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Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Clinical and laboratory correlates of chronic kidney disease (CKD) in sickle cell anaemia remain incompletely defined. In a multicenter cohort study, we evaluated the prevalence of persistent albuminuria (PA) and characteristics associated with PA, albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) using logistic, linear and multinomial regression models, respectively. Of 269 participants (median age: 30 years; 57.2% females), the prevalence of PA was 35.7%. Using baseline ACR values of <100 and ≥100 mg/g, the probabilities of PA were 30.0% and 94.6%, respectively. In multivariable logistic regression analyses, male sex (β = 0.80 [SE = 0.36], p = 0.024) and ACE inhibitors/ARBs use (β = 1.54 [SE = 0.43], p < 0.001) were associated with higher likelihoods of PA, while higher haemoglobin (β = -0.33 [SE = 0.13], p = 0.009) and HbF (β = -0.04 [SE = 0.02], p = 0.041) were associated with lower likelihoods of PA. In multivariable multinomial regression analyses, older age (β = 0.06 [SE = 0.02], p = 0.004) and higher alkaline phosphatase (β = 0.01 [SE = 0.00], p = 0.004) were associated with higher odds of having eGFR 60-90 versus eGFR>90 mL/min/1.73 m 2 using the cystatin C-based CKD-EPI-2012 equation. Additionally, higher systolic blood pressure (β = 0.11 [SE = 0.03], p = 0.001) and blood urea nitrogen (β = 0.45 [SE = 0.12], p < 0.001) were associated with higher odds, while higher haemoglobin (β = -1.22 [SE = 0.43], p = 0.004) was associated with lower odds of having eGFR<60 versus eGFR>90 mL/min/1.73 m 2 . PA and decreased eGFR are associated with measures of disease severity and comorbid conditions (Clinicaltrials.gov Identifier: NCT03277547)., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events., Methods: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sβ-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed., Findings: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001)., Interpretation: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials., Funding: Bayer Pharmaceuticals., Competing Interests: Declaration of interests MTG is a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning, which have been licensed by Globin Solutions; is a shareholder, advisor, and director in Globin Solutions; is a co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and is now licensed to Globin Solutions and Hope Pharmaceuticals; was a principal investigator in this investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease; and has previously served on Bayer HealthCare's Heart and Vascular Disease Research advisory board and previously on the Forma Therapeutics scientific advisory board. KIA has received research funding from Novartis, Novo Nordisk, and Takeda Pharmaceuticals; served on advisory boards for Novartis, Novo Nordisk, Agios Pharmaceuticals, Fulcrum Therapeutics, Pfizer, and Hillhurst Biopharmaceuticals; served as a consultant for Roche and Biomarin; and serves on a data monitoring committee for Vertex. AB is an equity holder in CRISPR Therapeutics. SAC served on a Pfizer advisory board. PCD reports research support from Novartis, Patient-Centered Outcomes Research Institute, National Institutes of Health, Food and Drug Administration, University of Pittsburgh, and University of Tennessee; consultancy for Vertex, Forma, Chiesi, and Speaker's Bureau for Novartis; and a pending patent for Point of Care Detection of Hemoglobin Sickling via Magnetic Fractionation. FER reports research funding from Novartis, Forma Therapeutics, and Agios. HJF reports research support from Merck, United Therapeutics, Cereno, and Janssen; and has served as a consultant for United Therapeutics, Janssen, Merck, Liquidia, and Sumitomo Pharma. GJK is an employee and equity holder in CSL Behring; is a co-inventor on a patent issued for a formulation of topical sodium nitrite, licensed to Emmaus Life Sciences; and previously served as a co-principal-investigator in this investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease. ESK is supported by grants N1UG3 HL143192–01A1 from the National Institutes for Health, 2UL1TR001430–05A1 from the National Center for Advancing Translational Sciences, and U1EMC27864–08–00 from the Health Resources and Services Administration; and receives research support from Bayer, Forma Therapeutics, Nov Nordisk, Novartis, and United Therapeutics. SL is the vice president of the National Alliance of Sickle Cell Centers; is a consultant for Pfizer and Novartis and served on an adjudication committee for Bluebird Bio and Novo Nordisk; has received research funding from Imara, Novartis, Takeda, CSL-Behring, Health Resources and Services Administration, Patient-Centered Outcomes Research Institute, and Alexion; and holds stocks through a trust in Pfizer and Teva. JL is a consultant for Forma Novo-Nordisk. EMN reports consultancies with Novo Nordisk, Shield Therapeutics and Chiesi Pharmaceuticals; and is on is an advisory board for Chiesi Pharmaceuticals, Novo Nordisk, and Shield Therapeutics. DL was a principal investigator and sub-investigator on clinical trials for the following companies between 2021 and 2023: Bioverativ, Celgene, Exact Sciences, Janssen Research and Development, Novartis, Sanofi-Aventis, Incyte, Takeda, Vifor Pharma, Global Blood Therapeutics, Forma Therapeutics, Novo Nordisk, Abbvie, Pfizer, and CSL Bering. CRM is the executive director of Food as Medicine Therapeutics; is on the scientific advisory board for Trility; is the inventor or co-inventor of several University of California San Francisco-Benioff Children's Hospital Oakland patents that include nutritional supplements for autism and apraxia (licensed to Lifetrients generating royalties); is an inventor or co-inventor of several Emory University School of Medicine patents or pending patents directed to the use of nutritional supplements for autism, coronaviruses, and kidney disease; is a consultant for Roche and CSL Behring; and is an editor for the sickle cell disease fever and sickle cell disease pain online reference for UpToDate. CM reports consultancies with Fulcrum, Sangamo, Sanguine, Pfizer, and Novo Nordisk; and served on an advisory board for CSL Behring, Alexion, Sanguine Bio, Bluebird Bio, Vertex, Pfizer, Agios, Novo Nordisk, and Fulcrum. WS reports consultancies with Alexion, Pfizer, Novartis, Agios, Novo-Nordisk, Bluebird Bio, and Vertex. JGT has received research funding from Bausch, Forma, Pfizer, and Vifer; and was a consultant for Bausch, Glycomimetics, and Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state due to alterations in the coagulation system. Despite concern for the development of venous thromboembolism (VTE) in this population, there are no standardized guidelines for routine thromboprophylaxis. The objective of this study was to assess thromboprophylaxis practices of adult and pediatric treaters of SCD before and during the coronavirus disease of 2019 (COVID-19) pandemic. A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through seven SCD-specific interest groups between May 29, 2020, and July 13, 2020. Of 93 total responses, 14% ( N  = 13) reported they only treat patients more than 21 years old; 38.7% ( N  = 36) only treat patients 0-21 years old and 47.3% ( N  = 44) reported they treat both. Our study showed that before the COVID-19 pandemic, 96% of adult practitioners would recommend pharmacologic thromboprophylaxis, mechanical thromboprophylaxis or both for hospitalized adults with thromboprophylaxis, but only 76% of pediatric treaters would recommend any thromboprophylaxis in hospitalized children ( P  < 0.0001), with 24% of pediatric treaters choosing no thromboprophylaxis at all. During the COVID-19 pandemic, pharmacologic thromboprophylaxis specifically was recommended for adults by 94% of treaters and for pediatric patients by 76% of treaters. These findings suggest that despite the lack of evidence-based thromboprophylaxis guidelines in adults and children with thromboprophylaxis, subspecialty treaters routinely provide pharmacologic thromboprophylaxis in their adult patients and will modify their practice in pediatric patients who are considered at a high risk for VTE., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sickle cell disease (SCD) is a collection of inherited hemoglobin disorders that results in chronic hemolytic anemia, vaso-occlusion, pain, and end organ damage. Surgery in the SCD population requires careful planning, as perioperative stressors can lead to increased sickling and risk of inducing or further exacerbating vaso-occlusive episodes (VOEs). Additionally, the underlying hypercoagulability and immunocompromised state due to SCD places patients at increased risk of both venous thromboembolism and infection. Judicious fluid administration, temperature regulation, thorough preoperative and postoperative analgesic planning, and preoperative transfusion are all crucial components of decreasing risks of surgery in patients with SCD., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

