 113
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Red Blood Cell Sickle Cell Trait Sickle Cell Disease Red Blood Cell Mutation Hemoglobinopathy Red Blood Cell Storage Red Blood Cell Transfusion Malaria
Date Deposited: 11 Dec 2015 21:21
Last Modified: 19 Dec 2016 14:43
URI: http://d-scholarship.pitt.edu/id/eprint/26660

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