Hemgolobin S-C Disease at the Emory University Georgia Comprehensive Sickle Cell Center at Grady Health System

Abstract Introduction Unlike sickle cell anemia (HbSS disease), little research has been devoted specifically to Hemoglobin SC (HbSC) disease. Though distinct, the disease is often treated simply as a milder form of HbSS disease. As a result, its associated manifestations are less well defined which leads to mismanagement of these patients in the medical community. The aim of this study was to further define HbSC disease and its manifestations, as well as evaluate the burden of chronic opiate use and healthcare utilization in this population. Design and Methods A retrospective chart review was performed utilizing patients from one of the largest sickle cell clinics in North America. Patients with hemoglobin electrophoresis confirmed HbSC disease that had been to the center between 2010 and 2016 were identified. Clinical data relating to baseline laboratory values, HbSC disease-related complications and acute care visits was then abstracted from patient's medical records and analyzed to further define this population. IRB approval was granted for this retrospective review. Results A total of 210 patients were included in the study. The cohort had a median age of 35 years (mean of 37.2 years, range of 18 to 81 years) and 57.1% were female while 42.9% were male. Steady state laboratory values included an average hemoglobin (HGB) concentration of 11.67 mg/dL. The incidence of chronic complications including chronic opiate use, avascular necrosis (AVN), retinopathy and pulmonary hypertension were 34.76%, 23.33 %, 65.22% (in those with a documented fundoscopic exam) and 2.38% respectively. The incidence of acute complications during the study period including venous thromboembolism, stroke, and acute chest syndrome were 7.62%, 0% and 1.9% respectively. A total of 183 patients (87.1%) had an acute care visit for vaso-occlusive pain crisis during the study period of 6 years (average of 3.51 visits/patient/year) while 113 patients (53.8%) required hospital admission for a vaso-occlusive pain crisis (average of 0.43 admissions/patient/year with an average length of stay of 3.91 nights). Subgroup analysis comparing those with and without chronic opiate use (more than 3 months chronic pain) revealed similar baseline demographics with median ages of 38 and 33 (average age of 38.5 vs. 36.5, p-value 0.31), respectively. The two groups were also similar in steady state laboratory values (Hemoglobin concentration of 11.69 mg/dL versus 11.65 mg/dL, p-value 0.86) and incidence of AVN (28.77% versus 20.44%, p-value 0.17). However, chronic opiate users did have a significantly higher number of acute care unit visits per year (average of 6.15 versus 1.35, p-value 0.0001) and hospital admissions per year (0.84 versus 0.22, p-value of 0.0001), with chronic opiate users (34.8% of the study population) accounting for 74% of all acute care visits and 71.2% of all hospital admissions. Conclusions This cohort helps to further define HbSC disease as a distinct entity from HbSS disease and demonstrates that, though often thought of as mild, this disease places a significant burden on the healthcare system. As expected, the degree of anemia was quite mild compared to that seen in HbSS disease and there were significantly less episodes of stroke and acute chest. However, the incidence of AVN was similar to that seen in HbSS disease and in those with a documented fundoscopic exam the degree of retinopathy was higher, demonstrating one of the characteristics that makes this disease unique. Subgroup analysis of those with chronic opiate use reveals a population with a propensity toward high health care utilization. These distinctions help to identify risks of morbid complications in this population as well as areas to focus efforts in screening and prevention. Disclosures No relevant conflicts of interest to declare.

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The Use of Chronic Transfusions in Sickle Cell Disease for Non-Stroke Related Indications

Blood ◽

10.1182/blood.v124.21.4934.4934 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4934-4934 ◽

Cited By ~ 1

Author(s):

Lindsay Mize ◽

Shelly Burgett ◽

Julia Xu ◽

Jennifer Rothman ◽

Nirmish Shah

Keyword(s):

