Optimizing Hydroxyurea Use in Children with Sickle Cell Disease: Least Tolerated Dose Is Effective

Abstract Abstract 4851 Background: Hydroxyurea (HU) is an antimetabolite that effectively ameliorates the course of sickle cell disease (SCD). Starting dose is usually 20 mg/kg/day and the dose is escalated up to 35 mg/kg/day in most of the centers. In Oman, due to high level of consanguinity, ethnic neutropenia affects around 10% of population rendering higher doses difficult to maintain in most of the patients. Materials and Methods: 161 patients (age 2–16 years, 61% male and 39% female) with SCD at Sultan Qaboos University Hospital, Muscat, Oman, were started on HU for clinically severe course (defined as: annual vaso occlusive crisis admissions more than 3, and/or occurrence of acute chest syndrome) with starting dose of 15 mg/kg and a mean dose of 18 mg/kg/day. All patients were included in the study except for 19 patients who were excluded for various reasons (8 lost follow up, 6 stopped HU by parents, and 5 stopped due to side effects: dizziness, abdominal pain, and myelosuppression). Remaining 142 patients were followed up for median treatment duration of 4 years (range, 1.5–10 years). Patients were assessed for clinical and laboratory response to HU. Results: There was significant reduction in the annual number of admissions due to vaso occlusive crisis (P <0.001, Wilcoxon Signed Ranks Test) with a mean of 4.7 and 1.5 before and after HU use respectively. There was also observed clinical improvement regarding the incidence of acute chest syndrome. Only 12 out of 39 patients initiated on HU for acute chest syndrome had a recurrent attack during a follow up period of 3–7 years. The laboratory parameters were consistent with previous reports: significant increase in hemoglobin level, fetal hemoglobin (HbF) level, Mean Corpuscular Volume, whereas significant decrease in platelet, absolute neutrophil, and absolute reticulocytic counts. All 142 patients tolerated the treatment well. Observed side effects included abdominal pain, dizziness, rash, tremor in one patient each. Of note, 21 patients (11.1%) developed neutropenia (ANC<1000 × 10̂9/l) while 7 patients (3.7%) had thrombocytopenia (<100 × 10̂9/l) which interrupted the treatment for period ranging from 3 weeks to 3 months only. Conclusion: In SCD patients with background of ethnic neutropenia, lower starting dose and limited range of dose escalation of HU ensured safety and yet did not affect efficacy. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2020-134202 ◽

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.

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Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽

10.1182/blood-2020-143454 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Satish Maharaj ◽

Simone Chang ◽

Karan Seegobin ◽

Marwan Shaikh ◽

Kamila I. Cisak

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Complete Blood Count ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Acute Chest Syndrome ◽

Adult Males ◽

Cell Disease ◽

Unequal Variances ◽

Recorded Data

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT>0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

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Polymorphisms in TNFα Are Associated with Cerebrovascular Events in Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.1540.1540 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1540-1540 ◽

Cited By ~ 1

Author(s):

Latorya A Barber ◽

Allison E Ashley-Koch ◽

Melanie E. Garrett ◽

Karen L Soldano ◽

Marilyn J. Telen

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Umbilical Vein ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Data Set ◽