Objective: To provide real-word evidence of patients with SCD initiating crizanlizumab, their use of other SCD treatments, and crizanlizumab treatment patterns., Methods: Using IQVIA's US-based, Longitudinal Patient-Centric Pharmacy and Medical Claims Databases patients with a diagnosis of SCD between November 1, 2018, and April 30, 2021, and ≥1 claim for crizanlizumab (date of first claim = index date) between November 1, 2019, and January 31, 2021 who were ≥16 years of age, and had ≥12 months of pre-index data were selected for analysis. Two cohorts were identified based on available follow-up time (3- and 6-month cohorts). Patient characteristics were reported along with pre- and post-index SCD treatments and crizanlizumab treatment patterns (e.g. total doses received, gap-days between doses, days on therapy, discontinuation, and restarts)., Results: 540 patients met the base inclusion criteria (345 in the 3-month cohort and 262 in the 6-month cohort. Most patients (64%) were female with a mean (SD) age of 35 (12) years overall. Concomitant hydroxyurea use was observed in 19-39% of patients, while concomitant L-glutamine use was observed for 4-8% of patients. 85% of 3-month cohort patients received at least two doses of crizanlizumab, while 66% of the 6-month cohort received at least 4 doses of crizanlizumab. The median number of gap days between doses was 1 or 2., Conclusions: 66% of patients who receive crizanlizumab receive at least 4 doses within 6-months. The low median number of gap days suggests high adherence.

