scholarly journals Impact of a grant program to spur advances in sickle cell disease research

2021 ◽  
Vol 5 (19) ◽  
pp. 3855-3861
Author(s):  
Sindy N. Escobar Alvarez ◽  
Elizabeth R. Myers
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Diseases ◽  
Median Number ◽  
Original Research ◽  
Cell Disease ◽  
Federal Grant ◽  
Financial Return ◽  
Hydroxyurea Treatment ◽  
Number Of Publications

Abstract More than 20 years ago, clinical trials and federal grant support for sickle cell disease (SCD) research were not on par with support for other genetic diseases. Faced with the opportunity to spur research and advance treatments for SCD, and at the recommendation of advisors, the Doris Duke Charitable Foundation (DDCF) offered an SCD research funding opportunity starting in 2009 through its Innovations in Clinical Research Awards (ICRA) program. Twenty-eight new grants of $450 000 for direct costs over 3 years and 7 renewals were awarded, for a total investment of $17 million. Only about half the research teams garnered follow-on funding directly related to their ICRA projects, but the financial return on the research investment was substantial (∼4 times the original $17 million or 300%). All but 1 of the ICRA investigative teams published original research reports that acknowledged DDCF as a source of funding; the median number of publications per team was 3. Major innovations in the diagnosis and treatment of SCD included but were not limited to a demonstration that genetic modification of BCL11A enhancer is a potentially important treatment modality, establishment that plerixafor mobilization is safe and effective for those with SCD, development and validation of a new diagnostic called SCD BioChip, and evidence that hydroxyurea treatment is safe and efficacious in African children. These outcomes show that relatively small research grants can have a substantial return on investment and result in significant advances for a disease such as SCD.

Retinal microvascular analysis using Fundus Fluorescein Angiography in Egyptian sickle cell disease patients

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Nayera H El Sherif ◽  
Mahmoud A Kenny ◽  
Waheed S Elhalfawy
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Fluorescein Angiography ◽  
Sickle Cell ◽  
Large Sample Size ◽  
Cell Disease ◽  
Fundus Fluorescein Angiography ◽  
Transfusion Therapy ◽  
Hydroxyurea Treatment ◽  
Trans Cranial Doppler

Abstract Background Sickle cell disease can affect retina of eye via vaso-occulsive changes that occur in micro-vessels of retina which could be analysed by using Fundus Fluorescein Angiography. Aim To analyze macular microvascular alternation in patients with SCD by Fundus Fluorescein Angiography (FFA) and to assess the role of potentially contributory Clinico-pathological factors including Trans-Cranial Doppler, genotypes, hydroxyurea, transfusion therapy and finally iron overload state on the development of macular alterations. Method This was across-sectional study which included 30 Sickle cell disease patients randomly recruited from the Paediatric Haematology clinic, children Hospital, Ain Shams University, Cairo, Egypt. Complete blood count (CBC), Trans-Cranial Doppler (TCD) and Fundus Fluorescein Angiography. Results In our study, there were 30 patients with mean age (14.1± 4.02), 5 patients had abnormal/conditional Trans-Cranial, 15 patients had Vaso-occlusive crises, 11 patients were on regular simple blood transfusion; all 30 studied sickle cell disease patients had normal Fundus Fluorescein Angiography and eye examination and only one patient hadabnormal visual acuity;A 29 years oldgirl who had five attacks of cerebral strokes last year, on regular simple blood transfusion and Hydroxyurea treatment with abnormal TCD and recurrent Vaso-occlusive crises in last two years, Although her vision is hand movement yet Fundus Fluorescein Angiography was normal. Conclusion we didn’t find any Retinal microvascular alternation in our studied SCD patients using Fundus Fluorescein Angiography, we related our results to the fact that our studied SCD patients were young and all our studied patients were on hydroxyurea therapy with fair compliance, further studies using large sample size are warranted in order to illustrate the utility of Fundus Fluorescein Angiography (FFA) as a tool for better detection of sickle retinopathy.

scholarly journals Hydroxyurea Treatment for Sickle Cell Disease

2002 ◽  
Vol 2 ◽  
pp. 1706-1728 ◽  
Author(s):  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Pharmacologic Therapy ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Globin Chains ◽  
Hydroxyurea Treatment ◽  
Erythroid Precursors

High fetal hemoglobin (HbF) levels inhibit the polymerization of sickle hemoglobin (HbS) and reduce the complications of sickle cell disease. Pharmacologic agents that can reverse the switch from γ- to β-chain synthesis — γ-globin chains characterize HbF, and sickle β-globin chains are present in HbS — or selectively increase the proportion of adult erythroid precursors that maintain the ability to produce HbF are therapeutically useful. Hydroxyurea promotes HbF production by perturbing the maturation of erythroid precursors. This treatment increases the total hemoglobin concentration, reduces the vaso-occlusive complications of pain and acute chest syndrome, and attenuates mortality in adults. It is a promising beginning for pharmacologic therapy of sickle cell disease. Still, its effects are inconsistent, trials in infants and children are ongoing, and its ultimate value — and peril — when started early in life are still unknown.

