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.

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.

scholarly journals Hydroxyurea Treatment Is Associated with Elevated Serum Erythropoietin Concentration but Suppressed Global Hypoxic Transcriptional Responses in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3380-3380
Author(s):  
Xu Zhang ◽  
Wei Zhang ◽  
Binal Shah ◽  
Galina Miasnikova ◽  
Adelina Sergueeva ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Meta Analysis ◽  
Hemoglobin Concentration ◽  
Cell Disease ◽  
Transcriptional Responses ◽  
Hemoglobin F ◽  
Causal Polymorphism ◽  
Hydroxyurea Treatment ◽  
F Cells

Abstract Background The level of distorted erythrocytes due to polymerization of hemoglobin S in sickle cell disease (SCD) (Science 1949;110:543) is a major determinant of the severity of hemolysis and microvascular occlusion (Lancet 2010;376:2018). Erythropoietin (EPO) is elevated in SCD due to hemolytic anemia and a related increase in hypoxia-inducible factors (HIFs) (Eur J Haematol 2007;78:183). Hydroxyurea (HU) is widely used in the treatment of SCD. HU inhibits ribonucleotide reductase (Semin Oncol 1992;19(3 Suppl 9):1-10) and promotes γ globin synthesis thereby increasing HbF-containing erythrocytes (F cells) while suppressing sickle β hemoglobin production (J Clin Invest 1984;74:652 and 2003;111:231). Increased level of F cells reduces hemolysis and ameliorates clinical complications in SCD. We and others have observed an increase in serum EPO level with HU treatment in SCD despite an increase in the hemoglobin concentration, and we hypothesized that this may be due to the known increased affinity of hemoglobin F for oxygen and related tissue hypoxia (Blood 2009;114:4639). Methods Messenger RNA from peripheral blood mononuclear cells (PBMCs) was profiled using Affymetrix Human Exon 1.0 ST Array. Hypoxic transcriptional alteration was defined in 15 Chuvash polycythemia (CP) patients vs. 17 control individuals. CP leads to constitutive up-regulation of HIFs in the absence of anemia or hypoxia. Transcriptional alteration in SCD was determined in 13 HbSS subjects without HU treatment vs. 16 control individuals, and that induced by HU treatment was determined in 19 HbSS subjects with vs. 13 without HU treatment. For meta-analysis on serum EPO concentration, genomic DNA isolated from PBMCs was hybridized to the Illumina Human 610-Quad SNP array. Genotypes were imputed to 1000 genomes project phase 1 data. A linear regression model was applied adjusting for age, gender, hemoglobin concentration, and HU treatment. Results Gene expression changes by HbSS highly correlated with those associated with homozygous VHLR200W (Pearson's r=0.79, Figure 1A). At 5% false discovery rate (FDR), expression levels of 377 genes were altered in both VHLR200W homozygotes and HbSS by >1.2 fold. For these hypoxic genes, the correlation of expression changes between HbSS and homozygous VHLR200W reached r=0.97 (Figure 1B). In contrast to our hypothesis, HU treatment in general suppressed expression changes induced by HbSS (r=-0.85, Figure 1C), especially for the hypoxic genes (r=-0.95, Figure 1D). In VHLR200W homozygotes, 62 of the hypoxic genes correlated with plasma EPO levels (adjusted P<0.05, n=42). These EPO-correlated genes were the most strongly up-regulated hypoxic genes in HbSS (red points in Figure 1B) and also the most strongly suppressed by HU treatment (red points in Figure 1D). Consistent with previous observations, we found that EPO was elevated by HU treatment in two SCD cohorts, and this persisted after adjusting for covariates including hemoglobin concentration which reflects hypoxic as well as inflammatory and hemolytic responses: Walk-PHaSST (β=0.49, P=2.5×10-15, n=586) and PUSH children (β=0.34, P=2.5×10-7, n=387). This observation suggests that biological signals independent of hypoxic regulation may contribute to EPO production under HU treatment. In a meta-analysis for the Walk-PHaSST and PUSH children cohorts, SNP rs60684937, located within the first intron of MAP2K6, an upstream regulator of HIF signaling (Mole Cell Biol 2005; 25:4853), was significantly associated with EPO levels at genome-wide significance (combined P=3.5×10-8). The C allele of the SNP decreased EPO levels in both Walk-PHaSST (β=-0.30, n=388) and PUSH children (β=-0.24, n=249) cohorts. This association was validated in an additional 89 SCD patients from the Howard cohort (β=-0.39, P=0.011). Further investigations are needed to determine whether the causal polymorphism affects protein function or gene regulation of the nearby genes. Discussion Our study demonstrates a prominent release from hypoxic transcriptional responses by HU treatment in SCD despite an increase in serum EPO, a defining characteristic of an up-regulated hypoxic response. Our study hypothesizes that hypoxia-independent signals trigger EPO production in the setting of HU therapy and it identifies a potential genetic determinant in this alternative pathway. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Case Report: Acute Stroke in Young Adult Patient with Moyamoya Syndrome Secondary to Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Oladipo Cole ◽  
Asia Filatov ◽  
Javed Khanni ◽  
Patricio Espinosa
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Moyamoya Disease ◽  
Conflicts Of Interest ◽  
Acute Chest Syndrome ◽  
African American Female ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Radiographic Findings

