Hemoglobin F or: How I Learned to Stop Wondering and Love the Flow Cytometer

Abstract Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a hemoglobinopathy that leads to red blood cell (RBC) sickling and a broad range of disease complications including vaso-occlusive crisis, acute chest syndrome, and retinopathy. Hydroxyurea, a drug used to treat SCD, is known to increase expression of hemoglobin F (HbF), a type of hemoglobin normally expressed in infancy; HbF levels between 10% and 20% are associated with decreased vaso-occlusive episodes and improved survival. Hereditary persistent hemoglobin F (HPHF), a typically asymptomatic hemoglobinopathy associated with sustained hemoglobin F (HbF) expression into adulthood (HbF >10%), in combination with SCD is associated with decreased complications. Laboratories typically determine the HbF level via high-performance liquid chromatography (HPLC). HbF levels approaching 30% on HPLC are thought to be protective against SCD complications. However, HbF may be found within a majority or minority of RBCs, pancellular (deletional HPHF) or heterocellular distribution (nondeletional HPHF), respectively. Additionally, the quantity of HbF within cells can range from low (<10 picograms/cell) to high (>35 picograms). We sought to determine the quantity and distribution of HbF required to protect against sickle cell disease symptoms both via traditional HPLC as well as flow cytometry. This retrospective study was conducted at a large academic medical center over a period of 2 months (January-February 2019). We collected blood from sickle cell patients that had a detectable HbF level on hemoglobin electrophoresis. We then stained RBCs from 16 of the patients for HbF and performed flow cytometry to examine the HbF distribution. We calculated the cellular concentration of HbF within each HbF+ cell using the formula (MHC × %HbF)/%F-cells. We performed a chart review to determine the native hemoglobin type, exposure to hydroxyurea, and clinical symptoms of sickle cell disease. We identified four patients over the age of 20 with HbS/HPHP and no exposure to hydroxyurea. Two of these patients experienced no sickle cell disease complications; the protected patients had heterocellular distribution of HbF, but had a high concentration of HbF per HbF+ cell (>35 picograms/cell). Notably, these asymptomatic patients both had HbF level by HPLC less than 30. One of the symptomatic HbS/HPHF patients had heterocellular expression of HbF with low cellular concentration (28 picograms/cell) while the other patient had pancellular HbF expression with very low cellular concentration (6.4 picograms/cell). Our study demonstrates that HPHF alone does not prevent sickle cell disease complications. Our study highlights the importance of quantifying the cellular concentration of HbF, which can provide useful information beyond that of HPLC. In addition, our study raises the potential of the clinical use of hydroxyurea in patients with sickle cell disease even in the presence of HPHF.

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Microfluidics in Sickle Cell Disease Research: State of the Art and a Perspective Beyond the Flow Problem

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.558982 ◽

2021 ◽

Vol 7 ◽

Author(s):

Anupam Aich ◽

Yann Lamarre ◽

Daniel Pereira Sacomani ◽

Simone Kashima ◽

Dimas Tadeu Covas ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Flow Problem ◽

Red Cells ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Intercellular Interaction ◽

Blood Disorder ◽

Resource Setting ◽

Wide Range

Sickle cell disease (SCD) is the monogenic hemoglobinopathy where mutated sickle hemoglobin molecules polymerize to form long fibers under deoxygenated state and deform red blood cells (RBCs) into predominantly sickle form. Sickled RBCs stick to the vascular bed and obstruct blood flow in extreme conditions, leading to acute painful vaso-occlusion crises (VOCs) – the leading cause of mortality in SCD. Being a blood disorder of deformed RBCs, SCD manifests a wide-range of organ-specific clinical complications of life (in addition to chronic pain) such as stroke, acute chest syndrome (ACS) and pulmonary hypertension in the lung, nephropathy, auto-splenectomy, and splenomegaly, hand-foot syndrome, leg ulcer, stress erythropoiesis, osteonecrosis and osteoporosis. The physiological inception for VOC was initially thought to be only a fluid flow problem in microvascular space originated from increased viscosity due to aggregates of sickled RBCs; however, over the last three decades, multiple molecular and cellular mechanisms have been identified that aid the VOC in vivo. Activation of adhesion molecules in vascular endothelium and on RBC membranes, activated neutrophils and platelets, increased viscosity of the blood, and fluid physics driving sickled and deformed RBCs to the vascular wall (known as margination of flow) – all of these come together to orchestrate VOC. Microfluidic technology in sickle research was primarily adopted to benefit from mimicking the microvascular network to observe RBC flow under low oxygen conditions as models of VOC. However, over the last decade, microfluidics has evolved as a valuable tool to extract biophysical characteristics of sickle red cells, measure deformability of sickle red cells under simulated oxygen gradient and shear, drug testing, in vitro models of intercellular interaction on endothelialized or adhesion molecule-functionalized channels to understand adhesion in sickle microenvironment, characterizing biomechanics and microrheology, biomarker identification, and last but not least, for developing point-of-care diagnostic technologies for low resource setting. Several of these platforms have already demonstrated true potential to be translated from bench to bedside. Emerging microfluidics-based technologies for studying heterotypic cell–cell interactions, organ-on-chip application and drug dosage screening can be employed to sickle research field due to their wide-ranging advantages.

