Crisis In Sickle Cell Disease Research Articles

Induction of Human Fetal Hemoglobin Expression by Selective Inhibitors of Histone Deacetylase 1 and 2 (HDAC1/2)

AbstractAbstract 3259 Introduction:Fetal hemoglobin (HbF) induction is an established therapeutic strategy in sickle cell disease (SCD), and could also be effective in treating beta-thalassemia (bT). The only drug with proven efficacy in SCD is hydroxyurea, which is cytotoxic, poorly tolerated, and only reduces the frequency and severity of SCD crises in a subset of patients. For bT there are no approved drug treatments and, for the most severe forms of bT, patients require repeated blood transfusions for life and chelation therapy to reduce iron overload. Fetal (γ) globin expression is silenced in adults partly through the action of a complex containing BCL11A and HDAC1/2. Genetic ablation and chemical inhibition of HDAC1 or HDAC2, but not HDAC3, resulted in the induction of γ-globin synthesis in adult bone marrow derived CD34+ erythroid cells (Bradner, Proc Natl Acad Sci 2010). While a variety of non-specific HDAC inhibitors have been used successfully to induce HbF, further clinical development has been limited by their variable efficacy and concerns over off-target side-effects observed in small clinical trials, potentially due to inhibition of HDAC3. Therefore, development of selective and potent HDAC1/2 inhibitors leading to HbF induction represents a refined and targeted therapeutic approach for the treatment of SCD and bT. Results:Recently, selective inhibitors for HDAC1 and 2 have been described for compounds containing a benzamide zinc chelating group (Witter, Bioorg Med Chem Lett 2008). Acetylon Pharmaceuticals has generated a library of structurally distinct compounds containing a modified benzamide biasing element. We have screened these molecules in an HDAC biochemical assay platform and found IC50 values for HDAC1 and 2 ranging from 5 to 10 nM and 10 to 30 nM, respectively, with approximately 10- to 100-fold selectivity over inhibition of HDAC3. These compounds had good oral bioavailability in rat, with exposure (AUC) exceeding 5000 hr*ng/mL following an oral dose of 5 mg/kg. Furthermore, half-life was found to range between 4 to 8 hours. In cultured human CD34+ bone marrow cells undergoing erythroid differentiation, these compounds induced a dose dependent increase in fetal hemoglobin expression, with a 5-fold induction observed at 1 μM. The γ-globin induction we observe is comparable to MS-275, a non-selective HDAC1/2/3 inhibitor, and decitabine, a DNA methyltransferase inhibitor which has been in clinical trials to induce HbF in SCD. The absolute levels of adult β-globin remained unchanged. These results were confirmed using flow cytometry, where a 2- to 4-fold increase in the number of cells expressing HbF protein was observed. Conclusion:These results suggest that inhibition of HDAC1 and 2 is sufficient to induce fetal globin expression. Our selective HDAC1/2 inhibitors have highly favorable oral pharmacokinetic profiles suitable for further development towards the treatment of SCD and bT. Disclosures:Shearstone:Acetylon Pharmaceuticals, Inc.: Employment. van Duzer:Acetylon Pharmaceuticals, Inc.: Employment. Bradner:Acetylon Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mazitschek:Acetylon Pharmaceuticals, Inc. : Consultancy, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc.: Employment. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment.

Soluble CD163 in young sickle cell disease patients and their trait siblings

CD163 is expressed on cells of monocyte-macrophage lineage and is the main hemoglobin-haptoglobin receptor. Inflammation and monocyte activation are predisposing factors to vaso-occlusion and pulmonary hypertension, which are serious complications in sickle cell disease (SCD). Siblings of SCD patients may have the same pathophysiology without displaying symptoms. We assessed soluble CD163 (sCD163) levels in 60 children with SCD and 30 sickle cell trait (SCT) siblings compared with 30 healthy controls as a potential marker for disease severity and treatment response. Patients were studied stressing on the presence of pulmonary hypertension by Dopplar-Echocardiography, sickling crisis, transfusion requirements, hydroxyurea response, hematological profile, high sensitivity C-reactive protein (hs-CRP) and serum sCD163. sCD163 was significantly elevated in SCD patients and SCT siblings compared with controls and the highest levels were in untreated SCD patients (P < 0.001). sCD163 was higher in patients with pulmonary hypertension, acute chest syndrome or stroke as well as in patients who developed sickling crisis during the study period (P < 0.05). Hydroxyurea-treated patients had lower sCD163 compared with untreated patients (P < 0.001). sCD163 was positively correlated to leukocyte count, HbS, hs-CRP, pulmonary artery pressure and tricuspid regurgitant velocity whereas inversely correlated to hemoglobin and HbF levels. The cut-off value of sCD163 at 1400 ng/ml could be considered a predictor for vaso-occlusive crisis in SCD with a sensitivity of 92.3% and specificity of 94.1%. sCD163 can be considered a biomarker for pulmonary hypertension, early crisis prediction and monitoring hydroxyurea response in SCD patients. Elevated sCD163 in trait siblings could reflect increased risk of sickling in challenging situations.