Clinical Complications ◽

Cerebrovascular Events ◽

Increased Risk

Abstract Abstract 1540 Poster Board I-563 Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that stimulates phagocytosis, neutrophil recruitment, and expression of adhesion molecule VCAM-1. Plasma levels of TNFα have been found to be increased in sickle cell disease (SCD), and in vitro studies show that TNFα causes increased adherence of sickle red blood cells to human umbilical vein endothelial cells. A polymorphism in the promoter region of the TNFα gene has previously been associated with stroke in children with SCD (Hoppe et al., 2007). The current study was designed to identify associations of additional TNFα single nucleotide polymorphisms (SNPs) with SCD clinical complications. We analyzed five SNPs in the TNFα gene in 509 DNA samples of SCD patients from Duke University, University of North Carolina at Chapel Hill, and Emory University. In our data set, cerebrovascular events (CVEs), including overt stroke, seizures, and transient ischemic attacks, occurred in 133 out of 509 SCD patients (26.1%). SNP genotyping was performed using Taqman genotyping assays from Applied Biosystems. Due to low minor allele frequencies (<0.05) for all the SNPs examined, genetic associations with SCD clinical complications were examined by using allele tests. After controlling for age, gender, and use of hydroxyurea, two of the five TNFα SNPs, rs2228088 and rs3093665, were significantly associated with CVEs (p=0.013 and 0.029, respectively). The odds that SCD patients with a G allele at rs2228088 suffered from CVEs were 0.485 times that for patients with the T allele, suggesting that the G allele had a protective effect. The odds of having the A allele at rs3093665 and suffering from CVEs was also reduced, at 0.45 compared to the C allele. Neither SNP was found to be in linkage disequilibrium (LD) with any of the other SNPs analyzed (r2≤0.002). There was also strong association of SNP rs2228088 with acute chest syndrome (ACS; p=0.003), occurring in 382 out of 509 SCD patients (75%). However, in this analysis, the G allele was associated with increased risk for ACS (OR=2.313). In addition to the association with CVEs, the SNP rs3093665 was also significantly associated with priapism (p=0.03), reported by 86 of 223 male SCD patients (38.6%). In this analysis, the A allele was protective, as had been observed for CVE (OR=0.188). Additionally, we found no difference in steady state plasma TNFα levels between genotypes for the two SNPs. The functional significance of these SNPs is presently unknown. SNP rs2228088 is a synonymous SNP located in the coding region, and rs3093665 is located in the 3' untranslated region of the TNFα gene. While the G to T change at SNP rs2228088 does not translate to a change in amino acid sequence, the A to C change at SNP rs3093665 may affect mRNA stability due to its location. It is also possible that one or both of these SNPs is in LD with another functionally relevant SNP. Our findings thus support previous data implicating TNFα polymorphisms in risk for central nervous system events. Interestingly, ACS has been previously associated with seizures, stroke and altered mental status in adults and children with SCD (Vinchinsky et al., 2000) and with silent cerebral infarcts and reversible posterior leukoencephalopathy syndrome in children with SCD (Henderson et al., 2003). However, in our dataset, ACS and the occurrence of CVEs were not associated (p=0.24). Further studies are required to elucidate these and other factors that potentially correlate with SCD clinical complications. Disclosures No relevant conflicts of interest to declare.

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A North American Experience Of Hemoglobin SC Disease, Its Complications, and Management

Blood ◽

10.1182/blood.v122.21.2221.2221 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2221-2221 ◽

Cited By ~ 1

Author(s):

Veronique Naessens ◽

Richard Ward ◽

Kevin H.M. Kuo

Keyword(s):

Sickle Cell Disease ◽

Avascular Necrosis ◽

Sickle Cell ◽

Care Center ◽

Comprehensive Care ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Baseline Hemoglobin ◽