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Building access to care in adult sickle cell disease: defining models of care, essential components, and economic aspects

Blood Advances ◽

10.1182/bloodadvances.2020001743 ◽

2020 ◽

Vol 4 (16) ◽

pp. 3804-3813

Author(s):

Julie Kanter ◽

Wally R. Smith ◽

Payal C. Desai ◽

Marsha Treadwell ◽

Biree Andemariam ◽

...

Keyword(s):

United States ◽

Sickle Cell Disease ◽

Access To Care ◽

Sickle Cell ◽

The United States ◽

Models Of Care ◽

System Level ◽

Cell Disease ◽

Blood Disorder ◽

Essential Components

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

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Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments]

Blood ◽

10.1182/blood.v86.2.776.bloodjournal862776 ◽

1995 ◽

Vol 86 (2) ◽

pp. 776-783 ◽

Cited By ~ 321

Author(s):

FM Gill ◽

LA Sleeper ◽

SJ Weiner ◽

AK Brown ◽

R Bellevue ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Course ◽

The United States ◽

Beta Thalassemia ◽

Acute Chest Syndrome ◽

Cooperative Study ◽

Cell Disease ◽

Splenic Sequestration ◽

Clinical Events

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.

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Prevalence of Pulmonary Hypertension (PHTN) in Sickle Cell Disease (SCD) Adolescents with Pulmonary Complications.

Blood ◽

10.1182/blood.v104.11.3759.3759 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3759-3759

Author(s):

Onyinye C. Onyekwere ◽

Andrew Campbell ◽

James Williams ◽

Peter Gaskin ◽

Sohail Rana ◽

...

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Pulmonary Complications ◽

Acute Chest Syndrome ◽

University Of Michigan ◽

Cell Disease ◽

Hemoglobin F ◽

Howard University ◽

History Of

Abstract Despite the high prevalence of PHTN in adults with SCD, the prevalence in the pediatric population with SCD is not known. We hypothesized that elevated pulmonary artery pressures may be found in SCD adolescents with history of pulmonary complications, such as acute chest syndrome (ACS), obstructive sleep apnea (OSA), asthma, and reactive airway disease. Thirty such sickle cell disease adolescents were screened at Howard University or University of Michigan for PHTN with Doppler echocardiography. We defined PHTN as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/sec (corresponding to a pulmonary artery systolic pressure greater than 35 mm Hg). PHTN was found in 16 SCD patients (53.3%) and 5 (16.7%) had TRV > 3.0 m/sec. Clinical findings according to the presences or absence of PHTN are shown in the table. Potential factors contributing to PHTN in patients with SCD include chronic hemolysis and chronic hypoxia. Our results suggest that PHTN is common among SCD adolescents with a history of pulmonary complications. Consideration should be given to screening such patients for PHTN and exploring treatment options. Further studies are urgently needed to clarify the prevalence and mechanisms of PHTN in adolescents with SCD. Clinical and demographic data of 30 SCD adolescents with pulmonary findings who underwent echocardiography at Howard University Hospital or University of Michigan PHTN (N = 16) No PHTN (N = 14) P Age in years (mean +/− SD) 15.9 +/− 3.2 17.4 +/− 2.3 0.17 Females (no. and %) 5 (31.3) 7 (50) 0.5 Hemoglobin SS Phenotype (no and %) 14 (87.5 11 (78.6) 0.5 Hemoglobin concentration (mean +/− SD) 8.0 +/− 2.1 9.3 +/−1.9 0.11 White blood cells (mean +/− SD) 10.9 +/− 2.9 9.7 +/− 3.7 0.4 Platelet (mean +/− SD) 475 +/− 172 364 +/− 240 0.17 Hemoglobin F percent (mean +/− SD) 5.1 +/− 3.5 6.4 +/− 5.5 0.6 Lactate dehydrogenase (mean +/− SD) 505 +/− 162 264 +/− 50 0.002 Total bilirubin (mean +/− SD) 4.1 +/− 2.6 3.4 +/− 2.6 0.5 Creatinine concentration (mean +/− SD) 0.6 +/− 0.2 0.7 +/− 0.2 0.18 Aspartate transaminase (mean +/− SD) 48 +/− 27 36 +/− 16 0.18 Alanine transaminase (mean +/− SD) 51 +/− 37 39 +/− 20 0.3

