Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea

Almeida, Camila B.; Souza, Lucas Eduardo Botelho de; Leonardo, Flávia C.; Costa, Fábio Trindade Maranhão; Werneck, Cláudio C.; Covas, Dimas Tadeu; Costa, Fernando Ferreira; Conran, Nicola

doi:10.1182/blood-2014-12-616250

Cited by 69 publications

(60 citation statements)

References 53 publications

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“…This association may be explained by potential anti-inflammatory effects of hydroxyurea 43 , either related to or independent of HbF% induction. However, because not all febrile events (those not leading to a hospitalization) were captured and clinician-induced selection bias (e.g., the “less adherent subset of patients” admitted due to clinician concern for poor adherence potentially reducing outpatient follow up) could have played a role, we cannot assume causality.…”

Section: Discussionmentioning

confidence: 99%

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

et al. 2017

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Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (p<0.0001), including vaso-occlusive pain (p<0.01) and acute chest syndrome (ACS) (p<0.01), and more than four times the odds of admission for fever (p<0.001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1,000×106/L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

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Section: Discussionmentioning

confidence: 99%

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

et al. 2017

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“…In a study of sickle cell and control mice, induction of intravascular hemolysis in control mice stimulated systemic and vascular inflammatory responses in conjunction with NO consumption, similar to the basal responses in sickle mice. 38 Vascular inflammatory effects included decreased leukocyte rolling and increased adhesion and extravasation. The role of cell-free hemoglobin was affirmed by the finding that administration of the free hemoglobin scavenger, haptoglobin, completely inhibited the inflammatory response.…”

Section: Hemolysis and Precapillary Pulmonary Hypertensionmentioning

confidence: 99%

Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Gordeuk

Castro

Machado

2016

Blood

115

101

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Pulmonary hypertension affects ∼10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments improve SCD-related pulmonary hypertension.

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“…1). Increased inflammatory cytokines in hemolytic RBC diseases may arise from endothelial activation, from oxidized hemoglobin and free hemin, reduction in NO, and/or other mechanisms (7,17,92,144). The release into the circulation of free hemin and ROS upon RBC hemolysis activates NF-jB and AP-1, which in turn increase the expression of proinflammatory cytokines (IL1, IL6, TNFa) and endothelial adhesion molecules (L-selectin, P-selectin, VCAM-1, ICAM-1) (200)(201)(202).…”

Section: Fig 2 Hbe Acts As a Bmentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea

Abstract: Key Points Hemolytic processes induce rapid systemic and vascular inflammation in C57BL/6 mice that is abolished by a single dose of hydroxyurea (HU). HU exerts some NO-dependent effects and should be investigated as an acute treatment of SCD and for other hemolytic disorders.

Cited by 69 publications

References 53 publications

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

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