Hemoglobin Sc Disease

Background The phenotype of hemoglobin SC (HbSC) disease is distinct from sickle cell anemia (SCA) (HbSS and S/b0) but management of adults is mostly derived from studies of the latter group. Longitudinal observational studies on the complications and outcomes of hemoglobin SC disease are largely confined to centers outside North America. The unique ethnic composition of our cohort, consisting of mostly Western Africans and West Indians, permits further characterization of the HbSC phenotype. Objective to describe the baseline characteristics and long-term complications of a cohort of adult HbSC patients followed in a Canadian sickle cell comprehensive care center. Methods A retrospective observational cohort study was conducted on all adult patients with HbSC disease attending a sickle cell comprehensive care center in Toronto, Canada from 1994 to 2013. Baseline demographics, acute and chronic complications attributable to sickle cell disease, and laboratory data were collected. Medians were used to describe continuous variables, while percentages or ratios for categorical variables. Logistic regression was used to examine factors influencing the main clinical complications. Results 104 patients were included in the analysis, comprising of 38.5% males and 61.5% females. Median length of follow-up was 3.5 years (1 - 19) and median age at last recorded visit was 35 years (18 - 68). Median baseline hemoglobin was 119 g/L (82 - 153 g/L), hematocrit 0.340 (0.250 - 0.440), and fetal hemoglobin (HbF) fraction 1% (0 - 7.7%). Most frequent complications encountered were retinopathy (55.8%) and symptomatic avascular necrosis (27.9%), followed by painful vaso-occlusive crises requiring emergency room visit (23.1%). Presence of retinopathy was associated with higher baseline hemoglobin (OR 2.72 for every 10 g/L of hemoglobin, p = 0.037) and older age (OR 2.72 for every decade, p < 0.001). Acute chest syndrome (7.7%), priapism (7.5% of men), and renal involvement (8.2%), were less common than reported in the literature, while the rates of venous thromboembolism (8.7%), symptomatic infarctive or hemorrhagic stroke (2.9%) were slightly more common. Median right ventricular systolic pressure on 2D-transthoracic echocardiogram was 29 mmHg (17 – 43 mmHg). No patient underwent a right heart catheterization. Two patients died from septic shock, both at the age of 29. Disease-modifying therapy most often consisted of hydroxyurea (28.8%), followed by exchange transfusion (6.7%) and phlebotomies (5.8%). Hydroxyurea significantly increased the median HbF fraction (from 1% to 2.75%, p = 0.004 by related-samples Wilcoxon signed rank test). Conclusion In this large North American cohort of adult patients, we have again shown that HbSC disease is not as benign as traditionally thought. As such, patients with HbSC disease warrant similar follow-up to that provided to SCA. Retinopathy, avascular necrosis and painful vaso-occlusive crises were the most common complications in our study, albeit lower than in other reported cohorts. The frequent use of hydroxyurea in this cohort is quite unique compared to other sickle cell comprehensive care centers reported in the literature. However, therapeutic phlebotomy is less often used compared to the European experience. We also observed a lower frequency of retinopathy, avascular necrosis, painful vaso-occlusive crises, priapism and acute chest syndrome. Whether this observation is due to hydroxyurea use or to other genetic or environmental factors remains to be determined. Further studies are also required to develop a more evidence-based therapeutic strategy for this genotype of Sickle Cell Disease. Disclosures: No relevant conflicts of interest to declare.

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Microparticles As Biomarkers Of Osteonecrosis Of The Hip In Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.2226.2226 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2226-2226

Author(s):

Anne M Marsh ◽

Raymond Schiffelers ◽

Ginny Gildengorin ◽

Frans A Kuypers ◽

Carolyn Hoppe

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Vascular Occlusion ◽

Predictive Biomarker ◽

Acute Chest Syndrome ◽

Mobility Limitations ◽

Cell Disease ◽

The Past ◽

D Dimer

Abstract Introduction Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) in children. ONFH is a debilitating condition that is associated with mobility limitations, chronic pain, and an impaired quality of life. While the mechanisms that cause ONFH remain unknown, ischemia from recurrent microvascular occlusion is likely to play a role. Vascular occlusion may result directly from obstruction by sickled cells, or indirectly via complex interdependent pathways characterized by sustained endothelial activation, chronic inflammation, and coagulation. Microparticles (MP) are small, cell membrane-derived vesicles generated in response to cellular activation, injury or apoptosis. MPs have emerged as potential modulators of inflammation and thrombosis and have been found to be elevated in patients with ONFH in the general population. Objective This pilot study examined whether microparticle levels in patients with SCD who have ONFH differ from SCD patients without ONFH, as well as healthy African American (AA) controls. Methods Subjects were recruited at their baseline status and were excluded if they had been transfused within the past 30 days, hospitalized for a vaso-occlusive pain episode, acute chest syndrome, fever or surgery within the past 30 days, or had bony lesions of the femur or hip due to causes unrelated to SCD. For MP analysis, whole blood was collected in sodium citrate tubes and centrifuged for 15 minutes at 1500 x g at 20° C to generate platelet poor plasma. Aliquots of the plasma were immediately frozen and stored at -80° C until the time of MP analysis. 300 μl samples were diluted in PBS and centrifuged at 10000 x g for 1hr and the supernatant was centrifuged at 100,000 x g for 2 hr. The pellet was re-suspended in 1 mL of PBS and subjected to nanoparticle-tracking analysis to determine concentration and size. Additional laboratory biomarkers of inflammation and coagulation, including highly-sensitive C-reactive protein (hs-CRP), von Willebrand factor antigen (vWF Ag), tissue factor (TF), and D-dimer were analyzed for differences between groups. Analysis of variance was used to compare MP and biomarker levels between the three groups. The institutional review board at Children's Hospital & Research Center Oakland approved the study protocol and written informed consent was obtained from all participants. Results Characteristics of the 30 subjects enrolled are shown in Table I. Total microparticle levels in ONFH(+) patients were 2.3-fold higher than in ONFH(-) patients, and 2.5-fold higher than in AA controls (Figure 1). Mean MP levels for ONFH(+) patients, ONFH(-) patients, and AA controls were 4.55 x 1010, 1.99 x 1010, and 1.85 x 1010, respectively. Microparticle levels in ONFH(-) SCD patients did not differ from AA controls. There were no statistically significant differences in hsCRP, vWF Ag, TF, or D-dimer levels between the ONFH(-) and ONFH(+) groups. Conclusions The results of this study demonstrate significantly elevated MP levels in individuals with SCD who have ONFH. Additional studies are needed to better understand the mechanistic effects of MPs on the development of ONFH and to determine whether MP levels may be useful as a predictive biomarker for early disease detection. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Disclosures: No relevant conflicts of interest to declare.