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Abnormal Pulmonary Function in Adults with Sickle Cell Disease: Association of Decreased DLCO with Systemic Disease.

Blood ◽

10.1182/blood.v106.11.316.316 ◽

2005 ◽

Vol 106 (11) ◽

pp. 316-316 ◽

Cited By ~ 4

Author(s):

Elizabeth S. Klings ◽

Diego F. Wyszynski ◽

Vikki G. Nolan ◽

Martin H. Steinberg

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Function ◽

Sickle Cell ◽

Pulmonary Function Tests ◽

Systemic Disease ◽

The United States ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Restrictive Physiology ◽

Abnormal Pulmonary Function

Abstract Pulmonary complications of sickle cell disease (SCD), including acute chest syndrome, pulmonary hypertension (PH) and pulmonary fibrosis, are common. Dyspnea and hypoxemia are equally common in this population. It is likely that pulmonary function tests (PFT) are abnormal in the SCD population, however, no extensive study has been reported to date. Moreover, the relationship between abnormal pulmonary function and other manifestations of SCD, such as PH, is unclear. We hypothesized that abnormalities of pulmonary function, particularly a low diffusion capacity for carbon monoxide (DLCO), may be associated with other complications of SCD. The Cooperative Study of Sickle Cell Disease (CSSCD) enrolled and followed more than 4,000 SCD patients who had visited one of 23 participating clinical centers across the United States between 1978 and 1998. Data were collected on many complications of the disease, and standardized collection of PFTs were part of the protocol. From the more than 1300 CSSCD patients who had the results of PFTs recorded, 310 adults (age≥ 20 years of age) homozygous for the Hb S gene without coincident α thalassemia and with sufficient data were identified. Predicted values for FEV1, FVC, FEV1/FVC, TLC, RV and DLCO were calculated using algorithms that accounted for gender, age, and height in the African American population (using STATA, version 9); data are presented as percent predicted. Based on criteria established by the American Thoracic Society, subjects were sub-classified into 7 groups: obstructive physiology; restrictive physiology; mixed obstructive/restrictive disease; low lung volumes with normal spirometry (LLV); LLV with a low DLCO, isolated low DLCO, or normal. The association of blood counts and serum chemistries between patients with low DLCO compared with those with a normal DLCO was assessed by multivariate linear regression (using SAS software version 8.2). Normal PFTs were present in only 31 of 310 (10 %) SCD patients. Overall, the adult SCD population was characterized by decreased total lung capacities (70.2 + 14.7% predicted) and DLCO (64.5 + 19.9 % predicted adjusted for hemoglobin concentration). The most common PFT patterns observed were restrictive physiology (35.8%), LLV with normal spirometry (34.2% of patients), and an isolated low DLCO (12.9%). The presence of a low DLCO was associated with an elevated platelet count (p=0.05), hepatic dysfunction [elevated ALT (p=0.07) with elevated AST (p=0.01)] and renal dysfunction [elevated BUN and creatinine (p=0.05, 0.07)]. Restrictive disease is marginally associated with a decrease in hematocrit (p=0.07) and Hb F levels (p=0.07). Pulmonary function is abnormal in 90% of adult SCD patients. Common abnormalities include restrictive physiology, LLV with normal spirometry and a decreased DLCO. The presence of a decreased DLCO may be a marker of more severe systemic disease that includes impaired renal and hepatic function and possibly complications of hemolytic anemia such as PH.

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Mitophagy Induction Is a Potential Therapeutic Approach for Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.267.267 ◽

2016 ◽

Vol 128 (22) ◽

pp. 267-267

Author(s):

Ramasamy Jagadeeswaran ◽

Benjamin Alejandro Vazquez ◽

Vinzon Ibanez ◽

Maria A Ruiz ◽

Robert E Molokie ◽

...

