Characteristics of sickle cell patients with frequent emergency department visits and hospitalizations.

Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. The Cooperative Study of Sickle Cell Disease, a large study enrolling >3000 patients, showed that the majority of SCD patients (80%) experienced 0-3 major pain crises/year. Only a small minority (~5%) experienced ≥6 VOEs/year.

Characteristics and potential biomarkers of adult sickle cell patients with chronic pain.

Objectives: In this study, we investigated the evolution of chronic pain in sickle cell patients (SCD) as an age-dependent phenomenon and studied the frequency of vaso-occlusive episode frequency, opioid use, quantitative sensory testing (QST), and biomarkers of chronic pain (CP).

Methods: We undertook a cross-sectional study of the evolution of CP in SCD. A total of 72 subjects (age 15-66) were enrolled.

Regulation of iron homeostasis through the erythroferrone-hepcidin axis in sickle cell disease.

Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion-dependent β-thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n = 22) and without IO (SCD non-IO cases, n = 11), and non-SCD controls (n = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non-SCD controls compared to SCD IO cases (0·3 vs.

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness.

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood.

Progressing Preemptive Genotyping of CYP2C19 Allelic Variants for Sickle Cell Disease Patients.

Aims: Interindividual variability in drug response and adverse effects have been described for proton pump inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, and anti-infectives, but little is known about the safety and efficacy of these medications in patients with sickle cell disease (SCD). We genotyped the CYP2C19 gene which has been implicated in the metabolism of these drugs in an SCD patient cohort to determine the frequencies of reduced function, increased function, or complete loss-of-function variants.

Materials And Methods: DNAs from 165 unrelated SCD patients were genotyped for nine CYP2C19 (*2, *3, *4, *5, *6, *7,*8, *12, and *17) alleles using the iPLEX ADME PGx multiplex panel.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

Background: 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.

Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management.

Interindividual variability in analgesic effects of nonsteroidal anti-inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel.

A new Aγ-globin chain variant: Hb F-Sykesville MD [Aγ113(G15)Val → Ile; HBG1: c.340G>A] detected in a Caucasian baby.

The total number of hemoglobin (Hb) variants currently included in the globin gene server database is 1626 (November 12 2014), of which 131 are fetal Hb variants. These variants are observed as two different subunits of fetal Hb, (G)γ- and (A)γ-globin chains. Of the 131 documented fetal Hb variants, 73 are (G)γ- and 58 are (A)γ-globin chain variants.

Two new γ chain variants: Hb F-Augusta GA [(G)γ59(E3)Lys → Arg; HBG2: c.179A > G] and Hb F-Port Royal-II [(A)γ125(H3)Glu → Ala; HBG1: c.377A > C].

The total number of hemoglobin (Hb) variants so far reported to the HbVar database is 1598 (April 9 2014) and 130 of them are fetal Hb variants. Fetal Hb are categorized as two different subunits, (G)γ- and (A)γ-globin chains, and γ chain variants can be observed in both subunits. There are 72 (G)γ- and 58 (A)γ-globin chain variants.

CYP2C9 allelic variants and frequencies in a pediatric sickle cell disease cohort: implications for NSAIDs pharmacotherapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. Racial differences in CYP2C9 allele frequencies impact NSAIDs efficacy and safety. We determined the frequencies of CYP2C9 alleles in an African American pediatric SCD cohort.

Two new hemoglobin variants: Hb Tallahassee [α3(A1)Ser→Tyr; HBA2: c.11C>A] and Hb madison-NC [β119(GH2)Gly→Ser; HBB: c.358G>A].

Of the 1570 reported hemoglobin (Hb) variants detected to date, 390 are α2-globin chain (some variants have yet to be identified by DNA analyses and are therefore presumed) and 827 are the result of mutations of the β-globin chain. Due to their location on the Hb structure, only a minority of these variants result in a clinical phenotype; most are silent and are detected during routine surveillance, are found incidentally during other disease-related investigations or following newborn screening programs. In this report we discuss phenotype/genotype and molecular characteristics of two new Hb variants, both of which were clinically silent.

Hb Fulton-Georgia [α20(B1)His→Pro; HBA1: c.62A>C]: a new α-globin variant coinherited with α-thalassemia-2 (3.7 kb deletion) and Hb SC disease.

We report a novel hemoglobin (Hb) variant that we named Hb Fulton-Georgia, caused by a point mutation in exon 1/codon 20 of the α-globin gene [α20(B1)His→Pro; HBA1: c.62A>C]. This α chain variant was identified in an adult African-American female with Hb SC disease who was also heterozygous for the α-thalassemia-2 (α-thal-2) (3.

Comparison of hematologic measurements between local and central laboratories: data from the BABY HUG trial.

Objectives: To investigate the concordance of blood count indices measured locally and at a central laboratory.

Design And Methods: In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated.

Results: Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p<0.

Thalassemia-like phenotype in a novel complex hemoglobinopathy with α, β, δ globin chain abnormalities.

The occurrence of multiple abnormalities of α, β, δ, and γ globin genes may lead to unusual and complex phenotypes when they arise simultaneously in the same individual. Here, we report the findings of an African American boy who coinherited 3 heterozygous globin gene abnormalities: the unstable β-globin chain variant; hemoglobin (Hb) Showa-Yakushiji [β110(G12) Leu→Pro], the δ-globin chain variant; HbB2 [δ16(A13) Gly→Arg] and α-thalassemia (α-thal); (α-/αα). Hb Showa-Yakushiji had been previously described in Japanese, Indian, and European populations.

Compound heterozygosity for hemoglobin S [beta6(A3)Glu6Val] and hemoglobin Korle-Bu [beta73(E17)Asp73Asn].

We report a case of compound heterozygous hemoglobins S [beta6(A3)Glu6Val] and Korle-Bu [beta73(E17)Asp73Asn] in a 2-year-old girl. This hemoglobin genotype is associated with a benign clinical course, much like the sickle cell trait; however, its laboratory characteristics are very similar to compound heterozygous hemoglobin S and hemoglobin D-Los Angeles [beta121(GH4)Glu121Gln], which produces severe sickling hemolytic anemia. We describe laboratory data used to resolve this important differential diagnosis and review the interactions between hemoglobin S and the variant hemoglobins that may account for the different clinical phenotypes in compound heterozygotes.