Sickle Cell Disease ◽

Acute Care ◽

Sickle Cell ◽

Emergency Department Visits ◽

Acute Chest Syndrome ◽

Blood Transfusions ◽

Recurrent Pain ◽

Cell Disease ◽

Pain Crisis

Abstract Introduction: Sickle cell disease (SCD) is a chronic disease that can cause significant complications including acute chest syndrome, recurrent pain and stroke. Current guidelines for the use of chronic transfusions include primary and secondary prevention of stroke. Although there is currently limited support for the routine use of transfusions for acute vaso-occlusive crisis (VOC), there has been increasing use of chronic transfusions as an alternative treatment for recurrent VOC. Moreover, there is evidence that patients on chronic transfusions have less VOC. We sought to review the outcomes of patients at our institution placed on chronic transfusions for non-stroke related indications. Methods: We performed a retrospective cohort study to summarize clinical and nonclinical features of sickle cell patients on transfusions for non-stroke related complications. Demographic, clinical, and laboratory information were summarized. Acute care events per month were calculated for both the year prior and up to one year following initiation of chronic transfusions. Acute care events were defined as emergency department visits or hospitalization. Results: Of the 378 patients with SCD treated in the pediatric specialty clinic, there were 21 patients being either chronically transfused or exchange transfused. Six (20%) of these patients were initiated on chronic blood transfusions (CBT) for recurrent pain crisis (median age = 12, range 8 to 17). One of these patients also had suspected hepatic sequestration. All patients were type SS and had been treated with hydroxyurea (HU) for an average length of 6.5 years (range 1 to 12 years) at a mean dose of 25 mg/kg (SD 4) prior to initiation of CBT. All patients continued on HU during chronic blood transfusions. Patients were on chronic transfusions for a median of 11 months (range 3 to 58 months) with mean %S while on transfusions of 39.6% (SD 10). Patients were transfused on average every 5 weeks (range 4 to 6 weeks). Following initiation of transfusions, 50% were started on chelation based on criteria of having a ferritin >1000 ng/mL. Mean peak ferritin was not significantly increased in the year following the start of CBT (513 ng/mL ± 343 vs. 1260 ± 934, p=0.13). There was one new alloantibodies (anti-Jk) reported following initiation of CBT, which developed within 3 months. Acute care visits per month were significantly higher in the year prior as compared to after initiation of chronic blood transfusions (1.04 ± 0.45 vs. 0.28 ± 0.22, respectively; p=0.006) (Figure 1). Discussion: We found that patients started on chronic transfusions for pain crisis had a non-significant increase in peak ferritin and a significant reduction in acute care visits. Prior to CBT, all patients had been initiated on hydroxurea (mean dose of 25mg/kg) in an attempt to treat recurrent VOC. However, following therapy for an average of 6.5 years, patients were placed on CBT to prevent further acute care visits and reduce morbidity. All patients were continued on HU while on CBT with no dose adjustment or effort to titrate to maximum tolerated dose. While on CBT, patients had a mean %S of 40%, which is higher than the recommended goal of 30% for stroke related indications. Importantly, despite the higher mean %S, there was a drastic and significant decrease in acute care visits. It should be noted that although only three patients (50%) of patients were placed on chelation, the remaining three had been on transfusions for less than or equal to 6 months and likely to require chelation with continued therapy. The expected elevated ferritin highlights the difficulty in long-term treatment with chronic transfusion and risk for eventual iron overload. The balance between the clinical benefit and potential long-term complications leads to individual assessment of the risks and benefits prior to initiation of chronic transfusions for VOC. These results advocate for the use of prospective studies to evaluate the role for chronic transfusions for non-stroke related indications in SCD. Figure 1 Figure 1. Disclosures Shah: Novartis: Speakers Bureau.

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A Standardized Clinical Flow Adhesion Assay of Whole Blood Adhesion to VCAM-1 Predicts Severe SCD Phenotypes in a 2-Yr Prospective Observational Follow-up of the Original Elipsis Cohort

Blood ◽

10.1182/blood-2019-126371 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3562-3562

Author(s):

Patrick C. Hines ◽

Ahmar Urooj Zaidi ◽

Xiufeng Gao ◽

Ke Liu ◽

Muhammad O. Shareef ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Whole Blood ◽

Hospital Admissions ◽

Phenotypic Variability ◽

Acute Chest Syndrome ◽

Adhesion Assay ◽

Cell Disease ◽

Equity Ownership

Sickle cell disease (SCD) is a complex, multi-organ system condition characterized by frequent and unpredictable vaso-occlusive episodes (VOEs) and significant phenotypic variability. Red blood cell (RBC) adhesion contributes to vaso-occlusive pathology, thus we have developed and validated a standardized clinical whole blood flow adhesion assay to VCAM-1 (FA-WB-VCAM) to serve as a clinical biomarker of RBC health in sickle cell disease and other conditions1-4. Blood for the FA-WB-VCAM assay is drawn in sodium citrate tubes and can be stored at 4oC for up to 48hrs. Whole blood samples are perfused through VCAM-1-coated channels and adherent blood cells are quantified manually to generate a clinical adhesion index (cells/mm2). We previously reported longitudinal steady-state FA-WB-VCAM adhesion indices established from every 3 weeks blood sampling over 6 months (mean=368.3 ±198.4 cells/mm2, range=83.50 - 917.0), and the correlation of steady state adhesion indices to a lifetime historical SCD severity index (SCDI) (r=0.5851, p=0.0003) 5,6. The lifetime historical SCDSI was calculated by quantifying the total number of objectively, documentable, vaso-occlusive end-organ events (VEEs), including acute chest syndrome/pneumonia, stroke, priapism, splenic sequestration, hepatic sequestration, and cholelithiasis, indexed over the total years of life (# VEEs/age; range=0.0 to 0.38 in ELIPSIS). The objective of this study was to determine if the FA-WB-VCAM could predict clinical SCD severity prospectively using various metrics of disease severity, including the SCDI over a 2-year period post ELIPSIS. First, we classified study subjects as "severe" or "mild/moderate" adhesion phenotypes defined by mean steady state adhesion indices acquired from every 3 week sampling over 6 months of the ELIPSIS study (severe adhesion phenotype: > 75th percentile, 455.9 cells/mm2; mild/moderate adhesion phenotype: < 75thpercentile). VEEs were verified by retrospective review of medical records, and a SCDSI over the 2-year period following the ELIPSIS study was established. Our data show that individuals with severe adhesive SCD phenotypes experienced significantly more VEEs compared to individuals with low/moderate severe adhesive SCD phenotypes (mean=55.67 ±69.78 compared to mean=17.04 ±20.58 respectively; p=0.01). SCD patients with severe adhesive phenotypes also had more hospital admissions (mean=5.67 ±2.29 compared to mean=2.88 ±3.41, p=0.001), ER visits (mean=36.00 ±63.42 compared to mean=9.20 ±15.65, p=0.02), transfusions (mean=4.33 ±3.74 compared to mean=1.60 ±2.55, p=0.01), acute chest syndrome/pneumonia (mean=1.56 ±0.73 compared to mean=0.20 ±0.65, p<0.001), and priapism (mean=2.56 ±5.57 compared to mean=0.00 ±0.00, p=0.003) when compared to low/moderate adhesive phenotypes. These data suggest that the FA-WB-VCAM assay may serve as a predictive biomarker for impending VEEs, and a monitoring biomarker to assess response to SCD-modifying therapies. Additional studies in a larger prospective cohort are required to definitively establish the clinical utility of the FA-WB-VCAM assay. Disclosures Hines: Functional Fluidics: Equity Ownership. Gao:Functional Fluidics: Equity Ownership. Liu:Functional Fluidics: Employment. White:Functional Fluidics: Equity Ownership.