Wheeze predicts sickle cell disease crisis

Wheeze predicts sickle cell disease crisis

The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease

The association of vascular endothelial growth factor (VEGFA) variants and VEGF secretion with sickle cell disease (SCD) vasoocclusive crisis (VOC) was investigated in 210 VOC patients and 114 pain-free control patients. VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020), and 936C/T (rs3025039) were carried out by real-time PCR. Higher frequency of rs2010963 C-allele, rs833068 A-allele, and rs3025020 C-allele and significant differences in rs2010963, rs833068, and rs3025020 genotype distribution were seen in VOC than steady-state patients. Increased VOC risk was seen with rs2010963 as heterozygous and more as homozygous, and in rs833068 and rs3025020 homozygous carriers. While there were no differences in VEGF levels between VOC and steady-state controls, there was a progressive decline in serum VEGF in rs2010963 and rs833068 heterozygous and homozygous genotypes, but an opposite trend was seen in VOC patients. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs833068, and rs833070, but weak or no LD between rs3025020 and rs3025039 and other SNPs. Six-locus (rs699947/rs833061/rs1570360/rs2010963/rs833068/rs833070) VEGFA haplotype analysis identified haplotype 111111 to be negatively (OR = 0.68) and haplotype 111222 to be positively (OR = 1.89) associated with VOC. rs2010963, rs833068, and rs3025020 were correlated with VOC type, while rs3025020 was correlated with hospitalization, VOC treatment, and duration. Specific VEGFA variants contribute to the pathogenesis of SCD VOC.

Prevalence of factor V Leiden (G1619A) and prothrombin gene (G20210A) mutation in Egyptian children with sickle cell disease

Patients with sickle cell disease (SCD) show activation of the blood coagulation. The purpose of the current study was to detect the prevalence of factor V Leiden (G1691A) and prothrombin gene (G20210A) mutations in a group of Egyptian children with SCD, and to clear out their possible role as genetic risk factors for vaso-occlusive crises (VOC) in SCD. The current study included fifty Egyptian SCD children and fifty age and sex matched healthy children as a control group. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism technique. Heterozygous factor V Leiden was significantly higher in the SCD patients (30 %) compared to controls (16 %), while there was no statistical difference between the two groups regarding heterozygous prothrombin gene (G20210A) mutation. Factor V Leiden conferred increased risk of VOC in SCD patients (OR = 1.7, 95 %CI = 1.01–3.43). Screening for factor V Leiden in SCD patients is recommended to verify patients at higher risk of VOC.

Successful epidural analgesia for a vaso-occlusive crisis of sickle cell disease during pregnancy: a case report

We describe a 19-year-old Cameroonian primigravid young woman with sickle cell disease who was admitted to a local hospital in Cameroon where the first author performed his internship gynecology and obstetrics. She presented at 28 weeks of gestation with severe pain in her left leg caused by a vaso-occlusive crisis. As recommended, high doses of intravenous morphine were administered, but without significant pain relief. She received a single bolus injection of 5 mg morphine, followed by a continuous infusion of 0.05 mg/kg/h during 48 h. Lumbar epidural blockade with bupivacaine combined with sufentanil successfully alleviated her severe peripheral ischemic pain induced by a vaso-occlusive crisis caused by sickle cell disease. Until now, only one case report and no clinical trials have been published concerning the use of epidural analgesia for treatment of a vaso-occlusive crisis of sickle cell anemia in a pregnant woman who is not in labor.

Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients

Acute splenic sequestration crisis (ASSC) is an unpredictable life-threatening complication of sickle cell disease (SCD) in infants. Here, our objective was to update available clinical information on ASSC. We retrospectively studied the 190 patients who were diagnosed at birth with SS or Sbeta(0) in the Paris conurbation between 2000 and 2009 and who experienced ASSC. They had 437 ASSC episodes (0.06/patient-year). Median age at the first episode was 1.4 years (0.1-7) and 67% of patients had more than one episode. Age was the only factor predicting recurrence: the risk was lower when the first episode occurred after 2 years versus before 1 year of age (hazard ratio, 0.60; 95% confidence interval, 0.41-0.88; P=0.025). A concomitant clinical event was found in 57% of episodes. The mortality rate was 0.53%. The treatment consisted in watchful waiting without prophylactic blood transfusions or splenectomy in 103 (54%) patients and in a blood transfusion programme in 55 (29%) patients. Overall, splenectomy was performed in 71 (37%) patients, at a median age of 4.5 years (range, 1.9-9.4). In conclusion, aggressive treatment may be warranted in patients experiencing ASSC before 2 years of age. Randomized controlled trials are needed to define the best treatment modalities.

