Extracellular Vesicles in Sickle Cell Disease: Plasma Concentration, Blood Cell Types Origin Distribution and Biological Properties

Abstract

Prototype of monogenic disorder, sickle cell disease (SCD) is caused by a unique single mutation in the β-globin gene, leading to the production of the abnormal hemoglobin S (HbS). HbS polymerization in deoxygenated condition induces the sickling of red blood cells (RBCs), which become less deformable and more fragile, and thus prone to lysis. In addition to anemia, SCD patients may exhibit a plethora of clinical manifestations ranging from acute complications such as the frequent and debilitating painful vaso-occlusive crisis to chronic end organ damages. Several interrelated pathophysiological processes have been described, including impaired blood rheology, increased blood cell adhesion, coagulation, inflammation and enhanced oxidative stress among others. During the last two decades, it has been shown that extracellular vesicles (EVs), defined as cell-derived anucleated particles delimited by a lipid bilayer, and comprising small EVs (sEVs) and medium/large EVs (m/lEVs); are not only biomarkers but also subcellular actors in SCD pathophysiology. Plasma concentration of m/lEVs, originated mainly from RBCs and platelets (PLTs) but also from the other blood cell types, is higher in SCD patients than in healthy controls. The concentration and the density of externalized phosphatidylserine of those released from RBCs may vary according to clinical status (crisis vs. steady state) and treatment (hydroxyurea). Besides their procoagulant properties initially described, RBC-m/lEVs may promote inflammation through their effects on monocytes/macrophages and endothelial cells. Although less intensely studied, sEVs plasma concentration is increased in SCD and these EVs may cause endothelial damages. In addition, sEVs released from activated PLTs trigger PLT-neutrophil aggregation involved in lung vaso-occlusion in sickle mice. Altogether, these data clearly indicate that EVs are both biomarkers and bio-effectors in SCD, which deserve further studies.

Extracellular Vesicles in Sickle Cell Disease: A Promising Tool

“…Indeed, similar to other tests based on blood samples, EVs quantification and characterization is less invasive than many other techniques used to directly assess biological states. Therefore, EVs could be biomarkers with a clinical utility in determining risk in several diseases, including SCD [ 9 ]. Originally described as cell dust [ 10 ], it has been shown that EVs play a role in cell-to-cell communication at both paracrine and systemic levels [ 11 , 12 ].…”

Circulating Small Extracellular Vesicles May Contribute to Vaso-Occlusive Crises in Sickle Cell Disease

“…The importance of different kinds of EVs in the pathogenesis of SCD is increasingly becoming appreciated (as reviewed by [36]). Several different roles have been documented for medium-sized EVs (microparticles) derived from red cells, monocytes, platelets, and endothelial cells [6].…”

The pathobiology of platelet and megakaryocyte extracellular vesicles: A (c)lot has changed

“…Sickle cell disease (SCD) is caused by a hemoglobin mutation, leading to the deformation of red blood cells and chronic complications including anemia, hypercoagulation, and inflammation. 55 In patients with SCD, vaso-occlusive crises can lead to pathologies such as lung injury. 56 Lung injuries in a humanized mouse model can be mediated via PEV-derived IL-1β and caspase-1, which activates platelets, neutrophils, and vascular cells, thus resulting in plateletneutrophil aggregates large enough to block pulmonary arterioles.…”

“…Sickle cell disease (SCD) is caused by a hemoglobin mutation, leading to the deformation of red blood cells and chronic complications including anemia, hypercoagulation, and inflammation 55 . In patients with SCD, vaso‐occlusive crises can lead to pathologies such as lung injury 56 .…”