Alterations of Hemoglobin Fractionation in a Sickle Cell Disease Patient on Voxelotor Therapy

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
S S Karimi ◽  
H Ni ◽  
L L Hsu
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Recent Literature ◽  
Disease Patient ◽  
Oxygen Affinity ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Low Oxygen ◽  
Hydroxyurea Treatment

Abstract Introduction/Objective Voxelotor is a molecule that allosterically binds to the alpha-chain of hemoglobin, resulting in increased oxygen affinity. This allosteric inhibition leads to prevention of hemoglobin polymerization and sickling of red blood cells in response to low oxygen tension. Voxelotor has been used to treat patients with Sickle Cell Disease (SCD) and recent literature indicates it may contribute to complex hemoglobin fractionation (HF) elution patterns. We report a novel case of a SCD patient on concurrent Hydroxyurea, Voxelotor and chronic RBC exchange transfusion treatment and discuss the implications of these three treatment modalities on HF and monitoring of SCD. Methods A 17-year-old female with SCD complicated by frequent vaso-occlusive crisis, and avascular necrosis managed with chronic RBC exchange and Hydroxyurea. Her HF prior to initiation of Voxelotor treatment showed 3.2% HbA2, 51% HbA, 6.0% HbF, and 41% HbS. Voxelotor therapy was initiated at 1500mg/day and HF was performed 10 days later. Whole blood was collected and subjected to High Performance Liquid Chromatography (HPLC) with reflex to RBC solubility and Capillary Electrophoresis. Results HF performed post-Voxelotor therapy revealed positive sickle solubility with a complex pattern of 2.7% HbA2, 49.2% HbA, 5.3% HbF, 15.7% HbS, 0% HbC, and two additional peaks of a 6.3% peak in the window-D region (retention time of 4.34) and 20.8% of an atypical Hb peak pattern (at the retentuin time of 4.18). The results reflected a complex HF of a HbSS patient on concurrent chronic RBC exchange transfusion, hydroxyurea therapy, and Voxelotor treatment. Post Voxelotor-therapy HF revealed a reduction in HbS from 41% to 15.7% with the emergence of two additional peaks. Chronic RBC exchange transfusion and Hydroxyurea treatment account for the observed fractionation of HbA and HbF, respectively. Based on recent literature, we attribute the emergence of the two additional peaks to Voxelotor therapy. All three therapies led to reduction in HbS. Conclusion Routine HF serves as an essential modality in diagnosis and monitoring of SCD. Voxelotor treatment alters the HF profile and may cause difficulty for interpretation. With the emergence of novel therapies, it is imperative for clinicians to provide medication information to clinical laboratories and pathologists to be fully aware of the effects of current treatments to correctly interpret and monitor SCD.

Stroke in hemoglobin (SD) sickle cell disease with moyamoya: successful hydroxyurea treatment after cerebrovascular bypass surgery

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2165-2167 ◽  
Author(s):  
Markus Schmugge ◽  
Hannes Frischknecht ◽  
Yasuhiro Yonekawa ◽  
Ralf W. Baumgartner ◽  
Eugen Boltshauser ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Bypass Surgery ◽  
Cerebral Arteries ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Hemoglobin F ◽  
Hydroxyurea Treatment ◽  
Neurologic Sequelae ◽  
Artery Obstruction

Abstract An 11-year-old boy with hemoglobin sickle disease (HbSD), bilateral stenosis of the intracranial carotid arteries, and moyamoya syndrome had recurrent ischemic strokes with aphasia and right hemiparesis. His parents (Jehovah's Witnesses) refused blood transfusions. After bilateral extracranial–intracranial (EC-IC) bypass surgery, hydroxyurea treatment increased hemoglobin F (HbF) levels to more than 30%. During a follow-up of 28 months, flow velocities in the basal cerebral arteries remained stable, neurologic sequelae regressed, and ischemic events did not recur. This is the first report of successful hydroxyurea treatment after bypass surgery for intracranial cerebral artery obstruction with moyamoya syndrome in sickle cell disease. The patient's religious background contributed to an ethically challenging therapeutic task.

