Inflammatory targets of therapy in sickle cell disease

Owusu-Ansah, Amma; Ihunnah, Chibueze A.; Walker, Aisha L.; Ofori-Acquah, Solomon F.

doi:10.1016/j.trsl.2015.07.001

Cited by 38 publications

(34 citation statements)

References 207 publications

(240 reference statements)

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“…[24]. Treatments targeting vascular dysfunction to prevent major organ damage are under evaluation and may have the greatest impact in adults with SCD [27].…”

Section: Mortality In Scdmentioning

confidence: 99%

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Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

2015

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Over the past 40 years, public health measures such as universal newborn screening, penicillin prophylaxis, vaccinations, and hydroxyurea therapy have led to an impressive decline in sickle cell disease (SCD)-related childhood mortality and SCD-related morbidity in high-income countries. We remain cautiously optimistic that the next 40 years will be focused on meeting current challenges in SCD by addressing chronic complications of SCD to reduce mortality and improve quality of life in a growing population of adults with SCD in high-income countries, while simultaneously decreasing the disparity of medical care between high and low-income countries.

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“…[24]. Treatments targeting vascular dysfunction to prevent major organ damage are under evaluation and may have the greatest impact in adults with SCD [27].…”

Section: Mortality In Scdmentioning

confidence: 99%

“…Hemolysis derived free heme induced endothelial dysfunction, and inflammation have been implicated in the development of pulmonary disease in SCD [99,100]. Innovative treatments targeting pulmonary specific inflammation and the arginine-NO system have been proposed and are under investigation [27,101].…”

Section: Pulmonary Complicationsmentioning

confidence: 99%

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

2015

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“…1 Hypoperfusion results in multiple organ damage. In patients with severe disease, symptoms manifest early and progress during childhood.…”

Section: Introductionmentioning

confidence: 99%

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease

Shenoy

Eapen

Panepinto

et al. 2016

Blood

176

158

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• Children with sickle cell disease engrafted unrelated donor marrow after reduced intensity conditioning.• A high incidence of GVHD and associated mortality compromised safety of the trial.Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n 5 12), transcranial Doppler velocity >200 cm/s (n 5 2), ‡3 vaso-occlusive pain crises per year (n 5 12), or ‡2 acute chest syndrome episodes (n 5 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1-and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ‡75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis.

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“…Inflammation and abnormal adhesion of sickle red blood cells (RBCs), leukocytes and platelets to the vascular endothelium are postulated to play a central role in the pathogenesis of vasculopathy associated with sickle cell disease (SCD) [3,4]. Endothelial cells in SCD display vasoconstrictive, proinflammatory and prothrombotic changes [1,5,6].…”

Section: Introductionmentioning

confidence: 99%

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy

Chen

Qiu

Lin

et al. 2016

Blood Cells, Molecules, and Diseases

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Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL. Increased expression of LOX-1 has been demonstrated in atherosclerotic lesions and diabetic vasculopathy. In this study, we investigate the expression of LOX-1 receptor in sickle cell disease (SCD) vasculopathy. Expression of LOX-1 in brain vascular endothelium is markedly increased and LOX-1 gene expression is upregulated in cultured human brain microvascular endothelial cells by incubation with SCD erythrocytes. Also, the level of circulating soluble LOX-1 concentration is elevated in the plasma of SCD patients. Increased LOX-1 expression in endothelial cells is potentially involved in the pathogenesis of SCD vasculopathy. Soluble LOX-1 concentration in SCD may provide a novel biomarker for risk stratification of sickle cell vascular complications.

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Inflammatory targets of therapy in sickle cell disease

Cited by 38 publications

References 207 publications

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy

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