scholarly journals Morphine for the Treatment of Pain in Sickle Cell Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Mihir Gupta ◽  
Lilian Msambichaka ◽  
Samir K. Ballas ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Studies ◽  
Severe Pain ◽  
Organ Damage ◽  
Cell Disease ◽  
Organ Function ◽  
Specific Effects ◽  
Organ Specific ◽  
Chronic Use

Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.

scholarly journals Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

2020 ◽  
Vol 11 ◽  
pp. 204062072095500
Author(s):  
Ifeyinwa Osunkwo ◽  
Deepa Manwani ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Management Strategies ◽  
Organ Damage ◽  
Care Utilization ◽  
Cell Disease ◽  
High Resource ◽  
Emerging Treatments

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Etiology of and Associations with Early Death in Adult Patients with Sickle Cell Disease At a Single Referral Institution.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2117-2117
Author(s):  
Courtney Fitzhugh ◽  
Darlene Allen ◽  
Wynona Coles ◽  
Cassie Seamon ◽  
Xiongce Zhao ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Cause Of Death ◽  
Sickle Cell ◽  
Causes Of Death ◽  
Conflicts Of Interest ◽  
Organ Damage ◽  
Death Certificates ◽  
Cell Disease ◽  
Organ Function ◽  
Significant Difference

Abstract Abstract 2117 Sickle cell disease (SCD) causes significant morbidity and early mortality. The largest study to date reported in 1994 a median survival of 42 years for men and 48 years for women with homozygous SCD1. One third died during a vaso-occlusive crisis, and 18% died of acute organ failure. Circumstances of death were unknown in 18% of patients. With improved patient care in the current era including hydroxyurea (HU) therapy, we sought to identify age and causes of death and associated clinical variables in adults with SCD at a single referral institution. We first reviewed death certificates and assigned one or more causes of death based on all listed data. We studied autopsy reports and medical records and communicated with medical providers when available to identify further causes of death. We then performed a cross sectional analysis of clinical features obtained at initial enrollment and compared those variables in patients who are now living versus deceased using univariate t-test or Chi-squared analysis in order to determine which factors may be associated with death. 528 patients with SCD evaluated at the National Institutes of Health between 2001 and 2010 were included. Out of 511 patients with known genotypes, 391 patients had homozygous SCD. 85 of 528 (16%) died at a median age of 43 years for men and 44 years for women. Death certificates were available for 55 (65%) patients. SCD and infection were the most common listed cause of death (12% each), followed by pulmonary hypertension and/or cor pulmonale (9%), cardiac etiology (8%), narcotic toxicity (7%), and other (31%). Cause of death was unavailable in 18 (21%) cases. Deceased patients were significantly older at the time of first enrollment compared to living patients (41.5 vs. 34.1 years, p<0.0001). There was no significant gender difference between groups. There was also no significant difference in the reported use of HU or fetal hemoglobin levels. Enrollment laboratories suggesting renal insufficiency in deceased patients included a higher creatinine, phosphorus, and uric acid (p<0.02). Hepatic dysfunction was also more prevalent in the deceased group as evidenced by significantly higher direct bilirubin and alkaline phosphatase and lower albumin (p<0.005). There was no difference in alanine transaminase levels. Lactate dehydrogenase (LDH) was significantly higher in deceased patients (p=0.01). As there was no significant difference in hemoglobin, indirect bilirubin, or absolute reticulocyte counts between groups, higher LDH in deceased patients suggests a non-erythrocytic source. Ferritin levels and percent saturation of transferrin were significantly higher and transferrin significantly lower (p<0.004) suggesting more iron overload in deceased patients. Lastly, brain natriuretic peptide levels (reported only in patients with creatinine <1mg/dL) and tricuspid regurgitant velocity were also significantly increased (p<0.0001), suggesting higher prevalence of cardiopulmonary disease in deceased patients. In summary, the most common listed cause of death was nonspecific and unrevealing, reported as SCD. Surprisingly, another common cause of death was infection. This may be due to the combination of poor organ function reserve and functional asplenia. Deceased subjects were older and more likely to have organ impairment at initial evaluation. These data suggest that while contemporary management of patients with SCD may decrease acute manifestations, end organ damage still occurs. Lastly, markers of organ function should be closely monitored as patients increase in age, and organ-specific and definitive disease-specific therapy should be considered before irreversible organ damage ensues. 1 Platt OS et al. NEJM, 1994. 330(23): 1639–1644. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Kelly M. Knee ◽  
Amey Barakat ◽  
Lindsay Tomlinson ◽  
Lila Ramaiah ◽  
Zane Wenzel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Organ Damage ◽  
Complete Elimination ◽  
Cell Disease ◽  
The Impact ◽  
2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