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Assessment of Bone Marrow Function in Sickle Cell Anaemia Patients Using Corrected Reticulocyte Counts

Blood ◽

10.1182/blood.v126.23.4581.4581 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4581-4581

Author(s):

Titilola S. Akingbola ◽

Chinedu Anthony Ezekekwu ◽

Joseph Yaria ◽

Santosh L. Saraf ◽

Lewis L. Hsu ◽

...

Keyword(s):

Bone Marrow ◽

Steady State ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Reticulocyte Count ◽

P Value ◽

Production Index ◽

Risk Of Death ◽

Increased Risk ◽

Reticulocyte Production

Abstract Introduction: Chronic hemolysis occurs in sickle cell anemia as a result of recurrent sickling and other abnormalities of the red blood cells including eryptosis. Exuberant reticulocytosis is anticipated to partially compensate for the resultant anemia. Sickle cell anemia patients may also have aplastic crisis, bone marrow (BM) infarction and erythropoietin deficiency which could lead to reticulocytopenia despite the anemia. High degree of reticulocytosis among asymptomatic infants with sickle cell anemia has been associated with an increased risk of death or stroke during childhood. Assessment of BM function in sickle cell anemia is important due to potential complications associated with both under-activity and hyperactivity. This study aimed at evaluating the erythropoietic function of the BM in steady state sickle cell anemia using corrected reticulocyte counts. Methods: This study was carried out at the hematology clinic in the University College Hospital, Ibadan. HbSS patients in steady state were recruited from the hematology clinic. Local ethical committee approval was obtained and all participants gave written informed consent. Patients with M. tuberculosis, Hepatitis B, HIV and P. falciparum infection were excluded. Peripheral blood samples were analyzed using Sysmex Ki-X21 for complete blood count (CBC) and standard point of care for serum electrolytes and liver function tests. The glomerular filtration rates were calculated using the Cockcroft-Gault formula. Reticulocyte counts were determined manually using fresh samples from K2 EDTA bottles and methylene blue stain. Two drops of stain were mixed with two to four volumes of anticoagulated blood and incubated at 37ºC for 15 minutes. Afterwards, the cells were re-suspended and blood films were made. Corrected reticulocyte count and reticulocyte production index were calculated. Participants were categorized according to corrected reticulocyte counts of greater than or less than 2.5%. Univariate and multivariate analyses were performed to determine variables associated with corrected reticulocyte count <2.5%. Results: 92 HbSS patients were recruited with a mean (SD) age of 19.6 (5.8) years. There was no correlation between age and eGFR (p-value: 0.227). Median (range) reticulocyte count, corrected reticulocyte count and reticulocyte production index were 5.5 (0.5 - 29.9), 3.3 (0.1 - 17.1) and 1.7 (0.2 - 8.6) respectively. 40 (43.5%) patients had corrected reticulocyte count <2.5% and 52 (56.5%) had a corrected count >2.5%. Those corrected reticulocyte count <2.5% were older (p: 0.013), taller (p: 0.041) and had higher aspartate transaminase (AST) levels (p: 0.006) than those with corrected counts >2.5% (Table 1). CBC parameters were not different when compared between both groups. Results of multivariate logistic regression analysis carried out showed that only AST was independently linked with corrected reticulocyte count <2.5% (R2: 0.172, p-value: 0.001) (Table 2). Table 1. Factors Associated with Low Reticulocyte Count Corrected count<2.5% Corrected count>2.5% p-Value Age (Mean, SD) 21.4 (6.3) 18.4 (5.0) 0.013 Gender (N, %) Male 22 (55.0) 28 (53.8) 0.912 Female 18 (45.0) 24 (46.2) Height (Mean, SD) 1.6 (0.1) 1.5 (0.1) 0.041 BMI (Mean, SD) 18.7 (3.1) 18.7 (3.0) 0.753 GFR (Mean, SD) 64.3 (37.7) 66.4 (29.3) 0.453 Bilirubin (Mean, SD) 1.7 (1.1) 1.9 (2.6) 0.674 AST (Mean, SD) 22.5 (13.5) 14.5 (6.6) 0.006 ALT (Mean, SD) 13.4 (7.7) 14.4 (11.1) 0.876 Table 2. Independent Predictors of Corrected Reticulocyte Count <2.5% or 95% CI p-Value Age 1.08 0.97 - 1.21 0.169 Height 19.8 0.11 - 366.10 0.259 AST 1.10 1.04 - 1.17 0.002 Hemoglobin 1.00 0.97 - 1.02 0.872 R2: 0.172, p: 0.001 Conclusion: Despite corrected reticulocyte count <2.5% in about half of the patients, there were similar hematological parameters and eGFR in both groups of patients. AST is a marker of hemolysis and low ALT rules out hepatic involvement. Since only 17.2% of the variability in BM response as assessed by corrected reticulocyte count could be accounted for by variables included in this study, there is a need to further evaluate the BM function of sickle cell patients to establish the causes of corrected reticulocyte count <2.5% in the setting of anemia, having ruled out erythropoietin as well as iron, folate or cobalamin deficiencies. This will aid the development of a functional algorithm for the individualized management of sickle cell disease patients with anemia. Disclosures No relevant conflicts of interest to declare.

