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NOVEL INSIGHTS INTO SPLEEN INJURY DURING THE FIRST 2 YEARS OF LIFE IN SCA CHILDREN: A LONGITUDINAL STUDY
Author(s): ,
Sara El Hoss
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Sylvie Cochet
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Michael Dussiot
Affiliations:
INSERM UMR1163, CNRS ERL8254, Laboratoire d’excellence GR-Ex, Université René- Descartes, Imagine Institute,Paris,France
,
Mickael Marin
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Catia Pereira
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Claudine Lapoumeroulie
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Mariane De Montalembert
Affiliations:
Service de Pédiatrie Générale, Hôpital Necker-Enfants Malades, Centre de Référence de la Drépanocytose, AP-HP,Paris,France
,
Caroline Le Van Kim
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Yves Colin Aronovicz
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
,
Wassim El Nemer
Affiliations:
Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
Valentine Brousse
Affiliations:
Service de Pédiatrie Générale, Hôpital Necker-Enfants Malades, Centre de Référence de la Drépanocytose, AP-HP,Paris,France;Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles,Paris,France
(Abstract release date: 05/17/18) EHA Library. El Hoss S. 06/17/18; 214590; S1589
Sara El Hoss
Sara El Hoss
Contributions
Abstract

Abstract: S1589

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 09:00 - 09:15

Location: Room A9

Background
In sickle cell anemia (SCA), the spleen is the first organ to be injured notably because impaired deformability and/or adhesion of sickled RBCs promotes their sequestration. Moreover, acute splenic sequestration crisis (ASSC), a life-threatening complication, happens in 10-30% of SCA infants, with 75% of first cases occurring before the age of 2 years. Determinants, predictive factors and consequences of ASSC are not established. 

Aims
Our study aims to evaluate the natural history of spleen dysfunction in a cohort of 47 SCA infants enrolled at 3-6 months and longitudinally followed-up to 24 months. Specifically, we analyzed RBC deformability and adhesion properties as potential determinants of ASSC and spleen injury. 

Methods

ASSC were recorded prospectively and defined by the sudden enlargement of spleen (> 2 cm compared to basal) with a decrease of Hb level (> 2 g/dL compared to previous measurement). Blood samples were analyzed at enrollment and at 12, 18 and 24 months. Evaluation of spleen function was based on quantification of Howell Jolly Bodies (HJB) using an imaging flow cytometry (IFC) based method. Irreversibly sickled cells (ISCs) as a marker of RBC decreased deformability were quantified by IFC. Expression, activation and adhesion function of Lu/BCAM, a known erythroid marker, were quantified using flow cytometry, phosphorylation and dynamic adhesion assays.

Results

At enrollment, patients had HJB in circulation slightly higher than healthy controls (0.3% and 0.1%, respectively). Expectedly, a significant increase in HJB at 18 months (0.8%) was observed. At enrollment, there was no significant difference in HJB between infants who underwent ASSC (n=7) during the follow-up period, as compared to the group that remained both asymptomatic and ASSC-free (n=16). However, the ASSC group showed significantly higher HJB at 24 months as compared to the ASSC-free group (1.52% and 0.54%, respectively), a finding demonstrating that ASSC significantly decreases spleen function.

Exploring the role of decreased deformability of RBCs in spleen injury, we observed the presence of ISCs at enrollment (0.96%) and a significant increase in ISCs at 18 months (1.61%). Moreover, the ASSC group showed significantly higher ISCs at enrollment than the ASSC-free group (1.61% and 0.54%). Thus, ISCs appear in the circulation before the occurrence of an ASSC, indicating a potential role as a predictive marker of ASSC.

Abnormal adhesion of RBCs to the spleen matrix in the open microcirculation might be another factor causing splenic injury. In particular, the spleen is lined with laminin, a known ligand for Lu/BCAM. We observed an increase in the expression and activation of Lu/BCAM with time. Moreover, we observed a significant increase in the number of adherent RBCs on laminin-coated channels between enrollment and 24 months (990 RBCs/mm2 and 1787 RBCs/mm2, respectively). However, there was no difference with respect to Lu/BCAM adhesion, expression and activation properties when comparing the ASSC group and the ASSC-free group.