Keyword(s):

Flow Cytometry ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Therapeutic Approach ◽

Research Funding ◽

Single Point Mutation ◽

Cell Disease ◽

Blood Disorder ◽

In Vivo Treatment

Abstract Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide. A single point mutation of the sixth amino acid of β-globin causes glutamic acid to be replaced by valine, rendering the hemoglobin susceptible to polymerization when deoxygenated. SCD patients suffer from the wide variety of disease manifestations including chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. In addition to the HbS polymerization-mediated rigid and fragile sickle-shaped red blood cell (RBC) formation, an excessive formation of intracellular reactive oxygen species (ROS) occurs in SCD red blood cells, which accelerates their hemolysis. This causes the release of ROS, free extracellular hemoglobin, hemin, and inflammatory cytokines that trigger disease progression. We analyzed levels of ROS in SCD patient RBCs and observed a higher fraction of intracellular ROS positive RBC in SCD (HbSS) compared to control (HbAA) RBC of adults [Control (HbAA): 7.1%± 1.4 %, n=11; SCD (HbSS): 25.3 % ± 4.3%, n=9; p<0.0004]. We also made the novel observation that mature RBCs from SCD patients abnormally contain mitochondria as evidenced by flow cytometry analysis of blood samples of 36 SCD patients and 14 normal human control subjects.[Control (HbAA):0.4 % ± 0.04%, n=14; SCD (HbSS): 7.8%± 0.9%, n=30; p<0.0001]. Further subset analysis from SCD patients with HbSC showed mitochondrial retention in their mature RBCs [HbSC: 2.2%± 0.6%,n=6 p<0.01], however to a lesser degree than patients with HbSS. Transmission electron microscopy confirmed the presence of mitochondria in mature RBC of patients with SCD. ROS analysis between mitochondria positive vs. negative fractions showed that mitochondria-positive (TMRM+) RBC fractions have higher levels of ROS compared to mitochondria-negative (TMRM-) RBC fractions. This data strongly suggests that retained mitochondria significantly contribute to the production of ROS in SCD RBCs. Similar to humans, a higher fraction of RBCs of SCD mice (B6;129-Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow/J) retain mitochondria compared to control mice RBC [Control (HbAA): 0.29% ± 0.18%; SCD (HbSS): 16.68%± 1.9%, p<0.0001]. While investigating RN-1, a lysine specific demethylase-1 (LSD-1) inhibitor, as a HbF inducing agent, we observed that SCD mice treated with RN-1 showed a reduction in the fraction of RBCs which retain mitochondria. Therefore, we investigated mitophagy-inducing drugs as a possible useful therapeutic approach for SCD by administering mitophagy-inducing agent Sirolimus. SCD mice treated with RN-1 (5mg), or Sirolimus (5mg) had a significant decrease in the fraction of mitochondria containing RBCs (RN1: 4.96± 1.0%, p<0.0005; Sirolimus: 6.4% ± 1.8%, p<0.002). We observed a reduction of ROS in mature RBCs coupled with decreased mitochondrial retention in RBCs after in vivo treatment with RN1 or Sirolimus as measured by co-staining of TMRM, APC-conjugated CD71antibody, and CM-H2DCFDA. We also observed a significant improvement in RBC survival after the in vivo treatment with Sirolimus or RN-1. RBC survival was measured by flow cytometry and calculated biotin positive circulating RBCs after 2 days of in vivo labeling [SCD treated with vehicle control: 40 %± 2.6%; SCD treated with RN1 (2.5mg): 69.9 ± 2.6%, p<0.004; Sirolimus (5mg): 67.5% ± 6.1%, p<0.04]. Based on this data, mitophagy-inducing drugs have the potential to be a novel therapeutic approach for the treatment of SCD patients. Disclosures Jagadeeswaran: Acetylon: Research Funding. DeSimone:EpiDestiny: Consultancy, Other: patents around decitabine and tetrahydrouridine. Lavelle:Acetylon: Research Funding. Rivers:Acetylon: Research Funding.

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Sickle cell disease promotes sex-dependent pathological bone loss through enhanced cathepsin proteolytic activity

Blood Advances ◽

10.1182/bloodadvances.2021004615 ◽

2021 ◽

Author(s):

Jada M Selma ◽

Hannah Song ◽

Christian Rivera ◽

Simone Andrea Douglas ◽

Abhiramgopal Akella ◽

...

