Plasma annexin A5 and microparticle phosphatidylserine levels are elevated in sickle cell disease and increase further during painful crisis

Tits, L.J.H. van; Heerde, Waander L. van; Landburg, Precious Pearl; Boderie, M.J.; Muskiet, Frits A. J.; Jacobs, Natalie L.; Duits, Ashley J.; Schnog, John‐John B.

doi:10.1016/j.bbrc.2009.09.102

Cited by 52 publications

(48 citation statements)

References 29 publications

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“…This supports previous reports of increased cell-free heme in SCD plasma (4 to 30 mM) vs controls (0.2 to 2 mM), with largely predominant erythrocyte MPs. 4,[30][31][32][33] Cryogenic transmission electron microscopy confirmed the vesicular nature of the material pelleted out of plasma by ultracentrifugation ( Figure 1A inset; supplemental Figure 2). FACS confirmed the near complete removal of MPs ( Figure 1A; .80% in SCD; P , .01).…”

Section: Resultsmentioning

confidence: 81%

“…28 MP levels are 3-to 10-fold higher in SCD patients during steady state than in healthy control subjects under steady-state conditions, 4,[29][30][31] and further increased 0.3-to 3-fold during VOC. [32][33][34] SCD MPs are mostly of red blood cell (RBC) origin 4,[30][31][32][33] and may be produced through accelerated aging of sickle cells during oxygenation/deoxygenation cycles, 28 under the influence of stress factors 35,36 and matrix proteins, 20 or during hemolysis in capillary beds.…”

Section: Introductionmentioning

confidence: 99%

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Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease

Camus

Moraes

Bonnin

et al. 2015

Blood

220

278

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International audienceIntravascular hemolysis describes the relocalization of heme and hemoglobin (Hb) from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MPs) concentrate cell-free heme in human hemolytic diseases, and that hemeladen MPs have a physiopathological impact. Up to one-third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MPs. Erythrocyte vesiculation in vitro produced MPs loaded with heme. In silico analysis predicted that externalized phosphatidylserine (PS) in MPs may associate with and help retain heme at the cell surface. Immunohistology identified Hb-laden MPs adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MPs adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of hemeladen MPs triggered rapid vasoocclusions in kidneys and compromised microvascular dilation ex vivo. These vascular effects were largely blocked by heme-scavenging hemopexin and by the PS antagonist annexin-a5, in vitro and in vivo. Adversely remodeled MPs carrying heme may thus be a source of oxidant stress for the endothelium, linking hemolysis to vascular injury. This pathway might provide new targets for the therapeutic preservation of vascular function in SCD

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Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease

Camus

Moraes

Bonnin

et al. 2015

Blood

220

278

View full text Add to dashboard Cite

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“…Moreover, the disease is associated to an hypercoagulable and pro-inflammatory state as well as endothelial dysfunction. 4 Previous studies reported an increase in circulating microparticle concentration in SCA adults compared to healthy controls in steady-state condition, 5,6 as well as in crisis. 7 Fetal hemoglobin (HbF) level, a widely recognized modulator of SCA severity, 8 declines rapidly during the neonatal period.…”

Section: Introductionmentioning

confidence: 96%

Fetal hemoglobin and hydroxycarbamide moduate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children

Nebor¹,

Romana²,

Santiago³

et al. 2013

Haematologica

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Design and Methods SubjectsThe study included 62 consecutive SCA children followed either at the Sickle Cell Disease Reference Centres of the University Hospital of Pointe-à-Pitre, Guadeloupe (n=41) and of the Robert Debré Mother and Child University Hospital in Paris (n=21), France. Overall, 27 boys and 35 girls between 2 months and 16 years of age were included. All children were at steadysate, i.e. free of any acute events for one month prior to blood sampling and transfusion-free for at least three months prior to blood sampling. Among the 62 children, 49 had never received HC and 13 had been treated with HC for at least six months at the time of the study, with an average dose of 21.8±3.2 mg/kg per day. This latter group was compared to a control group composed of 26 SCA children matched for sex and age, selected from the 49 SCA children untreated by HC. All the children's parents provided their written consent before inclusion in the study which had been approved by the ethical committees from Guadeloupe and Paris.

