Retention of poorly deformable red blood cells (RBCs
IntroductionRetention of poorly deformable red blood cells (RBCs) by the human spleen has been recognized as a critical determinant of pathogenesis of several RBC disorders, including hereditary spherocytosis and malaria. The severity of hereditary spherocytosis (HS), a syndrome resulting from mutations of RBC membrane proteins, 1 is related to the extent of decreased membrane surface area. Splenic retention is the dominant mechanism responsible for reduced life span of HS-RBCs, such that splenectomy is beneficial in reducing anemia in symptomatic HS patients. 1 Changes of RBC mechanical properties have also been observed in blood stored for 3 weeks or longer. 2 Prolonged storage influences the survival of RBCs after transfusion 3 and probably contributes to transfusion-related side effects, including respiratory distress and systemic sepsis. [3][4][5] Not least, the deformability of Plasmodium falciparum-infected red blood cells (Pf-RBCs) is also central in malaria pathogenesis. It progressively decreases as P falciparum matures in its host RBCs, from rings (ring-RBCs) 6 to trophozoites and then to schizonts. 7,8 When mature stages are sequestered in small vessels, they escape retention in the spleen. Ring-RBCs only rarely adhere to endothelial cells 9 and are found in the peripheral blood circulation. 10,11 We recently showed that a fraction of ring-RBCs is retained in isolated-perfused human spleens. 12 Ring-RBCs accumulated upstream from interendothelial slits, a spleen-specific microanatomic structure that retains RBCs with reduced deformability (rigid-RBCs). [13][14][15] In brief, in malaria as in several other RBC disorders, extensive RBC retention in the spleen is associated with anemia, 1,16,17 whereas impaired retention potentially favors adverse events, such as acute microvascular obstruction in malaria patients, 18,19 late vascular disorders in splenectomized patients with HS or thalassemia, 20,21 and acute organ dysfunction in critically ill patients transfused with "older" blood. 4 Exploration of how the human spleen senses poorly deformable RBCs would be facilitated by a physiologically relevant in vitro approach simpler than the ex vivo spleen perfusion system. To experimentally replicate the mechanical sensing of RBC by the splenic microcirculation, we first analyzed the fine structure of interendothelial slits in the human spleen. We realized that the geometry of narrow and short interendothelial slits would be accurately mimicked by spaces between microbeads. We then allowed RBCs to flow through a The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on April 8, 2019. by guest www.bloodjournal.org From mixture of 5-to 25-m-diameter microbeads. Heated RBCs, Pf-RBCs, and RBCs from patients with HS were retained in the microbead layer without hemolysis. The r...
