Adhesion molecules and high‐sensitivity C‐reactive protein levels in patients with sickle cell beta‐thalassaemia

Kanavaki, Ino; Lazaropoulou, Christina; Kattamis, Antonis; Tzanetea, Revekka; Kalotychou, Vassiliki; Rombos, Ioannis; Papassotiriou, Ioannis

doi:10.1111/j.1365-2362.2011.02551.x

Cited by 20 publications

(12 citation statements)

References 21 publications

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“…Soluble (s)ICAM-1, ICAM-3, VCAM-1, E-selectin and P-selectin levels were measured in only 14 of the 19 subjects, due to a change in availability of the adhesion marker assay kit. Baseline levels of these biomarkers were consistent with previous studies showing elevated levels in SCA patients compared to healthy, age- and race-matched control subjects (Al Najjar , et al 2016, Bhagat , et al 2012, Blann , et al 2008, Conran , et al 2004, Duits , et al 1996, Gurkan , et al 2005, Hatzipantelis , et al 2013, Kanavaki , et al 2012, Kato , et al 2005, Krishnan , et al 2010, Makis , et al 2006, Mohan , et al 2005, Qari , et al 2012, Rees , et al 1995, Saleh , et al 1999). …”

Section: Resultssupporting

confidence: 90%

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

et al. 2017

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Summary Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (p=0.0003), oral analgesic use (p=0.003) and circulating hs-CRP (p=0.003), soluble (s)E-selectin (p=0.01), sICAM-1 (p=0.02), sICAM-3 (p=0.02) and sVEGF (p=0.01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.

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Section: Resultssupporting

confidence: 90%

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

et al. 2017

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“…Various adhesion molecules, including ICAM-1, VCAM, P-selectin, and E-selectin, are elevated in SCA patients. 40 Hydroxyurea specifically decreased the expression of E-selectin on sickle mouse pulmonary epithelial and vascular endothelial cells. This effect was not observed for ICAM-1 or VCAM, similarly to previous findings in human SCA patients.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Lebensburger¹,

Howard²,

Hu³

et al. 2012

Blood

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Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in Eselectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyteendothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis. IntroductionSickle cell anemia (SCA) is characterized by chronic hemolytic anemia and vascular inflammation. Hydroxyurea therapy decreases vasoocclusive complications of SCA and reduces mortality, 1,2 but the mechanism of this benefit has been debated. Elevated white blood cell counts have been found to correlate with greater mortality in sickle cell disease (SCD), 3 and early studies suggested hydroxyurea reduced leukocytosis. 4,5 Subsequent studies found no statistical association between reduction of leukocytosis and mortality in SCA patients receiving hydroxyurea, implicating increased levels of hemoglobin F (HbF) as the main predictor of mortality. 6 A recent placebo-controlled clinical trial of hydroxyurea in pediatric SCA patients confirmed a highly significant decrease in total white blood cell and absolute neutrophil counts after hydroxyurea treatment as well as increases in hemoglobin and HbF levels. 7 A significant decrease in acute chest syndrome, which is oftentimes initiated by lung infection, also was observed in this study. 7 Bacteremia was recorded 6 times in the placebo group but only 3 times in the hydroxyurea-treated patients, 7 a trend that was not significant because of the low incidence. Although induction of HbF is generally accepted to be a major benefit of hydroxyurea therapy in SCA, the relative contribution of other factors, including decreased white blood cell counts, to positive outcomes remains a possibility that has yet to be explored.Modulation of leukocytosis by hydroxyurea raises the question of infection risk in SCA. Children with SCA have a 400-fold greater risk of fulminant, lethal pneumococcal sepsis than their healthy peers or patients with other hemolytic anemias, 8-10 a finding recapitulated in the sickle cell mouse model. 11 Despite administration of penicillin prophylaxis, pneumococcal polysac...

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“…26 Since then, little data has emerged in the medical literature describing the profile of clinical complications of HbSβ patients, and there is even less information comparing the level of clinical impairment of these patients regarding the impact of the thalassemia mutation. This particular group of patients show an intense endothelial activation profile even under steady state, with high concentrations of inflammatory markers 27 and a severe profile of organic impairment, as demonstrated by high rates of pulmonary hypertension 28 and renal dysfunction. 29 However, in general, what is known regarding the biology and clinical manifestations of sickle cell/β-thalassemia up to date comes largely from case reports or studies with limited sample numbers.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell/β-thalassemia: Comparison of Sβ⁰ and Sβ⁺ Brazilian patients followed at a single institution

et al. 2016

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Adhesion molecules and high‐sensitivity C‐reactive protein levels in patients with sickle cell beta‐thalassaemia

Abstract: Our findings demonstrate the high degree of endothelial activation and damage seen in sickle cell patients even in steady-state condition, as well as the important chronic inflammation underlying the pathophysiology of this widespread disease.

Cited by 20 publications

References 21 publications

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Sickle cell/β-thalassemia: Comparison of Sβ⁰ and Sβ⁺ Brazilian patients followed at a single institution

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Adhesion molecules and high‐sensitivity C‐reactive protein levels in patients with sickle cell beta‐thalassaemia

Abstract: Our findings demonstrate the high degree of endothelial activation and damage seen in sickle cell patients even in steady-state condition, as well as the important chronic inflammation underlying the pathophysiology of this widespread disease.

Cited by 20 publications

References 21 publications

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Sickle cell/β-thalassemia: Comparison of Sβ0 and Sβ+ Brazilian patients followed at a single institution

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Sickle cell/β-thalassemia: Comparison of Sβ⁰ and Sβ⁺ Brazilian patients followed at a single institution