Although sickle cell disease can be cured using allogeneic hematopoietic stem cell transplantation and possibly gene therapy and gene editing, these treatments remain unavailable to most patients. As understanding of the disease pathophysiology increases, progress is being made in developing drug therapies. Hydroxyurea, l-glutamine, crizanlizumab, and voxelotor are currently approved by the US Food and Drug Administration, with multiple others at various stages of testing. With the limited efficacy of individual agents, combinations of agents will likely be required for optimal outcomes. Clinical and surrogate endpoints, other than vaso-occlusive crisis, are increasingly being considered in the evaluation of novel drugs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Anemia and iron deficiency continue to be the most prevalent nutritional disorders in the world, affecting billions of people in both developed and developing countries. The initial diagnosis of anemia is typically based on several markers, including red blood cell (RBC) count, hematocrit and total hemoglobin. Using modern hematology analyzers, erythrocyte parameters such as mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), etc. are also being used. However, most of these commercially available analyzers pose several disadvantages: they are expensive instruments that require significant bench space and are heavy enough to limit their use to a specific lab and lead to a delay in results, making them less practical as a point-of-care instrument that can be used for swift clinical evaluation. Thus, there is a need for a portable and economical hematology analyzer that can be used at the point of need. In this work, we evaluated the performance of a system referred to as the cell tracking velocimetry (CTV) to measure several hematological parameters from fresh human blood obtained from healthy donors and from sickle cell disease subjects. Our system, based on the paramagnetic behavior that deoxyhemoglobin or methemoglobin containing RBCs experience when suspended in water after applying a magnetic field, uses a combination of magnets and microfluidics and has the ability to track the movement of thousands of red cells in a short period of time. This allows us to measure not only traditional RBC indices but also novel parameters that are only available for analyzers that assess erythrocytes on a cell by cell basis. As such, we report, for the first time, the use of our CTV as a hematology analyzer that is able to measure MCV, MCH, mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), the percentage of hypochromic cells (which is an indicator of insufficient marrow iron supply that reflects recent iron reduction), and the correlation coefficients between these metrics. Our initial results indicate that most of the parameters measured with CTV are within the normal range for healthy adults. Only the parameters related to the red cell volume (primarily MCV and RDW) were outside the normal range. We observed significant discrepancies between the MCV measured by our technology (and also by an automated cell counter) and the manual method that calculates MCV through the hematocrit obtained by packed cell volume, which are attributed to the artifacts of plasma trapping and cell shrinkage. While there may be limitations for measuring MCV, this device offers a novel point of care instrument to provide rapid RBC parameters such as iron stores that are otherwise not rapidly available to the clinician. Thus, our CTV is a promising technology with the potential to be employed as an accurate, economical, portable and fast hematology analyzer after applying instrument-specific reference ranges or correction factors., (© 2022. The Author(s).)

Sickle cell disease is a disorder characterized by chronic hemolytic anemia and multiorgan disease complications. Although vaso-occlusive episodes, acute chest syndrome, and neurovascular disease frequently result in complication and have well-documented guidelines for management, the management of chronic hemolytic and vascular-related complications, such as priapism, leg ulcers, and pulmonary hypertension, is not as well recognized despite their increasing reported prevalence and association with morbidity and mortality. This chapter therefore reviews the current updates on diagnosis and management of priapism, leg ulcers, and pulmonary hypertension., (Copyright © 2021 by The American Society of Hematology.)

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a medically and socially complex, multisystem illness that affects individuals throughout the lifespan. Given improvements in care, most children with SCD survive into adulthood. However, access to adult sickle cell care is poor in many parts of the United States, resulting in increased acute care utilization, disjointed care delivery, and early mortality for patients. A dearth of nonmalignant hematology providers, the lack of a national SCD registry, and the absence of a centralized infrastructure to facilitate comparative quality assessment compounds these issues. As part of a workshop designed to train health care professionals in the skills necessary to establish clinical centers focused on the management of adults living with SCD, we defined an SCD center, elucidated required elements of a comprehensive adult SCD center, and discussed different models of care. There are also important economic impacts of these centers at an institutional and health system level. As more clinicians are trained in providing adult-focused SCD care, center designation will enhance the ability to undertake quality improvement and compare outcomes between SCD centers. Activities will include an assessment of the clinical effectiveness of expanded access to care, the implementation of SCD guidelines, and the efficacy of newly approved targeted medications. Details of this effort are provided., (© 2020 by The American Society of Hematology.)

