Défaillance hépatique aiguë dans la drépanocytose à l'âge adulte (analyse de 7 observations)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation.: HU inhibits Lu/BCAM phosphorylation in sickle RBCs

International audienceSickle cell disease is characterized by painful vaso-occlusive crises during which abnormal interactions between erythroid adhesion molecules and vessel-wall proteins are thought to play a critical role. Hydroxyurea, the only drug with proven benefit in sickle cell disease, diminishes these interactions, but its mechanism of action is not fully understood. We report that, under hydroxyurea, expression of the unique erythroid laminin receptor Lu/BCAM was increased, but red blood cell adhesion to laminin decreased. Because Lu/BCAM phosphorylation is known to activate cell adhesion to laminin, it was evaluated and found to be dramatically lower in hydroxyurea-treated patients. Analysis of the protein kinase A pathway showed decreased intracellular levels of the upstream effector cyclic adenosine monophosphate during hydroxyurea treatment. Using a cellular model expressing recombinant Lu/BCAM, we showed that hydroxyurea led to decreased intracellular cyclic adenosine monophosphate levels and diminished Lu/BCAM phosphorylation and cell adhesion. We provide evidence that hydroxyurea could reduce abnormal sickle red blood cell adhesion to the vascular wall by regulating the activation state of adhesion molecules independently of their expression level

Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell disease

International audienceBACKGROUND: Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises. DESIGN AND METHODS: Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells. RESULTS: Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α(4)β(1) integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients. CONCLUSIONS: Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α(4)β(1) integrin on peripheral blood mononuclear cells

Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death

International audienceBackground: Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in sickle cell disease (SCD) characterized by recurrence of disease complications, recipient red blood cell (RBC) destruction, and frequently no detectable antibody. Phosphatidylserine (PS) exposure signs suicidal RBC death or eryptosis and is involved in vasoocclusive crisis (VOC).Study design and methods: Transfusion was monitored in 48 SCD patients for up to 20 days. PS exposure was evaluated in vivo on patient RBCs (PS-RBCs) at five time points and in vitro after incubation of donor RBCs with pretransfusion plasma.Results: Three VOC patients displayed DHTR with recurrent SCD features and no detectable antibody in two cases. In vitro, PS-RBC percentage was significantly increased by incubating donor RBCs with pretransfusion plasma samples from DHTR patients with no detectable antibody. No such increase was observed with samples from other patients. This result indicates that donor RBCs may be damaged by the environment of SCD patients, increasing the physiologic clearance of apoptotic RBCs. In vivo, PS-RBC percentage increased in all three cases after destruction of transfused RBCs, indicating that DHTR induces PS-RBCs and, possibly, subsequent VOC and autologous RBC destruction.Conclusion: This study clearly demonstrates that DHTR can occur in the absence of detectable antibody. In these cases, a mechanism of excessive eryptosis is proposed

Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell disease

Background Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises. Design and Methods Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells. Results Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α4β1 integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients. Conclusions Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α4β1 integrin on peripheral blood mononuclear cells. Key words: α4β1, Lu/BCAM, sickle cell disease, aggregates. disease. Haematologica 2010;95(11):1841-1848. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Chaar V, Picot J, Renaud O, Bartolucci P, Nzouakou R, Bachir D, Galactéros F, Colin Y, Le Van Kim C, and El Nemer W. Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell Aggregation of mononuclear and red blood cells through an α4β1-Lu/basal cell adhesion molecule interaction in sickle cell diseas