Conclusion

Our study shows that spleen dysfunction is initiated as early as 4 months of age in SCA infants. ASSC greatly contributes to spleen loss of function. Changes in RBC properties including morphology, expression and activation of Lu-BCAM are initiated very early in infancy and increase with age. Importantly, we show that ISCs are a predictive marker of ASSC. Impairment of RBC deformability rather than adhesion plays a major role in spleen trapping and thereafter loss of function.

Session topic: 27. Sickle cell disease

Keyword(s): Children, Sickle cell anemia, Spleen

Abstract: S1589

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 09:00 - 09:15

Location: Room A9

Background
In sickle cell anemia (SCA), the spleen is the first organ to be injured notably because impaired deformability and/or adhesion of sickled RBCs promotes their sequestration. Moreover, acute splenic sequestration crisis (ASSC), a life-threatening complication, happens in 10-30% of SCA infants, with 75% of first cases occurring before the age of 2 years. Determinants, predictive factors and consequences of ASSC are not established. 

Aims
Our study aims to evaluate the natural history of spleen dysfunction in a cohort of 47 SCA infants enrolled at 3-6 months and longitudinally followed-up to 24 months. Specifically, we analyzed RBC deformability and adhesion properties as potential determinants of ASSC and spleen injury. 

Methods

ASSC were recorded prospectively and defined by the sudden enlargement of spleen (> 2 cm compared to basal) with a decrease of Hb level (> 2 g/dL compared to previous measurement). Blood samples were analyzed at enrollment and at 12, 18 and 24 months. Evaluation of spleen function was based on quantification of Howell Jolly Bodies (HJB) using an imaging flow cytometry (IFC) based method. Irreversibly sickled cells (ISCs) as a marker of RBC decreased deformability were quantified by IFC. Expression, activation and adhesion function of Lu/BCAM, a known erythroid marker, were quantified using flow cytometry, phosphorylation and dynamic adhesion assays.

Results

At enrollment, patients had HJB in circulation slightly higher than healthy controls (0.3% and 0.1%, respectively). Expectedly, a significant increase in HJB at 18 months (0.8%) was observed. At enrollment, there was no significant difference in HJB between infants who underwent ASSC (n=7) during the follow-up period, as compared to the group that remained both asymptomatic and ASSC-free (n=16). However, the ASSC group showed significantly higher HJB at 24 months as compared to the ASSC-free group (1.52% and 0.54%, respectively), a finding demonstrating that ASSC significantly decreases spleen function.

Exploring the role of decreased deformability of RBCs in spleen injury, we observed the presence of ISCs at enrollment (0.96%) and a significant increase in ISCs at 18 months (1.61%). Moreover, the ASSC group showed significantly higher ISCs at enrollment than the ASSC-free group (1.61% and 0.54%). Thus, ISCs appear in the circulation before the occurrence of an ASSC, indicating a potential role as a predictive marker of ASSC.

Abnormal adhesion of RBCs to the spleen matrix in the open microcirculation might be another factor causing splenic injury. In particular, the spleen is lined with laminin, a known ligand for Lu/BCAM. We observed an increase in the expression and activation of Lu/BCAM with time. Moreover, we observed a significant increase in the number of adherent RBCs on laminin-coated channels between enrollment and 24 months (990 RBCs/mm2 and 1787 RBCs/mm2, respectively). However, there was no difference with respect to Lu/BCAM adhesion, expression and activation properties when comparing the ASSC group and the ASSC-free group.

Conclusion

Our study shows that spleen dysfunction is initiated as early as 4 months of age in SCA infants. ASSC greatly contributes to spleen loss of function. Changes in RBC properties including morphology, expression and activation of Lu-BCAM are initiated very early in infancy and increase with age. Importantly, we show that ISCs are a predictive marker of ASSC. Impairment of RBC deformability rather than adhesion plays a major role in spleen trapping and thereafter loss of function.

Session topic: 27. Sickle cell disease

Keyword(s): Children, Sickle cell anemia, Spleen

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