Effectiveness Of An Analgesia Protocol For The Treatment Of Painful Vaso-Occlusive Crisis Of Sickle Cell Disease Patients In Emergency Room: A Retrospective Cohort Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2222-2222
Author(s):  
Veronique Naessens ◽  
Richard Ward ◽  
Kevin H.M. Kuo
Keyword(s):  
Sickle Cell Disease ◽  
Emergency Room ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Care Center ◽  
Median Number ◽  
Cell Disease ◽  
Dose Time ◽  
Chi Squared ◽  
Opiate Administration

Background Painful vaso-occlusive crisis (VOC) is the most frequent complication of sickle cell disease (SCD) and the main reason for interacting with the emergency room (ER). Guidelines highlight the need for rapid opiate delivery (< 30 min.) via specific analgesia protocol in order to achieve rapid pain control and reduce length of stay (LOS). Objectives To determine the rate of utilization of an analgesia protocol for SCD patients presenting with painful VOC to ER. Secondary objectives are to examine the relationship between protocol use, LOS, discharge from ER, time to first opiate delivery, total amount of opiates, and time to readmission. Methods An analgesia protocol, developed according to the BCSH guideline, was deployed in the ER of a major SCD comprehensive care center in Canada since 2009. A retrospective observational study was conducted of all SCD patients who presented to the ER with painful VOC between August 2009 and September 2012. Frequent ER visitor was defined as >3 visits/year. Factors influencing protocol use and discharge from ER were examined via Chi-squared test and multivariable logistic regression. Mann-Whitney U test and multiple regression were used to examine factors related to time to first opiate administration, LOS in ER, total quantity of opiates used, and as well as time to readmission. Results 602 ER visits were included in the analysis, comprising of 116 patients (61 males, 55 females) with 82% HbSS or S/β0. The median number of visits in the observation period was 2 (1 to 90), with 12 patients responsible for 57% of visits. The protocol was used in only 51% of visits, frequent ER attenders were less likely to be treated by the protocol (OR 0.989 per additional visit, p=0.007). Higher pain score on presentation was significantly associated with protocol use (OR 1.194 per 1 point increment, p=0.001), which in turn reduced the time to first opiate administration (69 vs. 108 min., p<0.001). Visits treated by protocol were longer (457 min vs. 385 min. in ER, p<0.001), used more opiates (95 vs. 50 mg PO morphine equi-analgesic dose, p<0.001) and patients were less likely to be discharged home (OR 0.78, p=0.003), though it prolonged the time to next ER admission (22 vs. 15 days, p=0.008). The length of inpatient admission was not affected by prior use of the Protocol in ER. Conclusion In this, the largest single-center report of ER sickle cell care, the rate of protocol use was moderate and although it resulted in faster delivery of first opiate dose, time to delivery did not reach the recommended target of 30 minutes. Protocol use did not positively influence any other outcomes. The protocol was preferentially used in patients who attends the ER infrequently. Further refinement of the protocol may lead to improvements in utilization by ER staff, leading to shorter time to first analgesia administration. This in turn may result in the protocol having a greater impact on patient outcomes in ER. Disclosures: No relevant conflicts of interest to declare.

Quantification of Anti-Sickling Effect of Aes-103 in Sickle Cell Disease Using an in Vitro Microfluidic Assay

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2699-2699 ◽  
Author(s):  
E. Du ◽  
Laurel Mendelsohn ◽  
James S. Nichols ◽  
Ming Dao ◽  
Gregory J. Kato
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Dependent Manner ◽  
Cell Disease ◽  
Pdms Film ◽  
Patient Sample ◽  
Hydroxyurea Treatment ◽  
O2 Concentration