Descriptive Study: sleep disorders breathing and Polysomnographic changes in Children and Adolescents with Sickle Cell Disease

Abstract 4849 Introduction:-Sickle Cell Disease (SCD) is a chronic inflammatory disease and a public health problem in Brazil, due its prevalence and Brazilian people high miscegenation. The hypoxia is one of the trigger for vessel occlusive crises in SCD and the quality of sleep is important to maintain a good tissue oxygenation. The search for sleep-disordered breathing (SDB) must be made based on history, physical examination and polysomnography (PSN). These include the diagnosis of airway obstruction and sleep apnea/hypopnea, obstructive syndrome (SAHOS). The objective confirmation of disordered breathing during sleep is made by polysomnography, which identify and record and hypoxemic respiratory events during sleep. Objectives:Identify the most common sleep disordered breathing and changes in PSG in patients with sickle cell disease. Methods:We evaluated 38 children and adolescents with sickle cell disease (SS, SC, S-Beta), regularly monitored at the outpatient pediatric hematology ICP Bolivar Risso/Grendacc-FMJ, the clinical behavior before (two years) by a clinical protocol, physical examination and polysomnography. This study was approved by the Ethics Committee and signed Informed Consent. Results:Characterization of the group:distribution by sex: 19 boys/19 girls aged 2 to 17 years; genotype: Hb SS 20, 11 HbSC and 7 Sβ thalassemia. Clinical history and examination: It was found snoring present in four or more days a week and audible from other rooms in 14 patients (36%), difficulty breathing during sleep moderately difficult, with occasional sounds of “choking” the very difficult, paradoxical breathing in 6 patients (15%). Apnea witnessed over 2 to 3 times per night, in 4 patients (10%), diaphoresis during sleep over 2 to 3 times per week in 15 patients (39%) hyper-extended position of the neck during sleep or discreetly evident for almost all night in 4 patients (10%); mouth breathing at night several hours at night, almost every day, every night and night, in 20 patients (52%), restless sleep, with stirring frequently messy and covered in 23 patients (60%). On physical examination, he met retrognathia moderate and severe in 4 patients (10%), maxillary atresia moderate to severe in 10 (26%); goodwill previous moderate to severe in 12 patients (31%). The hypertrophy of tonsils (Brodsky) grade III and IV in 12 children (31%), the Mallampati score of 3 and 4 was identified in 7 patients (18). Polysomnography: periodic movements of the lower limbs (47%), from mild to severe snoring (37%), fragmented sleep (7.5%), apnea and hypopnea (5%), EEG features epileptoid (5%), normal (17.5%). Patients with less severe clinical behavior were those with minor changes in polysomnography. Conclusions:The study of sleep in patients with sickle cell disease, clinical and laboratory is essential to identify risk factors for situations of hypoxia. SDB is common in patients with DF, and their identification by clinical history and physical examination should be encouraged and be part of their clinical follow-up, indicating the completion of laboratory investigation when it will be necessary.Identification of SAHOS is rarely addressed in routine pediatric consultations or hematological and should be part of the script of an interview and clinical examination.The finding of the PSG member movements deserves further study because it has to be superior to those described in the literature. Disclosures:No relevant conflicts of interest to declare.