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ADULT SICKLE CELL ANAEMIA PATIENTS IN BONE PAIN CRISIS HAVE ELEVATED PRO-INFLAMMATORY CYTOKINES

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2018.017 ◽

2018 ◽

Vol 10 (1) ◽

pp. e2018017 ◽

Cited By ~ 4

Author(s):

Adekunle Emmanuel Alagbe ◽

John Ayodele Olaniyi ◽

Oladapo Wale Aworanti

Keyword(s):

Steady State ◽

Sickle Cell ◽

Plasma Levels ◽

Bone Pain ◽

Sickle Cell Anaemia ◽

Cross Sectional Study ◽

Cross Sectional ◽

Tnf Α ◽

Pain Crisis ◽

State Group

Background and Objective: Inflammatory markers that influence bone pain crisis (BPC) and other complications of sickle cell anaemia (SCA) are numerous and play various roles. This study determined the plasma levels of tumour necrosis factor (TNF) - α, interleukin - 8 (IL-8), and endothelin - 1 (ET-1) in adult SCA patients during BPC and in steady state. In addition, the plasma levels of these cytokines were correlated with the severity of BPC of the patients.Methods and Materials: Sixty adult SCA patients (30 during BPC and 30 during steady state) and 30 haemoglobin A controls were enrolled for this cross-sectional study. The severity of BPC was assessed clinically, and questionnaires were filled. Plasma levels of TNF- α, IL-8 and ET-1 were quantified by ELISA, and haematological parameters were determined using a 5-part auto-analyzer. Plasma levels were correlated with the severity of bone pain crisis. Results were considered statistically significant if p<0.05.Results: Plasma TNF-α, IL-8, and ET-1 were significantly elevated in the BPC group than in the steady state group and the controls. Plasma TNF-α, IL-8 and ET-1 were markedly higher in the severe BPC groups than the steady state and control groups, There was a positive correlation between TNF-α and ET-1 in the bone pain crisis group.Conclusion: Elevated levels of plasma TNF-α, IL-8, and ET-1 further establish the chronic inflammatory state in SCA and equally affirm their significant contribution, not only to pathogenesis but also to the severity of pain in SCA. Keywords: Sickle cell anaemia, Cytokines, Bone pain crisis, Severity, Steady state.

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Risk Factors for Intracranial Hemorrhage in Children with Sickle Cell Anemia.

Blood ◽

10.1182/blood.v104.11.1657.1657 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1657-1657

Author(s):