Severe Pain Profiles and Associated Sociodemographic and Clinical Characteristics in Individuals with Sickle Cell Disease

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Mitchell R. Knisely ◽  
Paula J. Tanabe ◽  
Qing Yang ◽  
Rita Masese ◽  
Meilin Jiang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Clinical Characteristics ◽  
Cell Disease

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

Reduced Oxidative Stress and Enhanced Nitric Oxide (NO) Bioavailability in Transgenic-Knockout Sickle Mice Expressing Fetal Hemoglobin (HbF) Is Mediated by Decreased Sickling and Hemolysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 842-842
Author(s):  
Trisha Dasgupta ◽  
Mary E. Fabry ◽  
Dhananjay K. Kaul
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Manipulation ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Multiple Organ ◽  
Protective Effects ◽  
Cell Disease ◽  
No Bioavailability

Abstract The primary event in the vaso-occlusive pathophysiology of sickle cell disease (SCD) is polymerization of hemoglobin S under deoxygenated conditions. In SCD, sub-clinical transient vaso-occlusive events caused by red cell sickling are likely to be more frequent resulting in “reperfusion injury” that generates reactive oxygen species and results in chronic oxidative stress that will contribute to multiple organ damage. In fact, previous studies have suggested that sickling is etiologic to repefusion injury and oxidative stress (Kaul and Hebbel, JCI, 2000), although the effect of antisickling therapy on oxidative stress has not been evaluated. Increasing the levels of antisickling fetal hemoglobin (HbF) by hydroxyurea therapy markedly reduces polymer formation. HbF exerts an ameliorating effect in sickle cell disease patients both on red cells and in the prevention of multiple organ damage. Here, we hypothesize that induction of HbF by genetic manipulation (in the absence of pharmacological manipulation) will reduce organ oxidative stress by reducing sickling and hemolysis, and thereby increase NO bioavailability. To test our hypothesis, we measured activity of selected antioxidants and lipid peroxidation (LPO) in BERK mice expressing exclusively human α- and βS-globins and varying levels of HbF, i.e., BERK (<1% HbF), BERKγM (20% HbF) and BERKγH (40% HbF). Percent sickled cells in venous samples (drawn in 2.5% glutaraldehyde solution in 0.1M cacodylate buffer) showed a distinct decrease with increased %HbF (P<0.05, multiple comparisons). Consistent with maximal sickling, BERK mice showed 5.4–6.9-fold increase in LPO in various tissues (muscle, kidney and liver) compared with C57BL controls (P<0.001). In contrast, BERKγM and BERKγH mice showed a marked decrease (73% and 80%, respectively) in LPO compared with BERK mice (P<0.001). Also, activity/levels of antioxidants (superoxide dismutase [SOD], catalase, glutathione peroxidase [GPx] and reduced glutathione [GSH]) showed significant decreases in BERK mice (P<0.001–0.00001). On the other hand, BERKγM and BERKγH mice showed significant increases in antioxidant activity (P<0.05–0.0001). Induction of HbF was associated with increased levels of NO metabolites (NOx) and reduced hemolysis; the latter is in agreement with our previous observations in BERKγM mice (Kaul et al. JCI, 2004). These results strongly suggest that reduced sickling and hemolysis in the presence of HbF cause increased NO bioavailability. NO is well known to exert antioxidative effects. Thus, we show for the first time that the induction of antisickling HbF leads to an increase in NO bioavailability and a decrease in oxidative stress, and that these protective effects are mediated primarily by reduced intravascular sickling.

