Lydian A. de Ligt

Sickle cell disease (SCD) is a chronic inflammatory state, characterized by increased plasma values of inflammatory and angiogenic proteins. Although red blood cell (RBC) transfusion is known to have immunomodulatory effects in other conditions, its potential effects on the inflammatory state in SCD remain largely unknown. This study aimed to explore the longitudinal effects of RBC transfusion on plasma inflammatory and angiogenic proteins in chronically transfused patients with SCD. Plasma samples were collected from SCD patients treated with either exchange ( N = 12) or top‐up ( N = 12) transfusion prior to transfusion and 1 h, 24–72 h, 1 and 2 weeks post‐transfusion. Proximity Extension Assay technology was used to measure plasma values of 21 proteins at each of these timepoints. Exchange transfusion resulted in decreased values of proteins released during inflammasome activation (IL‐1β, IL‐18), B cell survival and activation (TNFRSF13B/TACI, TNFRSF13C/BAFFR, TNFSF13/APRIL), angiogenesis (ANGPT2, VEGFA, KDR, CXCL12), and neutrophil differentiation, recruitment and activation (G‐CSF, G‐CSFR, CXCL1, CXCL5, CXCL6), at 1 h post‐transfusion, returning gradually to values comparable to pre‐transfusion values during 2 weeks post‐transfusion. In contrast, top‐up transfusion resulted in increased values of EPO and ANGPT1. While exchange transfusion seems to reduce the activation of pro‐inflammatory and pro‐angiogenic pathways, top‐up transfusion might result in reduced hypoxia and increased vascular stability as suggested by the increased values of EPO and ANGPT1. These results enhance our understanding of the effects of RBC transfusion on inflammatory and angiogenic pathways and suggest that exchange transfusion has a stronger effect on these pathways in SCD patients compared to top‐up transfusion.

Summary: In this study, we aimed to explore the inflammatory and angiogenic pathways in sickle cell disease (SCD). We used proximity extension assay technology (Olink) to measure 92 plasma proteins involved in inflammation and angiogenesis. Plasma samples were collected from 57 SCD patients (sickle cell anaemia/HbS‐β⁰ thalassaemia‐thalassaemia) in steady‐state and 13 healthy ethnicity‐matched healthy controls (HCs). From 15 patients, paired samples were collected during both steady‐state and vaso‐occlusive episodes (VOEs) and from 23 SCD patients longitudinal samples were collected before and after treatment with either voxelotor (n = 10), hydroxyurea (n = 8) or allogeneic haematopoietic stem‐cell transplantation (n = 5). Fifty plasma proteins were differentially expressed in steady‐state SCD patients as compared to HC. These included proteins involved in angiogenesis (i.e. ANGPT1, ANGPT2 and VEGFA), the IL‐18 signalling pathway (i.e. IL‐6, IL‐10, IL‐18), T‐cell activation (i.e. LAG3, PDCD1) and natural killer (NK)‐cell activation (CD244, NCR1, GZMB). While proteins involved in angiogenesis and the IL‐18 signalling pathway were further upregulated during VOE, levels of several proteins involved in the IL‐18 pathway, T‐cell and NK‐cell activation and angiogenesis, restored towards levels detected in HCs after curative or disease‐modifying treatment. These findings might contribute to a better understanding of SCD pathophysiology and identifying potential new targets for therapeutic interventions.

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic hemolytic anemia and recurrent microvascular occlusions, resulting in acute painful events and progressive organ damage. Although primarily a red blood cell disorder, the pathophysiology of SCD is increasingly characterized as a complex interplay between several different cell types and cellular processes. Evidence is accumulating that neutrophils are phenotypically different in SCD and have a significant contribution in the pathophysiology of the disease. In this review, we summarize the currently available evidence on the role of neutrophils in SCD pathophysiology, demonstrating that neutrophils in SCD have an activated phenotype and play an important role in vaso‐occlusion and inflammation in SCD. Activation of neutrophils in SCD is primarily driven by hemolysis and ischemia–reperfusion injury. The ameliorating effects of treatments, for example, hydroxyurea, might be partly mediated by decreasing neutrophil counts and reversing the pro‐inflammatory properties. Whether the novel anti‐sickling therapies, reducing hemolysis, have an anti‐inflammatory effect on neutrophils, remains to be elucidated.