John J. Strouse ◽

Michael R. DeBaun ◽

James F. Casella

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Ischemic Stroke ◽

Steady State ◽

Sickle Cell ◽

Intracranial Hemorrhage ◽

Sickle Cell Anemia ◽

Small Sample ◽

Acute Chest Syndrome ◽

Corticosteroid Administration

Background: Intracranial hemorrhage (ICH) is an uncommon, but devastating, complication of sickle cell disease (SCD) with mortality from 30 to 65%. Most reported cases are in adults; little is known about children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. Methods: Retrospective case-control study designed to characterize and evaluate risk factors for ICH among children with SCD age < 19 years hospitalized at Johns Hopkins Children’s Center from January 1979 to March 2004. Cases had SCD and ICH (intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic subdural and epidural hemorrhages were excluded). Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing the Division of Pediatric Hematology’s records. ACS was defined as a new pulmonary infiltrate and two of the following: chest or rib pain, dyspnea, fever, tachypnea, grunting, nasal flaring, or retractions. Blood pressure was adjusted for age, sex, and hemoglobin genotype. Results: We identified 7 cases (mean age=11.2 years, range 2 to 16 years) and 9 controls (mean age 6.2 years, range 2 to 8 years). As expected, cases were significantly older than controls (p<0.01). All cases and controls had sickle cell anemia. Cases presented with impaired mental status (5/7), bradycardia (5/7), headache (4/7), and emesis (3/7). They often had multiple sites of hemorrhage (5/7) and died during the initial hospitalization (4/7). Five had IPH involving the frontal, parietal, and/or temporal lobes (2 of the patients with IPH also had SAH, 1 had IVH and 1 had both SAH and IVH). Two additional patients had SAH (one also with IVH). Most cases and controls had elevated systolic blood pressure at the time of stroke (4/7 cases, 8/9 controls). Cases had lower steady-state hemoglobin (mean±SE 7.1±0.3 g/dl vs. 7.7±0.4 g/dl), lower steady-state blood pressures (systolic 104±9 vs. 117±5 mm Hg, diastolic 50±5 vs. 61±5 mm Hg) and higher steady-state leukocyte counts (16,590±2823/ul vs. 13,851±2184/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration was increased 2.8 g/dl (39.9%) from steady-state at the time of stroke in cases and was unchanged in controls (p=0.08). Other events in the two weeks before ICH associated with increased odds of ICH included transfusion (simple in 5 cases, erythrocytapheresis in 1), ACS (3 cases), and corticosteroid administration (high-dose dexamethasone for ACS in 2, stress doses for possible adrenal insufficiency in 1). Conclusions: In this group of children with SCD, ICH was associated with antecedent events including transfusion and possibly corticosteroids. Mortality was similar to that of adults with SCD and ICH. Limitations of this study include the small sample size and the retrospective design. The contribution of antecedent events to ICH in children with SCD deserves further evaluation. Odds Ratios of Intracranial Hemorrhage For Events in the Last 14 Days Event Odds Ratio (95% CI) P-value Transfusion 48 (1.8-2469) <0.01 ACS 6 (0.3-33) 0.26 Corticosteroids ∞ (1.3- ∞) 0.06

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Impact of Hydroxyurea on Thrombin Antithrombin Complex and Vaso-Occlusive Crisis in Pediatric Sickle Cell Disease.

Blood ◽

10.1182/blood.v108.11.5525.5525 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5525-5525

Author(s):

Mohsen Saleh Elalfy ◽

Ashraf M. Abdelmonem ◽

Soha Youssef ◽

Heba Ismail

Keyword(s):

Sickle Cell Disease ◽

Blood Transfusion ◽

Sickle Cell ◽

Coagulation System ◽

P Value ◽

Cell Disease ◽

Significant Difference ◽

Healthy Control ◽

Pain Crisis

Abstract Background: Several studies suggest that increased activity of the coagulation system may be important in the pathogenesis of vascular occlusion in sickle cell disease. Hydroxyurea (HU) has been shown to reduce the frequency of vaso-occlusive manifestations in both adults and children with sickle cell disease (SCD). Aim: To analyze the effect of HU on Thrombin-Antithrombin (TAT) as a marker of thrombin generation and hypercoagualbility in SCD and to find out the relation between TAT level and vaso-occusive crisis. Subjects and Method: we evaluated 37 child with sickle cell hemoglobinopathy (mean age 10.92±5.39 years) and 15 normal control children (mean age 9.75±6.34 years). Informed consent was obtained from patients and/or guardians and study approval by local IRB was obtained. Twenty-two patients (59.5%) were on HU, 15 (41.5%) patients did not receive HU, 7 (46.7%) of them were transfusion dependant. TAT assay was done in vitro using a sandwich enzyme immunoassay. Results: Mean patients’ age at institution of HU was 8.54± 3.85 years with median treatment duration of 4.5 years. Causes for initiating HU therapy were frequent blood transfusion in 11 patients (50%), frequent pain crisis (≥ 3/year) in 9 patients (41%), severe anemia and parents refusing blood transfusion in 1 patient (4.5%) and stroke in another patient (4.5%). HU dose was 20.82±4.95 mg/kg/day. We measured TAT in all patients and compared them to healthy control. There was significant difference in TAT level in sickle cell patients (198.86±185.7) compared to healthy control 2.91±0.94, [P value < 0.0001]. When the level of TAT was compared between the HU and non-HU groups we found that patients on HU had statistically significant lower TAT level (172.36 vs.225.37) [P=0.039]. There was also a significant negative correlation between HU dose and TAT level (p=0.03). A significant positive correlation between number of vaso-occlusive crisis/year [P=0.03], frequency of pain crisis/year [P=0.04], duration of pain crisis [P=0.03] and TAT level was observed. Conclusion: Hydroxyurea has significant inhibitory effect on thrombogenesis in sickle cell patients, which may be another mechanism for reducing vaso-occlusive crisis. Sickle cell children with higher TAT level had more frequent and severe vaso-occlusive crisis.

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Changes of BNP Level and Pulmonary Arterial Pressure during An Acute Sickle Cell Crisis, Comparison with Steady State

Blood ◽

10.1182/blood.v112.11.2503.2503 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2503-2503

Author(s):

Aref Agheli ◽

Chenthil Rathnasabapathy ◽

Ashish Sangal ◽

Zili He ◽

William Steier ◽

...

