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(Unpublished)
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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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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: |
11 Dec 2020 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/26660 |
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