Thrombosis and sickle cell disease De Franceschi, Lucia; Cappellini, Maria Domenica; Olivieri, Oliviero
Seminars in thrombosis and hemostasis,
04/2011, Letnik:
37, Številka:
3
Journal Article
Recenzirano
Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin, which has the unique property of polymerizing when deoxygenated. The pathophysiology of acute and chronic clinical ...manifestations of SCD have shown the central role of dense, dehydrated red cells in acute and chronic clinical manifestations of this pathology. Recent studies have indicated that SCD is characterized by a hypercoagulable state that contributes to the vaso-occlusive events in microcirculation, leading to acute and chronic sickle cell-related organ damage. This review discusses, in the context of SCD, (1) abnormalities in the coagulation system, (2) perturbation of platelet activation and aggregation, (3) vascular endothelial dysfunction, (4) the contribution of cell inflammatory responses, and (5) the connection with nitric oxide metabolism. We also review the available studies on the therapeutic approaches in clinical management of hypercoagulability in SCD.
The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of ...transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.
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•Genetic disruption of NCOA4 causes ferritin accumulation in tissues•NCOA4 deficiency blocks iron mobilization from ferritin storage and induces anemia•NCOA4-null mice are hypersensitive to iron overload
NCOA4 is crucial for autophagic ferritin degradation. Bellelli et al. find that genetic disruption of NCOA4 causes ferritin accumulation in tissues and defective iron mobilization from storage. NCOA4-null mice display impaired erythropoiesis associated with microcytic and hypochromic anemia, which is more pronounced in mice fed an iron-depleted diet.
Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a ...pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34+ cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
•Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may involve pseudohyperkalemia and perinatal edema.•This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.
Sickle cell disease (SCD) is an inherited red blood cell disorder with a worldwide prevalence. Acute vaso-occlusive crisis (VOC) is the main cause of hospitalization in patients with SCD. Growing ...evidence highlights the key role of inflammatory vasculopathy in both acute and chronic SCD related clinical manifestations. In a humanized mouse model for SCD, we found an increase of vWF activity and a reduction in ADAMTS13/vWF activity ratio similar to that observed in the human counterpart. rADAMTS13 was administered to humanized SCD mice before exposure to hypoxia/reoxygenation (H/R) stress as model of VOC. In SCD mice, rADAMTS13 reduced H/R induced hemolysis and systemic and local inflammation in lungs and kidneys. rADAMTS13 also diminished H/R induced worsening of inflammatory vasculopathy, reducing local nitric oxidase synthase expression. Collectively, our data provide for the first-time evidence that pharmacologic treatment with rADAMTS13 (TAK-755) diminished H/R induced sickle cell related organ damage. Thus, rADAMTS13 might be considered as a potential effective disease-modifying treatment option for sickle cell related acute events.
The human meniscus plays a crucial role for transmission and distribution of load across the knee, as well as shock absorption, joint stability, lubrication, and congruity. The aim of this study was ...to compare the complex geometry, and unique ultrastructure and tissue composition of the meniscus in healthy (control) and pathological conditions to provide understanding of structural changes that could be helpful in the future design of targetted therapies and improvement of treatment indications. We analyzed meniscus samples collected from 3 healthy multi-organ donors (median age, 66 years), 5 patients with traumatic meniscal tear (median age, 41 years) and 3 patients undergoing total knee replacement (TKR) for end-stage osteoarthritis (OA) (median age, 72 years). We evaluated the extracellular matrix (ECM) organization, the appearance and distribution of areas of calcification, and modifications of cellular organization and structure by electron microscopy and histology. The ECM structure was similar in specimens from traumatic meniscus tears compared to those from patients with late-stage OA, showing disorganization of collagen fibers and increased proteoglycan content. Cells of healthy menisci showed mainly diffuse chromatin and well preserved organelles. Both in traumatic and in OA menisci, we observed increased chromatin condensation, organelle degeneration, and cytoplasmic vacuolization, a portion of which contained markers of autophagic vacuoles. Areas of calcification were also observed in both traumatic and OA menisci, as well as apoptotic-like features that were particularly prominent in traumatic meniscal tear samples. We conclude that meniscal tissue from patients with traumatic meniscal injury demonstrate pathological alterations characteristic of tissue from older patients undergoing TKR, suggesting that they have high susceptibility to develop OA.
Oxidative events involving band 3 (Anion Exchanger 1) have been associated with RBC (red blood cell) removal through binding of NAbs (naturally occurring antibodies); however, the underlying ...mechanism has been only partially characterized. In addition to inducing direct membrane protein oxidative modification, oxidative treatment specifically triggers the phosphorylation of band 3 tyrosine residues. The present study reports that diamide, a thiol group oxidant, induces disulfide cross-linking of poorly glycosylated band 3 and that the oligomerized band 3 fraction is selectively tyrosine phosphorylated both in G6PD (glucose-6-phosphate dehydrogenase)-deficient and control RBCs. This phenomenon is irreversible in G6PD-deficient RBCs, whereas it is temporarily limited in control RBCs. Diamide treatment caused p72 Syk phosphorylation and translocation to the membrane. Diamide also induced p72 Syk co-immunoprecipitation with aggregated band 3. Moreover, following size-exclusion separation of Triton X-100-extracted membrane proteins, Syk was found only in the high-molecular-mass fraction containing oligomerized/phosphorylated band 3. Src family inhibitors efficiently abrogated band 3 tyrosine phosphorylation, band 3 clustering and NAbs binding to the RBC surface, suggesting a causal relationship between these events. Experiments performed with the non-permeant cross-linker BS(3) (bis-sulfosuccinimidyl-suberate) showed that band 3 tyrosine phosphorylation enhances its capability to form large aggregates. The results of the present study suggest that selective tyrosine phosphorylation of oxidized band 3 by Syk may play a role in the recruitment of oxidized band 3 in large membrane aggregates that show a high affinity to NAbs, leading to RBC removal from the circulation.
Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. ...Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases.
By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used β-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters.
Hemopexin treatment is a promising novel therapy to protect against heme-induced cardiovascular dysfunction in hemolytic disorders.
Terminal erythroid differentiation is the process during which proerythroblasts differentiate to produce enucleated reticulocytes. Although it is well established that during murine erythropoiesis in ...vivo, 1 proerythroblast undergoes 3 mitosis to generate sequentially 2 basophilic, 4 polychromatic, and 8 orthochromatic erythroblasts, currently there is no method to quantitatively monitor this highly regulated process. Here we outline a method that distinguishes each distinct stage of erythroid differentiation in cells from mouse bone marrow and spleen based on expression levels of TER119, CD44, and cell size. Quantitative analysis revealed that the ratio of proerythroblasts:basophilic:polychromatic:orthromatic erythroblasts follows the expected 1:2:4:8 ratio, reflecting the physiologic progression of terminal erythroid differentiation in normal mice. Moreover, in 2 stress erythropoiesis mouse models, phlebotomy-induced acute anemia and chronic hemolytic anemia because of 4.1R deficiency, the ratio of these erythroblast populations remains the same as that of wild-type bone marrow. In contrast, in anemic β-thalassemia intermedia mice, there is altered progression which is restored to normal by transferrin treatment which was previously shown to ameliorate the anemic phenotype. The means to quantitate in vivo murine erythropoiesis using our approach will probably have broad application in the study of altered erythropoiesis in various red cell disorders.
•The study establishes a reliable method to quantify differentiating mouse erythroblasts and to monitor terminal mouse erythropoiesis in vivo.•Quantitative analysis of erythropoiesis of thalassemia mice revealed stage-specific changes in terminal erythroid differentiation.
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