Journal
BLOOD ADVANCES
Volume 2, Issue 20, Pages 2581-2587Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2018024562
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Funding
- Fonds dedie Combattre les maladies parasitaires, Sanofi Aventis-Ministere de l'Enseignement Superieur et de la Recherche-Institut Pasteur
- Centre National de la Recherche Scientifique
- Institut Pasteur
- Region Ile de France
- Delegation Generale a l'Armement [056000032]
- European Union [242095]
- project Mechanisms of Erythrocytic Infection and Anemia in Malaria
- National Institutes of Health, National Heart, Lung, and Blood Institute [5P01HL078826-06]
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [DK26263]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL078826] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK026263, R01DK026263] Funding Source: NIH RePORTER
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The current paradigm in the pathogenesis of several hemolytic red blood cell disorders is that reduced cellular deformability is a key determinant of splenic sequestration of affected red cells. Three distinct features regulate cellular deformability: membrane deformability, surface area-to-volume ratio (cell sphericity), and cytoplasmic viscosity. By perfusing normal human spleens ex vivo, we had previously showed that red cells with increased sphericity are rapidly sequestered by the spleen. Here, we assessed the retention kinetics of red cells with decreased membrane deformability but without marked shape changes. A controlled decrease in membrane deformability (increased membrane rigidity) was induced by treating normal red cells with increasing concentrations of diamide. Following perfusion, diamide-treated red blood cells (RBCs) were rapidly retained in the spleen with a mean clearance half-time of 5.9 minutes (range, 4.0-13.0). Splenic clearance correlated positively with increased membrane rigidity (r = 0.93; P < 0001). To determine to what extent this increased retention was related to mechanical blockade in the spleen, diamidetreated red cells were filtered through microsphere layers that mimic the mechanical sensing of red cells by the spleen. Diamide-treated red cells were retained in the microsphilters (median, 7.5%; range, 0%-38.6%), although to a lesser extent compared with the spleen (median, 44.1%; range, 7.3%-64.0%; P < .0001). Taken together, these results have implications for understanding the sensitivity of the human spleen to sequester red cells with altered cellular deformability due to various cellular alterations and for explaining clinical heterogeneity of RBC membrane disorders.
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