Keyword(s):

Steady State ◽

Right Ventricular ◽

Sickle Cell ◽

Ventricular Dysfunction ◽

Right Ventricular Dysfunction ◽

Acute Chest Syndrome ◽

Cardiac Complications ◽

Significant Difference ◽

Sickle Cell Crisis ◽

Pulmonary Arterial

Abstract Background: The heart is frequently involved in Sickle Cell Anemia (SCA). Cardiomegaly is a usual finding, significant arrythmias and sudden death are common, and 30% of patients with both homozygous and heterozygous SCA develop Pulmonary Arterial Hypertension (PAH), a major risk factor for higher mortality in this population. Brain Natriuretic Peptide (BNP) and echocardiographic data could provide important prognostic and diagnostic information about PAH in SCD. High levels of BNP, which is released from ventricular cardiomyocytes in response to their stretch, reflect cardiac chamber volume and pressure overload in various conditions. In patients with PAH, BNP levels correlate with the severity of Pulmonary Artery Pressure (PAP) elevation and right ventricular dysfunction. In human, the half life of BNP is 20 minutes, reflecting the fluctuation of BNP levels during different stages of any acute cardiac pathology. Methodology: The hypothesis of this prospective IRB approved study was to investigate the BNP level and PAP elevation during an acute Sickle Cell Crisis (SCC), in particular in those with intrathoracic structures involvement. Between December 2006 and July 2008, 81 patients were registered after a written informed consent was obtained. We collected the BNP levels and echocardiographic data of patients with SCD and compared them in two group; those who were admitted with Sickle Cell Crisis (SCC) and those who returned to clinic in Steady State (SS) for follow up. The data were obtained on the first day of admission in SCC group. The primary endpoint was the elevation of the BNP level and the secondary endpoint was elevation of the PAP during a SCC, which were compared with SS patients. The inclusion criterion was age above 18 and having one of the sickle cell syndromes, requiring hospital admission. Results: Forty nine patients (59%) were female, and 34 (41%) patients were male. Their ages ranged from 19 to 65, mean (SD) 30.2 (9.7) years. The mean (SD) levels of BNP were significantly higher in patients who were admitted with one of the acute complications or vaso-occlusive crisis of sickle cell, [177.3 (23.4) pg/ml], when compared with its levels in SS, [34.17 (6.1) pg/ml], (95% CI 61.4 to 225.0, p<.001) (Figure 1). An elevated BNP level was defined as levels more than 100 pg/ml. A further subgroup analysis revealed that the BNP levels were even more significantly higher in patients with acute chest syndrome or other intrathoracic events [(n= 17, mean (SD) 363.6 (121.3) pg/ml], when compared with those of simple acute sickle cell crisis, [(n= 35, mean (SD) 167.7 (26.8) pg/ml] (p=.038) (Figure 1). Topographic data about heart chambers’ sizes, volumes, and pressures were obtained by Echocardiography and compared in two groups. While only 23.1% of patients in SS group had elevated PAP with a mean (SD) of 43 (2.1) mmHg, 41.1% (n=21) of patients with SCC had elevated PAP with mean (SD) 45.9 (2.1) mmHg, with no significant difference between two groups with PAH (p=.608). Conclusion: Patients with either homozygous or heterozygous forms of SCA can have cardiac complications, such systolic and diastolic dysfunction. Hypoxemia leads to raised levels of BNP production. In patients with SCA, an elevated BNP level largely reflects the severity of right ventricular dysfunction associated with PAH. Our data revealed that BNP level and PAP are increased during vaso-occlusive crisis of SCA, in particular during those life-threatening complications, such acute chest syndrome. These changes seem to be temporary and with clinical improvement, the majority of patients’ BNP levels and PAP return to the baseline, although some will never normalize. Figure Figure

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Clinical Complications in Adult Patients with Sickle Cell Anemia and β-Thalassemia-Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4767.4767 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4767-4767

Author(s):

Giovanna Graziadei ◽

Alessia Marcon ◽

Martina Soldarini ◽

Ilaria Gandolfi ◽

Luisa Ronzoni ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Acute Chest Syndrome ◽