Keyword(s):

Sickle Cell Disease ◽

Bone Loss ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Bone Microarchitecture ◽

The United States ◽

Cell Disease ◽

Female Mice ◽

Blood Disorder ◽

The Impact

Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis and osteopenia and other bone related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD)1,2. Previous SBD models have failed to distinguish the age- and sex-specific characteristics of bone morphometry. In this study, we use the Townes mouse model of SCD to study the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by high-resolution quantitative micro-computed tomography (microCT) and the 3D reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. Particularly, SCD female mice are prone to trabecular bone loss while cortical bone degradation occurs in both sexes. Additionally, we describe the impact of genetic knockdown of cathepsin K and E-64 mediated cathepsin inhibition on SBD.

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Stem Cell Transplantation for Children with Sickle Cell Anemia: Factors Associated with Parent and Patient Interest

Blood ◽

10.1182/blood.v118.21.1079.1079 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1079-1079

Author(s):

Roth Michael ◽

Julie Krystal ◽

Deepa Manwani ◽

Catherine Driscoll ◽

Rosanna J. Ricafort

Keyword(s):

Stem Cell ◽

Sickle Cell Disease ◽

Life Span ◽

Disease Severity ◽

Sickle Cell ◽

The United States ◽

Life Goals ◽

Acute Chest Syndrome ◽

Cell Transplant ◽

Cell Disease

Abstract Abstract 1079 BACKGROUND: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States affecting more than 70,000 children and adults. SCD is associated with significant morbidity and mortality with a mean life expectancy of approximately 45 years in patients with more severe Hb SS. Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment for sickle cell disease. Currently hematologists consider HSCT only for patients with a history of multiple pain crises, stroke, renal disease and/or multiple episodes of acute chest syndrome. However, factors that influence patients' and parents' interest in HSCT for SCD are not known. METHODS: We designed and administered a 40 question survey to assess the interest in HSCT as a cure for SCD in parents and adolescents with HbSS or HbSBetaThalassemia0. The survey tool assessed factors that may influence interest in HSCT including demographic data, disease severity, views on prognosis and Health Related Quality of Life (PedsQL4.0). All participants were given a handout on the risks and benefits of a HSCT prior to completing the survey. Participants' who responded they definitely or probably would undergo HSCT if recommended by their hematologist were categorized as “likely would undergo HSCT” while participants who responded they would maybe, probably not, or definitely would not undergo HSCT were categorized as “less likely would undergo HSCT”. RESULTS: Ninety parents and 42 adolescents completed the survey, with only 1 parent refusing to participate. Forty six percent (39/85) of parents would likely have their child undergo HSCT and 34% (14/41) of adolescents would likely undergo HSCT if it was recommended by their hematologist. Adolescents with better social function and better overall emotional function were more likely to undergo transplant (50% (10/20) vs. 19% (4/21), p=0.04) (53% (9/17) vs. 21% (5/24), p=0.03), respectively. Parents of children age>7 who believe their child's life span will be shortened secondary to SCD were more likely to undergo transplant (100% (3/3) vs. 35% (15/43), p=0.03). In addition, parents of children who have received an exchange transfusion were more likely to undergo transplant (62% (18/29) vs. 38% (20/53), p=0.04). Disease severity represented by the number of pain crises, episodes of acute chest, or presence of a stroke were not associated with increased parent or adolescent interest in HSCT. In addition, 50% (11/22) of parents of children who would not qualify for HSCT based on current disease severity criteria would likely undergo HSCT. In this cohort, parents who believed their child's disease would not get better were more likely to go forward with transplant (100% (5/5) vs. 31% (5/16), p=0.007). The majority of parents believe their child's sickle cell disease will get better (63% (55/87)), will not likely prevent their child from achieving life goals (83% (71/86)), and will not shorten their child's lifespan (88% (74/84)). Forty six percent (19/41) of adolescents believe their sickle cell disease will get better, 74% (31/42) believe it will not prevent them from achieving life goals, and 64% (27/42) believe sickle cell disease will not shorten their lifespan. CONCLUSIONS: There is a strong interest in HSCT in our patient cohort that was not pre-selected based on disease severity. Parents had an interest in HSCT based on both disease severity and perception of prognosis, while adolescents' interest in HSCT was directly related to higher psychosocial functioning. The current standard inclusion criteria for HSCT for children with SCD exclude a number of children whose parents are interested in HSCT. The finding of perception of a normal life span in the majority of patients and parents is troubling and suggests a need for more thorough education regarding the long term sequelae of SCD and the role for HSCT as a cure. Disclosures: No relevant conflicts of interest to declare.