Introduction: Sickle cell disease (SCD) is an orphan disease in the United States, but is highly prevalent worldwide. Only two drugs, hydroxyurea and L-glutamine, are approved for this disease. With an improved understanding of the pathophysiology of SCD as well as the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of drugs for SCD., Areas Covered: This review summarizes published studies of drug therapies and ongoing trials of novel agents., Expert Opinion: The development of drugs with different mechanisms of action offers opportunities for combination and individualized therapy in SCD. In addition to acute pain crisis, the evaluation of other SCD-related complications, exercise capacity, patient reported outcomes and validated surrogate endpoints are necessary to advance drug development. It is important to involve sites in sub-Saharan Africa and India, which have the highest burden of SCD, in trials of novel therapies., Competing Interests: Declaration of Interests KIA has served on clinical advisory boards and/or served as a consultant for Global Blood Therapeutics, Modus Therapeutics, Novartis and Bioverativ. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Although recent studies show an improved survival of children with sickle cell disease in the US and Europe, for adult patients mortality remains high. This study was conducted to evaluate the factors associated with mortality in adult patients following the approval of hydroxyurea. We first evaluated the association between selected variables and mortality at an academic center (University of North Carolina). Data sources were then searched for publications from 1998 to June 2016, with meta-analysis of eligible studies conducted in North America and Europe to evaluate the associations of selected variables with mortality in adult patients. Nine studies, combined with the UNC cohort (total n=3257 patients) met the eligibility criteria. Mortality was significantly associated with age (per 10-year increase in age) [7 studies, 2306 participants; hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.10-1.50], tricuspid regurgitant jet velocity 2.5 m/s or more (5 studies, 1577 participants; HR: 3.03; 95%CI: 2.0-4.60), reticulocyte count (3 studies, 1050 participants; HR: 1.05; 95%CI: 1.01-1.10), log(N-terminal-pro-brain natriuretic peptide) (3 studies, 800 participants; HR: 1.68; 95%CI: 1.48-1.90), and fetal hemoglobin (7 studies, 2477 participants; HR: 0.97; 95%CI: 0.94-1.0). This study identifies variables associated with mortality in adult patients with sickle cell disease in the hydroxyurea era., (Copyright© Ferrata Storti Foundation.)

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross-matching for future transfusions and may sometimes trigger life-threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14-27 days). RBC antibody formation was significantly associated with the age of RBC units (P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71-7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66-35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso-occlusive complications. Although increased echocardiography-derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies (P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding., Competing Interests: The authors have no conflicts of interest to disclose., (© 2015 Wiley Periodicals, Inc.)

Background: Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients., Methods: We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria., Results: The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11-0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome., Conclusions: In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation., (© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction: The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbβ3 receptor, in SCD patients during acute painful episodes., Materials and Methods: In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1., Results: Thirteen patients (SS - 10, Sβ(0) - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25years) or placebo (N=4; 3 females; median age - 31years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use., Conclusions: In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899., (© 2013.)

Although echocardiography-derived tricuspid regurgitant jet velocity (TRV) is associated with increased mortality in sickle cell disease (SCD), its rate of increase and predictive markers of its progression are unknown. We evaluated 55 subjects (median age: 38 years, range: 20-65 years) with at least two measurable TRVs, followed for a median of 4·5 years (range: 1·0-10·5 years) in a single-centre, prospective study. Thirty-one subjects (56%) showed an increase in TRV, while 24 subjects (44%) showed no change or a decrease in TRV. A linear mixed effects model indicated an overall rate of increase in the TRV of 0·02 m/s per year (P = 0·023). The model showed that treatment with hydroxycarbamide was associated with an initial TRV that was 0·20 m/s lower than no such treatment (P = 0·033), while treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was associated with an increase in the TRV (P = 0·006). In summary, although some patients have clinically meaningful increases, the overall rate of TRV increase is slow. Treatment with hydroxycarbamide may decrease the progression of TRV. Additional studies are required to determine the optimal frequency of screening echocardiography and the effect of therapeutic interventions on the progression of TRV in SCD., (© 2013 John Wiley & Sons Ltd.)