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“…[5][6][7][8] Circulating MP levels in SCD patients may also increase 0.3-to 3-fold during VOCs versus steady-state. [9][10][11] In steady-state SCD, MPs are mostly of erythrocyte origin, but they can also originate from platelets, 5 endothelial cells, and leukocytes during VOCs. 6,8,9,11 Erythrocyte MPs are generally assumed to be a consequence of intravascular erythrocyte vesiculation in SCD, in possible connection with hemolysis, but the precise molecular regulation of intravascular hemolysis and MP shedding remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease

Camus

Gausserès

Bonnin

et al. 2012

Blood

120

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Patients with sickle cell disease suffer from painful crises associated with disseminated vaso-occlusions, increased circulating erythrocyte microparticles (MPs), and thrombospondin-1 (TSP1). MPs are submicron membrane vesicles shed by compromised or activated cells. We hypothesized that TSP1 mediates MP shedding and participates in vaso-occlusions. We injected TSP1 to transgenic SAD mice with sickle cell disease and characterized circulating phosphatidylserine؉ MPs by FACS. TSP1 stimulated MPs in plasma and initiated vaso-occlusions within minutes. In vitro, TSP1 triggered rapid erythrocyte conversion into spicule-covered echinocytes, followed by MP shedding. MP shedding was recapitulated by peptides derived from the TSP1 carboxyterminus. We purified MPs shed by erythrocytes in vitro and administered them back to SAD mice. MPs triggered immediate renal vaso-occlusions. In vitro, MPs triggered the production of radical oxygen species by endothelial monolayers, favored erythrocyte adhesion, and induced endothelial apoptosis. MPs also compromised vasodilation in perfused microvessels. These effects were inhibited by saturating MP phosphatidylserine with annexin-V, or with inhibitors of endothelial ROS production. We conclude that TSP1 triggers erythrocyte MP shedding. These MPs induce endothelial injury and facilitate acute vaso-occlusive events in transgenic SAD mice. This work supports a novel concept that toxic erythrocyte MPs may connect sickle cell anemia to vascular disease. (Blood. 2012;120(25): 5050-5058) IntroductionSickle cell disease (SCD) is a form of hemolytic anemia that results from a point mutation (HbS) in the gene of the globin ␤-chain. The mutation makes HbS susceptible to polymerize during hypoxic stress, producing long intracellular fibers that are responsible for drastic membrane and cytoskeletal remodeling. The HbS fibers polymerize and depolymerize in response to blood oxygenation and deoxygenation cycles. The repeated changes in red blood cell (RBC) shape cause a permanent loss of the biconcave phenotype, producing condensed cells with diverse degrees of crenation, and covered in cone-shaped membrane figures known as spicules. [1][2][3] The remodeled erythrocytes become progressively dehydrated and rigid. Fully and irreversibly remodeled erythrocytes are termed sickle erythrocytes with respect to their ultimate shape.Sickle erythrocytes display a strong predisposition to adhere to the endothelium, get trapped in small capillaries and reduce blood flow. Highly vascularized organs, such as kidneys, bones, and lungs are the seat of disseminated vascular occlusions and recurrent ischemic injury. 4 In some of these organs, ischemia causes extremely painful episodes termed vaso-occlusive crises (VOCs). These crises are attributed to stress factors, such as hypoxia, physical exercise, infection, trauma, or stress. However, the molecular basis for the development of vaso-occlusions in SCD has yet to be explained and several different triggers of VOCs may exist.After getting trapped in capillaries,...

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Plasma annexin A5 and microparticle phosphatidylserine levels are elevated in sickle cell disease and increase further during painful crisis

Cited by 52 publications

References 29 publications

Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease

Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease

Fetal hemoglobin and hydroxycarbamide moduate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children

Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease

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