P Value ◽

Cell Disease ◽

Transfusion Therapy ◽

Clinical Complications ◽

Significant Difference ◽

The Mean

Abstract Abstract 4767 Background. Sickle-Cell Disease (SCD) is one of the most common severe monogenic inherited disorders worldwide, due to hemoglobin S (HbS), with reduced affinity for the oxygen. HbS polymerization, leading to erythrocyte rigidity, vaso-occlusion and hemolytic anemia, is central in the pathophysiology and crucial for the clinical outcome. The term SCD refers to Sickle Cell Anemia (SCA) due to homozygosis for βS allele, HbS/β-thalassemia (T-SCD) due to compound of β-thal and βS allele, and HbSC disease, owing to the coinheritance of βS and βcalleles. SCD is a multiorgan disease characterized by recurrent acute events and progressive organ damage, worsening during the life. Aims. This is a retrospective monocentric study aimed to assess and compare the clinical complications among 59 adult SCD patients, followed at the Hereditary Anemia Centre of the Foundation IRCCS “Ca Granda” Ospedale Maggiore Policlinico, in Milan, Italy. Methods. Mutation analysis of the b globin gene was established by direct DNA sequencing on the ABI Prism 310 genetic analyzer. Clinical and hematological features were evaluated by routine tests and physical examination, with special attention to the erythropoiesis stress parameters as LDH values and extramedullary erythropoietic (EE) masses. Results. Fifty-nine adult SCD patients, 16 SCA and 43 T-SCD, were evaluated. In T-SCD patients detected b-mutations were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2%. The mean age of SCA patients was 36±9 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years, while the mean age at the presentation in our Centre was 32±8 years in SCA patients and 31±10 years in T-SCD ones. Five out of 16 (31.2%) SCA patients and 16/43 (37.2%) T-SCD patients were male. HbF mean levels were 6.9±5.1% and 10.1±7.2%, respectively in SCA and T-SCD group; surprisingly Hb mean levels were lower in SCA (9.3±1.3 g/dl) than in T-SCD (9.9±1.4 g/dl) patients. Comparing SCA and T-SCD, there was statistically significant difference in splenic features: splenectomy was performed in 2/16 (12.5%) SCA patients vs 21/43 (48.8%) T-SCD patients (p-value < 0.01). Splenomegaly was absent in SCA, while was detected in 11/22 (50%) T-SCD (p-value < 0.0001); all SCA patients had functional asplenia, not observed in T-SCD patients; splenic infarctions were absent in SCA patients and were detected in 7/22 (31.8%) T-SCD patients, of whom 5 had splenomegaly and 2 had normal spleen size (pvalue <0.001). On the other side, there was not statistically significant difference in the prevalence of stroke, acute chest syndrome (ACS), bone pain crisis, sepsis, leg ulcers and priapism. However, we observed some clinical differences, even if not statistically significant. Cholecistectomy was performed in 4/16 (25%) SCA patients vs 17/43 (39.5%) T-SCD patients, and gallstones were detected respectively in 5/12 (41.7%) and in 14/26 (53.8%) of SCA and T-SCD patients. Thrombotic events were absent in SCA patients, compared to 4/43 (9.3%) T-SCD patients. Furthermore, we detected EE in 3/16 (18.6%) SCA and in 3/43 (7%) T-SCD, all carrying b° thal mutations. We underlie that Hb levels and LDH values were higher in SCA than in T-SCD patients (823±295 vs 689±209 U/L). About the treatment, 14/16 (87.5%) SCA and 31/43 (72%) T-SCD underwent to top-up transfusion; 5/43 (11.6%) T-SCD were regularly transfused. Seven out of 16 (43.8%) SCA and 18/43 (41.8%) T-SCD patients were treated with Hydroxycarbamide (HU). Criteria for transfusion therapy were: painful crisis not responsive to HU, major clinical complications, such as stroke or ACS, extramedullary erythropoietic masses associated with high LDH levels and low Hb values. Conclusions. These data suggest that SCA and T-SCD patients have similar clinical course. Splenomegaly is present only in T-SCD patients, probably due to the increased amount of extravascular hemolysis. Surprisingly, SCA patients showed EE and lower Hb levels with higher LDH values compared to T-SCD ones. This could be related to the prevalence of intravascular hemolysis, that can lead to erythropoietic stress in SCA, even if tissues are better oxygenated in these patients because of biochemical characteristic of HbS in terms of decreased oxygen affinity. These observations could be important to evaluate transfusion and HU treatment. Disclosures: Cappellini: Novartis: Research Funding.

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Lower Continuous Infusion, Higher Bolus Dose Patient-Controlled Analgesia Results in Shorter Hospitalization in Children with Sickle Cell Vaso-Occlusive Pain Crisis

Blood ◽

10.1182/blood.v126.23.523.523 ◽

2015 ◽

Vol 126 (23) ◽

pp. 523-523

Author(s):

Tabetha Todd ◽

Jonica Huntman ◽

Gianna W. Sparks ◽

Monica L. Hulbert

Keyword(s):