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Implementation of a European Cohort to Follow Sickle Cell Children and Adults Treated with Hydroxycarbamide

Blood ◽

10.1182/blood.v124.21.564.564 ◽

2014 ◽

Vol 124 (21) ◽

pp. 564-564

Author(s):

Mariane De Montalembert ◽

Frédéric Galacteros ◽

Jean Antoine Ribeil ◽

Uwe Kordes ◽

Jean Benoit Arlet ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Safety Profile ◽

Conflicts Of Interest ◽

Subcutaneous Tissue ◽

Acute Chest Syndrome ◽

Control Group ◽

Cell Disease ◽

Skin Reactions ◽

Number Of Patients

Abstract Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is a multicenter prospective non interventional study implemented in Europe to collect more information about the safety profile of HU and morbi-mortality in SCD patients treated with HU. The study responds to EMA (European Medicines Agency) request and has been approved by the Ethical of Necker Enfants Malades Hospital (Paris, France).The ongoing study involves the largest number so far of patients with SCD treated with HU. Primary endpoints of ESCORT HU are to determine frequency of adverse events, and possible consequent changes of HU treatment. Secondary endpoints are to evaluate morbi-mortality of the disease although in the absence of control group. From June 2008 to June 2014, 483 patients (255 females; 228 males) were enrolled from 3 European countries, Greece (24%), Germany (19%), and France (56%). 67% patients were adults, median aged 37.35 yrs (17-83.5) and 33% were children, median aged 11.06 yrs (2.6-16.9). genotypes were HbS/HbS in 71.4% cases, and compound heterozygotous HbS/β-thalassemia in 22.8 % (Table 1). 137 (28.4%) patients experienced 421 events (Table 2). 132 (32.2%) of these events may be attributed to HU. The safety profile is roughly similar in children and adults. As expected the most frequent side effects were firstly blood disorders (n=86 events, 42.4%) such as neutropenia or thrombocytopenia. In all cases, these cytopenias were rapidly resolved with the transitory stop of HU. 71 events related to skin and subcutaneous tissue disorders were observed, mostly cutaneous dryness, skin reactions, alopecia and nails or skin pigmentation; 4 patients had a leg ulcer (34.8%). Most of these events are ongoing or stabilized despit the decrease of HU. No secondary cancer has been reported until now. Even if HU is an old drug with a relatively well-known safety profile, some uncertainties remain in terms of long-term safety as well as tolerance in the youngest people. The main interest of ESCORT HU is to offer the possibility of safety surveillance of hydroxycarbamide in European sickle cell patients. Table 1 Demographic data Adults Children < 17 years old Total Number of patients 322 (67%) 161 (33%) 483 Females/Males 183/139 72/89 255/228 Median age (yrs) (range) 37.35 (17-83.5) 11.06 (2.6-16.9) 28.58 Genotype SS 206 (64%) 139 (86.3%) 345 (71.4%) SC 1 (0.3%) 3 (1.86%) 4 (0.8%) Sβ0 51 (15.8%) 11 (6.8%) 62 (12.8%) Sβ+ 46 (14.2%) 2 (1.2%) 48 (9.9%) Other 18 (5.5%) 6 (3.7%) 24 (4.9%) Treatment with HU before enrollment in ESCORT HU No of pts 232 83 315 (65%) Median duration (range) of HU treatment before ESCORT HU 8.2 yrs (0.5 ans-24 yrs) 3. 1 yrs ( 71 days – 8.9 yrs) 6.85 (71 days-24 years)] HU ESCORT Daily mean dose (mg/kg/d) 16.11 ± 4.79 19.63 ± 4.69 17.32 ± 4.94 Abstract 564. Table 2 The most frequent events of hydroxycarbamide in the two populations of SCD patients ADULTS CHILDREN No ofGerman(%) No of adults No ofEpisodes(%) No of children Total(% /411) Events Related to HU treatment (Siklos®)(%**) Blood and lymphatic system disorders (%) 32 (17.7) 22 54 (31.03) 28 86 (20.9) 56 (65.1) Skin and subcutaneous tissue disorders (%) 42 (23.2) 28 29 (16.7) 19 71 (17.3) 46 (64.8) Nervous system disorders Headache (24), Dizziness/vertigo (14), 32 (17.7) 23 12(6.9) 10 44 (10.7) 11 (25) Gastrointestinal disorders Nausea (14), diarrhea (8), other (14) 20 (11) 17 23 (13.2) 16 43 (10.4) 7 (16.3) Metabolic and nutrition disorders: vit D deficiency (17), weight gain (5) 13 (7) 11 18 (18.3) 18 36 (8.75) 4 (11.1) Fever 11 (6) 10 12(6.9) 7 23 (5.6) 1 (4.3) Cardiac disorders (hypertension, bradycardia, chest pain, cardiomegaly) 4 4 2 2 6 1 (16.6) General disorders : fatigue 5 5 0 0 5 0 Hepatobiliary disorders 2 2 0 0 2 0 Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Harmatoma, benign vulvar sebaceous cyst 2 2 0 0 2 0 Renal & urinary disorders 2 2 0 0 2 0 Reproductive system and breast disorders 3 3 0 0 3 0 Other 13 13 21 14 34 6 (17.1%) 181 80 /181(24.8%) 174 57 / 174(35.4%) 411 132/411 (32.2%) ** compared to the total number of “system organ class” events Disclosures No relevant conflicts of interest to declare.

