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Title: Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders

Abstract

In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into themore » pathogenic role of human spleen in RBC diseases.« less

Authors:
 [1]; ORCiD logo [1];  [1];  [2]; ORCiD logo [3];  [1];  [4]
  1. Brown Univ., Providence, RI (United States). Div. of Applied Mathematics
  2. Institut National de la Transfusion Sanguine, Paris (France). Faculte´ de Me´decine Universite´ Paris Descartes
  3. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Materials Science and Engineering
  4. Nanyang Technological Univ. (Singapore)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Argonne National Lab. (ANL), Argonne, IL (United States); UT-Battelle LLC/ORNL, Oak Ridge, TN (Unted States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1565683
Grant/Contract Number:  
AC02-06CH11357; AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 38; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology

Citation Formats

Li, He, Lu, Lu, Li, Xuejin, Buffet, Pierre A., Dao, Ming, Karniadakis, George E., and Suresh, Subra. Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders. United States: N. p., 2018. Web. doi:10.1073/pnas.1806501115.
Li, He, Lu, Lu, Li, Xuejin, Buffet, Pierre A., Dao, Ming, Karniadakis, George E., & Suresh, Subra. Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders. United States. doi:10.1073/pnas.1806501115.
Li, He, Lu, Lu, Li, Xuejin, Buffet, Pierre A., Dao, Ming, Karniadakis, George E., and Suresh, Subra. Thu . "Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders". United States. doi:10.1073/pnas.1806501115. https://www.osti.gov/servlets/purl/1565683.
@article{osti_1565683,
title = {Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders},
author = {Li, He and Lu, Lu and Li, Xuejin and Buffet, Pierre A. and Dao, Ming and Karniadakis, George E. and Suresh, Subra},
abstractNote = {In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into the pathogenic role of human spleen in RBC diseases.},
doi = {10.1073/pnas.1806501115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 38,
volume = 115,
place = {United States},
year = {2018},
month = {9}
}

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