Moyamoya disease, well described in literature, is a chronic cerebrovascular occlusive disorder. It is characterized by progressive stenosis/occlusion of the terminal portions of the internal carotid arteries (ICA) and the proximal portions of the middle cerebral arteries (MCA). Less frequently described is Moyamoya syndrome, the name given to radiographic findings consistent with Moyamoya disease, but with an identifiable cause. The diseases associated with Moyamoya Syndrome include Sickle Cell Disease (SCD), Thalassemias, and Down's Syndrome to name a few. Common complications of Moyamoya include both ischemic and hemorrhagic strokes. Upon literature review, Moyamoya syndrome caused by SCD is not well described. When it is, the discussion is centered around the pediatric patient population and surgical management. Our case report describes a 22-year-old African American female with SCD who initially presented with Acute Chest Syndrome. Her hospital course was complicated by development of overt debilitating neurologic deficits. Subsequently, she was found to have Moyamoya Syndrome on neuroimaging. She was successfully treated with medical management without any surgical intervention. This case highlights the necessity of thorough examination, differential diagnosis, imaging findings, and consideration of predisposing syndromes in the work-up for Moyamoya syndrome; especially individuals with Sickle Cell Disease. Disclosures No relevant conflicts of interest to declare.

Low Fixed Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Disease in Nigeria

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 981-981
Author(s):  
Titilola S. Akingbola ◽  
Bamidele Tayo ◽  
Santosh L. Saraf ◽  
Binal N. Shah ◽  
Chinedu A Ezekekwu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Low Dose ◽  
Adverse Outcome ◽  
Clinical Malaria ◽  
Fixed Dose ◽  
Cell Disease ◽  
Hemoglobin F ◽  
The Us

Abstract Background: The vast majority of births with sickle cell anemia occur in Africa 1 and early-life mortality, generally before age five years, is as high as 90% 2,3. Hydroxyurea was approved for sickle cell anemia by the US FDA in 1998 but is not commonly used in Africa due to fear of toxicity, lack of awareness and limited availability. Hemoglobin F is a protective factor that decreases severity of sickle cell anemia, and hydroxyurea treatment leads to an increase in hemoglobin F. In the US, hydroxyurea is typically initiated at a dose of 15 mg/kg followed by dose escalations of up to 35 mg/kg if tolerated with a goal of maximal tolerated dose and maximal response in hemoglobin F. Neutropenia and thrombocytopenia are the usual limitations to achieving maximal dose. In the landmark Multicenter Study of Hydroxyurea, the clinical response to hydroxyurea correlated strongly with a reduction in the neutrophil count as well as an increase in the fetal hemoglobin concentration as reflected in percentage of F cells. A striking decrease in pain crises was observed in the first three months of therapy, before dose escalation and before maximal increase in hemoglobin F levels 4. Furthermore, hydroxyurea in the range of 10-15.9 mg/kg/day was reportedly effective in decreasing the frequency of pain episodes in children and adolescents in Oman 5, and hydroxyurea 10 mg/kg/day decreased pain episodes in children and adults with sickle cell anemia in India 6. From these perspectives, we reasoned that a fixed dose of hydroxyurea 10 mg/kg/day is reasonable to investigate in the African setting where the safety in relationship to the resources and infectious exposures is not known. Methods: We assigned 48 sickle cell anemia patients to hydroxyurea 500 mg/day for 24 weeks to determine safety and efficacy; 28 had high-risk disease based on hemoglobin F&lt;8.6% and absence of alpha-thalassemia. We defined a clinically meaningful adverse outcome category as ≥10% of patients developing platelets &lt;50,000/uL, granulocytes &lt;500/uL, clinical malaria and/or active tuberculosis. Picking up refills every four weeks was the adherence metric. We analyzed the results on an intent-to-treat basis. Results: The median (interquartile range) age was 25 (22-27) years and the median hydroxyurea dose 9.8 (9.1-10.4) mg/kg per day. The patients complied with treatment for a median of 20 (16-24) weeks. Four (8.3%) developed a pre-specified adverse outcome: clinical malaria (N=2), thrombocytopenia in combination with malaria (N=1), pulmonary tuberculosis (N=1). During therapy the median hemoglobin increased by 9.0 g/L, mean corpuscular volume by 11.2 fL and body weight by 3.0 kg while median white blood cells declined by 2600 per uL and platelets by 127,000 per uL (P&lt;0.001). The median hemoglobin F increased from 4.1% (2.3-6.3%) at baseline (N=27) to 8.5% (6.3-12.9%) during therapy (N=24) (P&lt;0.001). Conclusion: Our results suggest that low, fixed-dose dose hydroxyurea for sickle cell anemia in Nigeria is associated with a low adverse outcome rate and with improvements in blood counts, hemoglobin F and body weight. The effects on vaso-occlusive episodes and on the risks of recrudescent tuberculosis and malaria-associated thrombocytopenia should be assessed in further studies. Acknowledgment: Supported by a grant from the Doris Duke Foundation. References 1. Williams TN, Obaro SK. Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011;27:315-20. 2. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med 2011;41:S398-405. 3. Makani J, Cox SE, Soka D, et al. Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania. PLoS One 2011;6:e14699. 4. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. 5. Sharef SW, Al-Hajri M, Beshlawi I, et al. Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective. Eur J Haematol 2013. 6. Patel DK, Mashon RS, Patel S, Das BS, Purohit P, Bishwal SC. Low dose hydroxyurea is effective in reducing the incidence of painful crisis and frequency of blood transfusion in sickle cell anemia patients from eastern India. Hemoglobin 2012;36:409-20. Disclosures Ezekekwu: American Society of Hematology: Other: The Visitor training program was sponsored by ASH. Hsu: AstraZeneca steering committee for HESTIA trial: Research Funding. Gordeuk: Emmaus Life Sciences: Consultancy.

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.

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