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Incidence and Risk of Delayed Hemolytic Transfusion Reaction in Sickle Cell Disease Patients Based on a Prospective Study

Blood ◽

10.1182/blood.v128.22.95.95 ◽

2016 ◽

Vol 128 (22) ◽

pp. 95-95 ◽

Cited By ~ 1

Author(s):

France Pirenne ◽

David Narbey ◽

Philippe Chadebech ◽

Armand Mekontso-Dessap ◽

Pablo Bartolucci ◽

...

Keyword(s):

Sickle Cell Disease ◽

Prospective Study ◽

Sickle Cell ◽

Acute Chest Syndrome ◽

Transfusion Reaction ◽

Cell Disease ◽

Hemolytic Transfusion Reaction ◽

Delayed Hemolytic Transfusion Reaction ◽

Prospective Longitudinal

Abstract Background Delayed hemolytic transfusion reaction (DHTR) is a life threatening complication of transfusion in sickle cell disease (SCD). This syndrome is underestimated because of a clinical picture that resembles a vaso-occlusive crisis (VOC) and the frequent absence of detectable antibodies. Several retrospective studies have evaluated the frequency of DHTR based on case reports. We conducted a prospective, longitudinal, single center study to determine the incidence of DHTR and the risk of developing DHTR depending on the transfusion regimen: chronic versus punctual. Methods and patients SCD patients aged over 18 years, undergoing a transfusion, were enrolled in this study. A total of 697 transfusion episodes (TE) in 312 patients were included during 30 months. Some patients had multiple TE during the period. The post transfusion outcome of the patients was assessed up to one month after the included TE. DHTR was confirmed based on the rapid disappearance of HbA (> 50% 15 days post-transfusion) associated with two of the following criteria up to three weeks after transfusion: VOC symptoms, dark urine, worsening anemia, increased LDH. Transfusion episodes were divided into chronic (336 TE in 111 patients) and punctual (361 TE in 201 patients). Chronic transfusions were defined as regular transfusions to treat chronic complications or for primary/secondary prevention of complications. Short transfusion program during pregnancy was considered as punctual transfusions if patients were not previously regularly transfused. The study obtained approval of the local Ethics Committee. Results Follow-up of the patients after transfusion showed 15 DHTR during the study. They all developed in punctually transfused patients. Thus, patients who are transfused punctually have a significantly higher risk of developing DHTR than those in a regular transfusion program (p < 0.001). When considering only punctual transfusions, the incidence of DHTR is 4.2% per transfusion episode (IC 95% [2.6; 6.9]) and 7.5% per patient during the 30 months of the study (IC 95% [4.6; 12.4]). In these DHTR cases, the transfusion indication was surgery (n = 6), pregnancy (n = 3), acute chest syndrome (n = 3), stroke (n = 1), profound anemia (n = 1), and VOC prevention before a school exam (n = 1 case). Two patients died of multi-organ failure following severe intravascular hemolysis. The median hemoglobin decrease for all DHTR cases after the triggering transfusion was 4.4 g/dl [IQR 3.6-5.2]; the highest LDH level was 879 [IQR 680-1423]. Ten patients developed newly formed antibodies, but only five among them displayed antibodies with significant serological features (anti-Fya, anti-S, anti-Jka, anti-HI). In the five other cases, the antibodies were of unspecified specificity or auto antibodies in the RH blood group (the genetic RH background was known). Finally, antibodies were undetectable for five cases, confirmed by long-term patient follow up. Conclusion This prospective study demonstrates, for the first time, that DHTR is a frequent reaction in adult SCD patients, developing only in occasionally transfused patients. This finding highlights that adult patients with regular transfusion who did not previously encountered DHTR are not susceptible to developing this severe reaction. A mechanism linked to acute situations can be suggested as already shown for the induction of allo-immunization. However, many cases developed without detectable antibodies, confirming the complex pathophysiology of this syndrome. A bio-clinical scoring system to predict DHTR, based on this study, is under development and will be presented. Disclosures Michel: Roche: Research Funding.