Predictors of Mortality in Children and Adolescents with Sickle Cell Disease: The PUSH Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 515-515 ◽  
Author(s):  
Mehdi Nouraie ◽  
Sohail R. Rana ◽  
Oswaldo L Castro ◽  
Lori Luchtman-Jones ◽  
Craig Sable ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Children And Adolescents ◽  
Sickle Cell ◽  
Severe Pain ◽  
Blood Transfusions ◽  
Cell Disease ◽  
Risk Of Death ◽  
The Past ◽  
History Of

Abstract Abstract 515 Background: Recent studies indicate that the disease-specific mortality In sickle cell anemia is about 6% in children up to 18 years and 15% in the 18–30 year age group, yielding a cumulative mortality of 21% by age 30 years. It is important to identify children at high risk so that early interventions can be developed to reduce this high mortality. Methods: We prospectively enrolled 505 children and adolescents with sickle cell disease in 2005–2010, 380 with hemoglobin SS and 130 with other genotypes. The median age at enrollment was 12 years with a range of 3 to 20 years. Baseline clinical features, echocardiography, six-minute walk test and pulmonary function testing were performed at steady-state. Follow-up for mortality has been performed in 470 of the participants at a median of 37 months after enrollment, range of 1 to 59 months. Results: Six of 470 patients (1.3%) died during the follow-up period, five with hemoglobin SS and one with hemoglobin SC. The median age at the time of death in these six participants was 20 years, range of 15 to 23 years. Death occurred during the follow-up period in 2.7% of participants over 12 years of age at enrollment and 3.7% of those over 15 years of age. The causes of death were stroke in 4, multiorgan failure in 1 and unknown in 1. Death occurred in 5.9% of 51 participants with a history of stroke versus 0.7% of 416 without stroke history; in 3.5% of 113 participants with a history of asthma versus 0.6% of 354 without asthma history; in 4.9% of 103 participants with 10 or more blood transfusions lifetime versus 0.3% of 359 with less than 10 blood transfusions; in 3.3% of 90 participants with two or more severe pain episodes in the past year versus 0.8% of 380 participants with less than two severe pain episodes in the past year. In age-adjusted analyses, the hazards ratio (95% CI) of death was 6.1 (1.2-30.5) for history of stroke (P=0.029), 10.2 (1.2-89.5) for history of frequent blood transfusions (P=0.036), 5.8 (1.1-31.8) for history of asthma (P=0.044) and 1.07 (1.00-1.14) for frequent severe pain episodes (P=0.047). Clinical findings associated with these risk factors included higher concentrations of markers of hemolysis for history of stroke and history of frequent blood transfusions, decreased FEV1/FVC and increased total lung capacity for history of asthma, and lower concentrations of markers of hemolysis and high ECHO-determined tricuspid regurgitation velocity for history of frequent severe pain episodes. Conclusions: Over a median of three years of observation of this cohort, no deaths occurred among 248 sickle cell disease children 12 years of age or younger at enrollment but there were 6 deaths among 222 participants 13–20 years of age at enrollment. In bi-variate age-adjusted analyses, histories of stroke, asthma, frequent blood transfusions and frequent pain episodes were associated with an increased risk of death. Strikingly, four of the five deaths in which the cause was known were due to stroke. The present data on mortality in the PUSH study suggest that prevention of stroke is critical in improving the survival in adolescents and young adults with sickle cell disease. Disclosures: No relevant conflicts of interest to declare.

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