Continuous Infusion ◽

Sickle Cell ◽

Medical Records ◽

Dose Regimen ◽

Pain Control ◽

Categorical Variables ◽

Acute Chest Syndrome ◽

Patient Controlled Analgesia ◽

Pain Crisis ◽

Lower Continuous

Abstract Background: Children with sickle cell disease (SCD) and vaso-occlusive pain crisis (VOC) require opioid analgesia, but there is little evidence to determine the most effective strategy for opioid dosing via patient-controlled analgesia (PCA) for this patient population. In January 2013, the opioid PCA dosing strategy for VOC at St. Louis Children's Hospital was changed from high continuous infusion/low demand dose (regimen A, Table) to lower continuous infusion/higher demand dose (regimen B, Table). In this retrospective cohort study, we tested the hypothesis that hospital length of stay (LOS), intravenous opioid utilization, and opioid side effects would be reduced in regimen B compared with regimen A. Methods: All hospitalizations for VOC management during January 1-July 31, 2012, and January 1-July 31, 2013, were identified from pharmacy records and patients' electronic medical records. Opioid doses, ibuprofen, and supportive care were part of standardized VOC order sets for both time periods. In both regimens, PCA opioid was weaned by 20-25% daily after achieving pain control, until equivalent to home opioid dose. Inclusion criteria were diagnosis of any SCD phenotype; admission for VOC; and treatment with morphine or hydromorphone PCA. Subjects were excluded for age 18 years or older; opioid continuous infusion ordered without patient-controlled demand dose; intensive care unit admission; opioid PCA ordered > 24 hours after hospital admission; post-operative PCA; participation in a clinical trial; or discharge diagnosis other than VOC. Data were abstracted from subjects' medical records into a REDCap database. Opioid administration was recorded as morphine equivalents (1 mg hydromorphone = 6.667 mg morphine). Data were analyzed in SPSS version 21 (IBM, Armonk, NY). Continuous variables were compared with the independent-samples Mann-Whitney U-test, and categorical variables with Fisher's exact test. The level of significance was specified as p<0.05. Results: Of 303 hospitalizations identified during the study period, 101 met all criteria for analysis: 45 in 2012 (all regimen A) and 56 in 2013 (2 regimen A, 54 regimen B). The median number of hospitalizations per subject was 2 (range 1-8). Age, sex, SCD type, acute chest syndrome diagnosis, and hydroxyurea use were not significantly different between regimens. The median LOS was significantly shorter for regimen B hospitalizations at 5 days [interquartile range (IQR) 4, 6.25] versus 6 days (IQR 4, 9) for regimen A hospitalizations (p=0.004). The median total morphine equivalents administered per admission was significantly less in regimen B (150 mg, IQR 74.8-349) than in regimen A (246 mg, IQR 129-601; p=0.03). This was due to fewer morphine equivalents given by continuous infusion in regimen B hospitalizations (median 90.3 mg, IQR 52-158) than in regimen A (median 191 mg, IQR 102-361; p<0.001). Total morphine equivalents delivered by demand dose were not significantly different between groups (p=0.077), but a greater fraction of opioid was delivered by demand dose in regimen B (median 0.38, IQR 0.21, 0.48) compared to regimen A (median 0.09, IQR 0.021, 0.22) (p<0.001). Ondansetron was prescribed for nausea in 33.3% of regimen B versus 55.3% of regimen A admissions [odds ratio 0.65 for regimen B (95% confidence interval 0.43, 0.97, p=0.029)]. Conclusion: In this cohort of children with SCD treated for VOC with two different opioid PCA regimens, lower continuous infusion/higher demand dose opioid resulted in significantly shorter LOS, less opioid exposure, and less use of antiemetics. Pain control may be improved when patients control a greater fraction of the opioid they receive. These results should guide future prospective studies of VOC management. Table. Regimen A Regimen B Morphine Continuous infusion (CI) 0.05-0.1 mg/kg/hour 0.03 mg/kg/hour Demand dose 0.0085-0.017 mg/kg (17% of CI) 0.03 mg/kg(100% of CI) Demand dose lockout 20 minutes 20 minutes Hydromorphone Continuous infusion 0.015 mg/kg/hour 0.003 mg/kg/hour Demand dose 0.0025 mg/kg(17% of CI) 0.003 mg/kg (100% of CI) Demand dose lockout 30 minutes 20 minutes Disclosures No relevant conflicts of interest to declare.

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Sickle Cell Acute Chest Syndrome: Pathogenesis and Rationale for Treatment

Blood ◽

10.1182/blood.v94.5.1555.417k36_1555_1560 ◽

1999 ◽

Vol 94 (5) ◽

pp. 1555-1560 ◽

Cited By ~ 6

Author(s):

Marie J. Stuart ◽

B.N. Yamaja Setty

Keyword(s):

Steady State ◽

Sickle Cell ◽

Adhesion Molecule ◽

Inhibitory Effect ◽

Acute Chest Syndrome ◽

Endothelial Adhesion Molecule ◽

Sickle Erythrocyte ◽

Sickle Erythrocytes ◽

Cell Adhesion Molecule 1

Acute chest syndrome (ACS) is a leading cause of death in sickle cell disease (SCD). Our previous work showed that hypoxia enhances the ability of sickle erythrocytes to adhere to human microvessel endothelium via interaction between very late activation antigen-4 (VLA4) expressed on sickle erythrocytes and the endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1). Additionally, hypoxia has been shown to decrease the production of nitric oxide (NO) which inhibits VCAM-1 upregulation. Based on these observations, we hypothesize that during ACS, the rapidly progressive clinical course that can occur is caused by initial hypoxia-induced pulmonary endothelial VCAM-1 upregulation that is not counterbalanced by production of cytoprotective mediators, including NO, resulting in intrapulmonary adhesion. We assessed plasma NO metabolites and soluble VCAM-1 in 36 patients with SCD and 23 age-matched controls. Patients with SCD were evaluated at baseline (n = 36), in vaso-occlusive crisis (VOC; n = 12), and during ACS (n = 7). We observed marked upregulation of VCAM-1 during ACS (1,290 ± 451 ng per mL; mean ± 1 SD) with values significantly higher than controls (P < .0001) or patients either in steady state or VOC (P < .01). NO metabolites were concomitantly decreased during ACS (9.2 ± 1.5 nmol/mL) with values lower than controls (22.2 ± 5.5), patients during steady state (21.4 ± 5.5), or VOC (14.2 ± 1.2) (P< .0001). Additionally, the ratio of soluble VCAM-1 to NO metabolites during ACS (132.9 ± 46.5) was significantly higher when compared with controls (P < .0001) or patients either in steady state or VOC (P < .0001). Although hypoxia enhanced in vitro sickle erythrocyte-pulmonary microvessel adhesion, NO donors inhibited this process with concomitant inhibition of VCAM-1. We suggest that in ACS there is pathologic over expression of endothelial VCAM-1. Our investigations also provide a rationale for the therapeutic use in ACS of cytoprotective modulators including NO and dexamethasone, which potentially exert their efficacy by an inhibitory effect on VCAM-1 and concomitant inhibition of sickle erythrocyte-endothelial adhesion.

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