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Five years of experience with hydroxyurea in children and young adults with sickle cell disease

Blood ◽

10.1182/blood.v97.11.3628 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3628-3632 ◽

Cited By ~ 132

Author(s):

Alina Ferster ◽

Parvine Tahriri ◽

Christiane Vermylen ◽

Geneviève Sturbois ◽

Francis Corazza ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Laboratory Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Significant Difference ◽

History Of ◽

Ischemic Attack

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P = .0002) and days in the hospital (P < .01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support.

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Risk Factors Predisposing Development of Priapism in Sickle Cell Disease Patients

Blood ◽

10.1182/blood-2018-99-118475 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4917-4917

Author(s):

Salam Alkindi ◽

Said AlMufargi ◽

Anil Pathare

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Cardiovascular Response ◽

Acute Chest Syndrome ◽

Serum Total Bilirubin ◽

Cell Disease ◽

Retrospective Case ◽

Chi Square ◽

Sexual Stimulation

Abstract Background and Purpose: Penile erection and detumescence are complex physiologic processes, which require delicate neurohormonal and cardiovascular response. Priapism is defined as a persistent and painful erection lasting longer than four hours without sexual stimulation. Stuttering priapism is characterized by a self-limited, recurrent, and intermittent erection, frequently occurring in patients with sickle cell disease(SCD). The aim of this study was to identify the clinical and laboratory features in SCD patients with priapism in Oman. Methodology: In this retrospective case-control study, medical records of all patients with SCD who developed priapism were retrieved from the hospital information system and compared in a 1: 1 ratio with age and gender matched SCD patients who did not ever had priapism. Addition information extracted include hematological and laboratory parameters, treatment, and complications. Data obtained were analyzed using IBM SPSS version 23. The study was conducted following approval from the hospital medical research and ethics committee. Results & Discussion: Amongst the forty-one SCD patients evaluated, in the 21 patients with priapism (mean age 24.7 yrs), there was a significantly higher WBC, platelet, retic counts, LDH and serum total bilirubin as compared to controls (p<0.05, student's t test). However, there was no significant differences in the incidence of vaso-occlusive crisis, acute chest syndrome, pulmonary hypertension or cerebrovascular accident (p >0.05, Chi Square test). Patients with priapism were managed with exchange transfusion (100%), aspiration (52%) and shunting (5%). Interestingly, none of these patients showed impotence, although 10% manifested with infertility. Conclusions: Priapism in this SCD cohort is a disease of the young, and seen predominantly in the hemolytic phenotype of the disease. Patients with priapism showed high WBC's, Platelets, Bilirubin, LDH and retics with a lower hemoglobin as compared to the controls. Favorable outcome is dependent on early intervention and almost half of these patients needed surgical intervention. Disclosures No relevant conflicts of interest to declare.