Introduction: Acute chest syndrome (ACS), a leading cause of morbidity and mortality in sickle cell disease (SCD), is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. There is increasing knowledge regarding the etiology and pathogenesis of ACS in SCD. A high index of suspicion is required for the diagnosis of ACS. Treatment of ACS involves the judicious use of intravenous fluids and analgesics, aggressive incentive spirometer and pulmonary toileting, antibiotics and transfusion therapy., Areas Covered: This review evaluates the epidemiology, clinical and laboratory presentation, etiology and pathogenesis of ACS. It also reviews the standard treatments as well as experimental treatments in ACS., Expert Opinion: Despite an increased understanding of its etiology and pathogenesis, ACS remains a leading cause of morbidity and mortality in SCD. In patients admitted with a painful crisis, there is need for a high index of suspicion, as pain episodes may be a prodrome for the development of ACS. Patients with a diagnosis of ACS should be aggressively managed to prevent clinical deterioration. Clinical trials using novel drugs for the treatment of ACS are greatly warranted.

Goal: Human Papillomavirus (HPV) is found to be increasingly implicated in head and neck cancers. The objective of this study was to determine the primary site of origin of HPV positive squamous carcinomas metastatic to lymph nodes of the neck., Methods: Surgical pathology records from January 1, 2000 to July 31, 2007 were used to identify surgically removed neck lymph nodes with the diagnosis of metastatic squamous carcinoma. Specimens in formalin-fixed, paraffin-embedded blocks were examined for HPV (+) by analyzing sequencing data generated by PCR and immunostaining for the expression of the p16INK biomarker, which is overexpressed if Rb is not present. H & E stained slides were also reviewed for histological classification. The available retrospective demographics were extracted from the charts to determine trends of confounding factors., Results: Of the 43 patient samples, 41 contained adequate DNA to test for HPV. The mean age of the 41 patients was 62 years. All of the patients smoked and 39/41 patients consumed alcohol. The overall HPV (+) incident rate was 27% (11/41) by PCR with strongly diffuse or strong focal p16 staining. 9 of the 34 males and 2 of the 7 females had HPV (+) carcinomas. The average age of the 2 HPV (+) females was 44, compared to the HPV (-) females who averaged 70. The average age of the HPV (+) males was 56 compared with the average age 55 of the HPV (-) males. HPV (+) carcinomas appeared to arise from multiple sites in the oropharynx, particularly the tonsils and tongues, including unknown primaries. By histological exam, most metastatic HPV(+) squamous carcinomas were poorly differentiated (basaloid) microscopically and grossly cystic., Conclusion: The 27% HPV (+) squamous cancers metastatic to neck lymph node originated from multiple sites in the oropharynx. The HPV (+) female population, although a total of only 2, tended to be much younger than the HPV (-) ones, whereas the HPV (+) male population was similar in age to the HPV (-) male population.

The recent surge of interest in fluconazole is due to its approval by the U.S. Food and Drug Administration for use as a single 150-mg oral dose in the treatment of vaginal candidiasis. Fluconazole is a triazole antifungal agent that acts primarily by inhibiting sterol synthesis in the fungal cell membrane. Recent studies have shown that a single dose of oral fluconazole is as effective as intravaginal antifungal agents. Many physicians and patients prefer this single-dose regimen because of its low rate of side effects, cost-effectiveness and ease of administration.

Due to constraints in conducting specific tests for diagnosis of perinatal infection, the present study was carried out to find out the value of cord serum IgM levels as a screening procedure for intrauterine infection in full term intrauterine growth retarded (IUGR) babies. Thirty five consecutively born full term IUGR singleton babies and their mothers (having weight greater than 40 kg, height greater than 145 cm, Hb 8 g/dl and normal blood pressure) formed the study group. Ten full term singleton babies weighing greater than or equal to 3000 g and their mothers served as controls. In the study population both mean cord serum IgM (26.8 mg/dl) and mean maternal serum IgM (142.42 mg/dl) were raised as compared to the mean cord serum IgM (13.76 mg/dl) and mean maternal serum IgM (100.16 mg/dl) of the control group. However, statistically the rise was significant only between the maternal cord serum IgM levels. But all the same, cord serum IgM levels exceeding 20 mg/dl and 30 mg/dl were found in 51.43 and 22.8% of full term IUGR neonates, respectively whereas among the control neonates only 20.0% had levels exceeding 20 mg/dl and none had levels above 30 mg/dl suggesting possible intrauterine antigenic challenge to perinatal infection in higher proportion of IUGR babies. Cord serum IgM levels were also seen to increase with increase in birth weight. Idiopathic IUGR babies having cord serum IgM levels greater than 30 mg/dl should undergo specific immunological tests and follow up.