Abstract Background: Under hypoxic conditions, sickle hemoglobin (HbS) polymerizes, causing morphologic distortion (sickling) of red blood cells (RBCs) in sickle cell disease (SCD). Aes-103 (5-hydroxymethylfurfural, 5-HMF) can stabilize the R-state and increase the oxygen affinity of hemoglobin, inhibiting the intracellular polymerization of HbS. Using a microfluidics-based hypoxia assay, we were able to track sickling of individual cells and quantify the anti-sickling effect of Aes-103 at millimolar (mM) levels in blood from SCD patients on hydroxyurea treatment (on-HU) and not on hydroxyurea treatment (off-HU). Method: We have developed a microfluidic assay that utilizes a gas permeable polydimethylsiloxane (PDMS) film 150 µm in thickness, to create a severe hypoxia microenvironment in a 5 µm deep chamber to measure cell sickling in vitro at 37°C. The hypoxia condition was 5 minutes in total, consisting of an initial oxygen-rich stage (20% O2), a transient deoxygenating stage (O2 concentration decreased to 5% within 15 second), and a steady-stage stage (O2 concentration decreased further and maintained at 2% for the rest of time). Blood samples from 3 on-HU and 3 off-HU patients were incubated with Aes-103 at concentrations of 0.5, 1, 2, and 5 mM for one hour at 37 degrees C, washed with Phosphate Buffered Saline and suspended in RPMI-1640 containing 1% w/v Bovine Serum Albumin for in vitro testing. Sickle RBCs undergoing sickling typically form spiky edges and a dark coarse texture due to intracellular HbS polymerization visually enhanced by a bandpass filter (Fig. 1A). The anti-sickling effect of Aes-103 was then quantified by the maximum sickled fraction (fraction of all RBCs that were morphologically distorted) under the hypoxia condition. Results: In the absence of Aes-103, the sickled fractions varied from 34% to 73% (Mean ± SD: 54% ± 18%). With the presence of Aes-103, the mean sickled fraction decreased with drug concentration (Fig. 1B), which can be well fitted with linear regression (R2= 0.95). With 2 mM Aes-103 incubation, each patient sample showed a significant decrease in cell sickling from its baseline. Addition of Aes-103 at 5 mM concentration prevented majority of RBCs from sickling (sickled fraction ≤ 5%). The sickled fraction of one patient sample was nearly zero. The distribution of sickled fractions does not completely correlate with the patient's HU status in this limited sample size (Fig. 1C). We also observed that hypoxia-induced sickling at baseline showed an apparent bimodal distribution, although the slope of response to Aes-103 concentration was similar. Conclusions: Our microfluidic assay enabled a rapid, quantitative characterization of cell sickling in vitro within a few minutes and using a single drop of whole blood patient sample. We confirmed the anti-sickling efficacy of Aes-103 for both on-HU and off-HU patient samples in a dosage-dependent manner. This assay has potential as a biomarker for drug development and monitoring for in vivo effect of potential anti-sickling therapeutics. Figure 1. (A) Identification of cell sickling from a microscopic image (arrows indicate the sickled RBCs). (B) Sickled fraction as a function of Aes-103 concentration. (C) Variation in response among different on-HU and off-HU patient samples. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Three-Year Follow-Up of Hydroxyurea Treatment in Severely Ill Children with Sickle Cell Disease

1997 ◽  
Vol 19 (4) ◽  
pp. 313-318 ◽  
Author(s):  
M. de Montalembert ◽  
M. Belloy ◽  
F. Bernaudin ◽  
F. Gouraud ◽  
R. Capdeville ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hydroxyurea Treatment

scholarly journals Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4639-4644 ◽  
Author(s):  
Victor R. Gordeuk ◽  
Andrew Campbell ◽  
Sohail Rana ◽  
Mehdi Nouraie ◽  
Xiaomei Niu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Tricuspid Regurgitation ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Systolic Pulmonary Artery Pressure ◽  
Cell Disease ◽  
Hemoglobin F ◽  
Hydroxyurea Treatment ◽  
Relationship Of

AbstractHydroxyurea and higher hemoglobin F improve the clinical course and survival in sickle cell disease, but their roles in protecting from pulmonary hypertension are not clear. We studied 399 children and adolescents with sickle cell disease at steady state; 38% were being treated with hydroxyurea. Patients on hydroxyurea had higher hemoglobin concentration and lower values for a hemolytic component derived from 4 markers of hemolysis (P ≤ .002) but no difference in tricuspid regurgitation velocity compared with those not receiving hydroxyurea; they also had higher hemoglobin F (P < .001) and erythropoietin (P = .012) levels. Hemoglobin F correlated positively with erythropoietin even after adjustment for hemoglobin concentration (P < .001). Greater hemoglobin F and erythropoietin each independently predicted higher regurgitation velocity in addition to the hemolytic component (P ≤ .023). In conclusion, increase in hemoglobin F in sickle cell disease may be associated with relatively lower tissue oxygen delivery as reflected in higher erythropoietin concentration. Greater levels of erythropoietin or hemoglobin F were independently associated with higher tricuspid regurgitation velocity after adjustment for degree of hemolysis, suggesting an independent relationship of hypoxia with higher systolic pulmonary artery pressure. The hemolysis-lowering and hemoglobin F–augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease.

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