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Progression of Pulmonary Hypertension in Patients with Sickle Cell Disease.

Blood ◽

10.1182/blood.v106.11.3187.3187 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3187-3187 ◽

Cited By ~ 3

Author(s):

Kenneth I. Ataga ◽

Charity Moore ◽

Susan Jones ◽

Oludamilola Olajide ◽

Dell Strayhorn ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Left Ventricular ◽

Right Atrial ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Original Cohort ◽

The Mean

Abstract Introduction: The prevalence of pulmonary hypertension (PHT) is high in patients with sickle cell disease (SCD). Although most patients have only mild increases in their pulmonary artery systolic pressure (PASP), the presence of PHT is strongly associated with an increased risk of death. While PHT seen in SCD is thought to progress over time, both the rate of development of PHT and the factors that affect disease progression remain unknown. Methods: The 41 subjects in this study were drawn from an original cohort of 60 patients followed in the Sickle Cell Clinic at UNC-Chapel Hill. All patients were previously evaluated for PHT (defined using an age-, sex-, and BMI-adjusted reference range). Of the 60 patients in the original cohort, six are now deceased and 13 others were not available for repeat evaluation. The PASP was determined using Doppler echocardiography and then applying the modified Bernoulli equation (PASP = 4V2 + right atrial pressure). Individuals were not studied if they: 1) showed clinical evidence of left ventricular failure; 2) had a recent acute illness (e.g., vaso-occlusive crisis); or 3) had experienced an episode of acute chest syndrome within the preceding 4 weeks. Means and standard deviations were calculated for all measures at the time of initial evaluation and at the time of follow-up. Results: Of the 41 subjects in our study, PHT was originally present in 12, while no evidence of PHT was present in 29. Of the 29 subjects who initially had no evidence of PHT, 4 (or 14%) have now developed PHT (mean follow-up period of 3.3 ± 0.4 years). In these 4 subjects, the mean PASP at the time of initial and follow-up evaluations respectively were: 37.0 ± 2.0 mm Hg vs. 55.8 ± 11.0 mm Hg. The patients who developed PHT during the course of the study had lower systolic BP (143 ± 12 mm Hg vs. 128 ± 12 mm Hg), lower fetal hemoglobin levels (6.2 ± 5.7 % vs. 4.2 ± 3.7 %), and higher platelet counts (276 ± 119 X 103/μL vs. 426 ± 96 X 103/μL) at the time of their follow-up analyses. By contrast, 3 of the 12 subjects (or 25%) who were thought to have PHT at the time of their original evaluations were found to have normal PASP determinations at the time of their repeat echocardiograms (mean follow-up period of 3.2 ± 0.6 years). In these latter 3 subjects, the mean PASP values at the time of the initial and follow-up evaluations respectively were: 40.0 ± 4.6 mm Hg vs. 33.7 ± 4.7 mm Hg. Conclusion: In this small group of patients with SCD, we found that PHT developed in 14% of subjects who had no evidence of PHT 3 years earlier. Based on this observation, it seems that periodic echocardiograms to screen for the development of PHT would be appropriate. On the other hand, our observation that some patients initially classified as having PHT failed to have elevated PASP measurements at the time of follow-up illustrates the limitation of a single echocardiographic evaluation in establishing this diagnosis. Because of the increase in PASP that occurs during acute vaso-occlusive episodes, and the difficulty usually encountered in distinguishing steady state from crisis, the initial elevation of the PASP in these patients could have resulted from sub-clinical crisis states. For these reasons, a patient found to have an elevated PASP at the time of a screening echocardiogram should have a repeat study, and perhaps a right heart catheterization, before the diagnosis of PHT is firmly established.

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