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.
Highlights
Sickle cell disease (SCD) is one of the most frequent autosomal recessive genetic disorder that affects about 3.2 million people worldwide [1, 2]
It has been recently shown that medium/large Extracellular vesicles (EV) (m/lEVs) released during red cell storage, can trigger coagulation activation through the canonical intrinsic pathway and through the activation of a non-canonical pathway in which Kalikrein directly activates factor IX leading to thrombin generation [135]. This observation suggests that red blood cells (RBCs)-derived m/lEVs could be more efficient than platelet-derived m/lEVs in coagulation activation, but whether m/lEVs produced in the plasma of SCD patients exhibit similar biological properties remains unknown
Structural characteristics and biological properties of EVs vary according to triggering factors [138, 139], we designed studies aiming at analyzing the biological properties of m/lEVs directly isolated from SCD patients in various clinical conditions. In these more pathophysiological relevant conditions, we have shown that m/lEVs isolated from patients at steady state induced ICAM-1 expression in cultured endothelial cells and thereby increased the adhesion of neutrophils [140]
Summary
Sickle cell disease (SCD) is one of the most frequent autosomal recessive genetic disorder that affects about 3.2 million people worldwide [1, 2]. Enhanced autooxidation of HbS induces the production of reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide and hydroxyl radical as well as the release of heme from sickle RBCs [25, 26, 42] Another significant source of ROS is related to the repeated episodes of ischemia-reperfusion occurring during repeated vaso-occlusive events and inducing high plasma levels of xanthine oxidase and NADPH oxidase [27, 28]. Enhanced oxidative stress may lead to endothelial damages through peroxidation of the lipid membrane and/or DNA fragmentation and cellular apoptosis [33] and has been linked to vascular alterations in SCD patients [34]. Activation of neutrophils, one of the blood cell type playing a key role in vaso-occlusive process [16], by heme induces the formation of neutrophil extracellular
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