Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin-oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction.
View Article and Find Full Text PDFEtavopivat is an investigational, once daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: 1 single-dose, 2 multiple ascending doses, and 1 open-label (OL).
View Article and Find Full Text PDFIntroduction: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity.
Methods/results: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor.
Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies.
View Article and Find Full Text PDFWe consider the dynamics of a collection of n>1 populations in which each population has its own rate of growth or decay, fixed in continuous time, and migrants may flow from one population to another over a fixed network, at a rate, fixed over time, times the size of the sending population. This model is represented by an ordinary linear differential equation of dimension n with constant coefficients arrayed in an essentially nonnegative matrix. This paper identifies conditions on the parameters of the model (specifically, conditions on the eigenvalues and eigenvectors) under which the variance of the n population sizes at a given time is asymptotically (as time increases) proportional to a power of the mean of the population sizes at that given time.
View Article and Find Full Text PDFObjective: Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike.
View Article and Find Full Text PDFCrizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.
View Article and Find Full Text PDFSickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center.
View Article and Find Full Text PDFRed blood cell transfusions are common in patients with sickle cell disease who are at increased risk of stroke. Unfortunately, transfusion thresholds needed to sufficiently dilute sickle red blood cells and adequately restore oxygen delivery to the brain are not well defined. Previous work has shown that transfusion is associated with a reduction in oxygen extraction fraction and cerebral blood flow, both of which are abnormally increased in sickle patients.
View Article and Find Full Text PDFExpert Rev Hematol
June 2022
Introduction: Sickle cell disease (SCD) describes a group of heritable blood disorders caused by the polymerization of sickle hemoglobin (HbS). HbS polymerization leads to anemia and vaso-occlusion, a process that impedes delivery of oxygen to tissues throughout the body, resulting in end-organ damage (EOD). Given the lifelong complications associated with SCD, identification and treatment of early symptoms in childhood is increasingly important.
View Article and Find Full Text PDFBackground: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality.
View Article and Find Full Text PDFIEEE J Transl Eng Health Med
November 2019
Patient and health provider interaction via text messaging (TM) has become an accepted form of communication, often favored by adolescents and young adults. While integration of TM in disease management has aided health interventions and behavior modifications, broader adoption is hindered by expense, fixed reporting schedules, and monotonic communication. A low-cost, flexible TM reporting system (REMOTES) was developed using inexpensive cloud-based services with features of two-way communication, personalized reporting scheduling, and scalable and secured data storage.
View Article and Find Full Text PDFSickle cell disease (SCD) is among the most common genetic diseases in the United States, affecting approximately 100,000 people. In the United States, SCD is characterized by a shortened life expectancy of only about 50 years in severe subtypes, significant quality-of-life impairments, and increased healthcare utilization and spending. SCD is characterized by chronic hemolytic anemia, vaso-occlusion, and progressive vascular injury affecting multiple organ systems.
View Article and Find Full Text PDFBackground: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.
View Article and Find Full Text PDFgenes are highly polymorphic and encode the most complex of the 35 human blood group systems. This genetic diversity contributes to Rh alloimmunization in patients with sickle cell anemia (SCA) and is not avoided by serologic Rh-matched red cell transfusions. Standard serologic testing does not distinguish variant Rh antigens.
View Article and Find Full Text PDFBackground: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.
Methods: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada.
Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States.
View Article and Find Full Text PDFGonadal hypofunction is described in male and female patients with sickle cell anemia (SCA) after bone marrow transplant (BMT) and in males treated with hydroxyurea (HU). Anti-Müllerian hormone (AMH) is a serum marker of ovarian reserve. This study describes AMH and follicle-stimulating hormone (FSH) levels in female SCA subjects treated with supportive care (SCA-SC), HU (SCA-HU) and BMT (SCA-BMT).
View Article and Find Full Text PDFHigh-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide.
View Article and Find Full Text PDFAnnu Int Conf IEEE Eng Med Biol Soc
August 2015
Sickle cell disease (SCD) is the most common inherited disease, and SCD symptoms impact functioning and well-being. For example, adolescents with SCD have a higher tendency of psychological problems than the general population. Acceptance and Commitment Therapy (ACT), a cognitive-behavioral therapy, is an effective intervention to promote quality of life and functioning in adolescents with chronic illness.
View Article and Find Full Text PDFAnnu Int Conf IEEE Eng Med Biol Soc
August 2013
Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias.
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