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PedsQL™ Sickle Cell Disease Module: Feasibility, Reliability and Validity

Blood ◽

10.1182/blood.v120.21.476.476 ◽

2012 ◽

Vol 120 (21) ◽

pp. 476-476

Author(s):

Julie A. Panepinto ◽

Cristiane B. Bendo ◽

Sylvia Torres ◽

Timothy McCavit ◽

Christina J. Bemrich-Stolz ◽

...

Keyword(s):

Sickle Cell Disease ◽

Construct Validity ◽

Sickle Cell ◽

Severe Disease ◽

The United States ◽

Self Report ◽

Measurement Properties ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Parent Proxy

Abstract Abstract 476 Background: Sickle cell disease (SCD) is an inherited chronic disease characterized by complications such as recurrent painful vaso-occlusive events that can require hospitalizations and contribute to early and increased mortality. Prior work using generic health-related quality of life (HRQL) instruments has demonstrated that patients with SCD experience significantly impaired HRQL in their baseline state of health that worsens during acute complications of the disease. To better understand differences in health status in children with SCD, we developed the PedsQL™ SCD Module to measure SCD-specific HRQL. The goal of this study was to determine the measurement properties for the child self- and parent-proxy reports for the newly developed PedsQL™ SCD Module. We hypothesized that the PedsQL™ SCD Module would be feasible and reliable and that children with more severe SCD would have worse HRQL than those with mild disease as measured by the PedsQL™ SCD Module. Methodology: This was a cross-sectional study conducted at 5 sites across the United States. Study participants were children with SCD ages 2–18 years who presented to clinic for a routine visit. HRQL was the main outcome measured with the newly developed 43-item PedsQL™ SCD Module which includes nine scales: Pain/Hurt (PH, 9 items), Pain Impact (PI, 10 items), Pain Management/Control (PMC, 2 items), Worry I (WO1, 5 items), Worry II (WO2, 2 items), Emotions (EM, 2 items), Treatment (TR, 7 items), Communication I (CO1, 3 items), Communication II (CO2, 3 items). Higher scores indicate better HRQL and lower SCD symptoms. Missing items were used to determine feasibility and Cronbach's alpha was used to determine reliability. HRQL of children with mild and severe disease were compared using an independent t-test to determine construct validity. Severe disease was defined as patients with 3 or more hospitalizations for pain in the 3 years prior, history of stroke and/or prior acute chest syndrome. Results: A total of 321 families (313 parents, 243 children ages 5–18 years) completed questionnaires. The average age of the children (46.7% boys) was 9.62 years (SD = 4.88). Feasibility was established, with 3% or less missing data for the module. The PedsQL™ SCD Module was reliable and distinguished between children with mild and severe SCD (Table 1). Conclusions: The PedsQL™ SCD Module performed well and demonstrated strong measurement properties in patients with SCD. Overall, both the parent-proxy report and child self-report differentiated between patients with severe and mild SCD supporting construct validity of the module. Although these are the first results using the PedsQL™ SCD Module, it has shown great potential as being a strong measure of HRQL for patients with SCD. Future studies incorporating the PedsQL™ SCD Module will benefit from the measure's disease-specific scales and overall ability to distinguish between mild and severe symptoms. Continually, these studies will help further define its' measurement properties and advance our knowledge of the HRQL in patients with SCD. Disclosures: Off Label Use: Hydroxyurea is approved for use in sickle cell disease in adults but not children. Varni:Mapi Research Trust: Dr. Varni holds the copyright and the trademark for the PedsQL™ and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality Other, PedsQL™, PedsQL™ Patents & Royalties.

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A cautionary note regarding hydroxyurea in sickle cell disease

Blood ◽

10.1182/blood.v83.4.1124.bloodjournal8341124 ◽

1994 ◽

Vol 83 (4) ◽

pp. 1124-1128

Author(s):

EP Vichinsky ◽

BH Lubin

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Course ◽

Fetal Hemoglobin ◽

Organ Damage ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Transfusion Therapy ◽

History Of ◽

Hbf Level

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

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