Inhibition of E-Selectin Inflammatory Function by the Glycomimetic GMI-1070

Abstract 851▪FN2▪This icon denotes a clinically relevant abstract Introduction:E-selectin expression by endothelium plays dual roles in inflammation by supporting slow rolling and subsequently eliciting integrin activation and arrest of leukocytes. This process may be important for immune surveillance. In a previous mouse model of sickle cell disease, E-selectin mediated outside-in signaling results in upregulated leukocyte Mac-1 and increased red cell capture, exacerbating vaso-occlusion. This process was attenuated by infusion of GMI-1070, a novel synthetic small molecule pan-selectin antagonist. GMI-1070 is now in Phase II clinical trial to determine efficacy in treatment of vaso-occlusive crisis (VOC) of sickle cell disease (SCD). Here, we studied its dose dependent effects in SCD subjects not in VOC on neutrophil activation and its effects on E-selectin mediated β2 integrin activation and rolling and arrest in shear flow. Methods:Samples were obtained from 4 SCD subjects not in VOC enrolled in a Phase I study of the effects of GMI-1070, a pan-selectin antagonist that preferentially inhibits E-selectin. An intravenous (IV) loading dose of 20 mg/kg was followed 10 hours later by a dose of 10 mg/kg. Samples were drawn before the loading dose, then 4 and 8 hours after the initial infusion. Polymorphonuclear Neutrophil (PMN) activation was analyzed in whole blood and isolated cell assays. Monoclonal antibodies and fluorescent-activated cell sorting (FACS) were used to assay expression of CD11b/CD18 (Mac-1), CD62L (L-selectin), and the high affinity active conformation of CD18 (327C) as markers of neutrophil activation. E-selectin mediated activation of CD18 was achieved in isolated PMN by incubating with E-selectin-IgG and goat antibody F(ab')2 fragment to crosslink E-selectin-IgG PMN activation was assessed by surface expression of high affinity CD18 by the mAb 327C and FACS in the presence of various concentrations of GMI-1070. PMN rolling and arrest on an inflammatory substrate was quantified using a lab on a chip assay. Whole blood or isolated PMN were perfused through a microfluidic flow chamber at a shear stress of 2 dynes/cm2. The flow chamber had immobilized E-selectin and ICAM-1 to support PMN rolling and adhesion. Video recordings of PMN interacting with this substrate were taken to quantify the number of rolling versus arrested cells and to measure rolling velocity in the presence of GMI-1070. Results:An inverse relationship between the serum concentration of GMI-1070 and either activated CD18 or upregulated CD11b was observed. In the flow chamber assays, 6 of 7 samples showed GMI-1070 diminished PMN arrest that also correlated with diminished integrin activation. Incubation of PMN with GMI-1070 blocked CD18 activation in response to E-selectin-IgG cross-linking, with an IC50 of 0.5 mM. PMN rolling and arrest was measured following shearing of isolated PMN on E-selectin and ICAM-1 using a lab on a chip assay. The mean rolling velocity of 2 mm/sec was increased to 6 mm/sec at a GMI-1070 concentration of 20 mM, with an IC50 of 5.5 mM for the increase in rolling velocity. In contrast, an IC50 = 0.8 mM was required to antagonize the fraction converting from rolling to arrest under shear flow. Summary and Conclusions:There was a dose dependent inhibitory effect on PMN activation after IV administration of GMI-1070 as measured in ex vivo whole blood samples in a small cohort of SCD subjects at steady state. A systematic study of the activity of GMI-1070 on isolated PMN revealed two distinct patterns of inhibition. At low concentrations (IC50 = 0.5mM), GMI-1070 effectively blocked the capacity of E-selectin to activate CD18, in response to cross-linked ligands, and mediate arrest. Only at higher concentrations (IC50 = 5.5mM) did we observe a significant alteration in the capacity of GMI-1070 to increase the rolling velocity and frequency of capture on a substrate of E-selectin under fluid shear stress. This differential capacity to alter function reveals that slow rolling, which is mediated by recognition of a number of sialylated ligands on the surface of PMN can be distinguished from the processes associated with the transition to arrest. Thus, treatment with GMI-1070 at doses that efficiently block vascular occlusion may spare some PMN rolling and immune surveillance function. Disclosures:Simon:GlycoMimetics Inc.: Research Funding. Chase:GlycoMimetics Inc.: Research Funding. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership.

Costs, Persistence, and Hospitalizations Associated with the Use of Iron-Chelating Therapies in Sickle Cell Disease in Medicaid Patients

Abstract 3152 Objective:Patients with Sickle Cell Disease (SCD) receiving chronic blood transfusions require iron chelation therapies (ICTs) and good adherence to ICT to avoid sequellae of iron overload. This study evaluated cost, persistence, and medication adherence to ICTs based on a nationwide sample of Medicaid recipients with SCD. Methods:This retrospective cohort study evaluated healthcare claims from 2006 to 2010 captured within the Thomson Reuters 10 states Medicaid MarketScan database. Patients with ≥ 1 SCD diagnosis code (282.6x), ≥ 2 claims for ICT medications (deferoxamine (DFO), deferosirox (DFX)), continuously enrolled for ≥ 6 months prior to ICT initiation through 365 days post initiation of ICT were included. ICT utilization was obtained using NDC codes and HCPCS codes. Patients were classified into 3 groups based on their ICT use: DFO only, DFX only, and switches from DFO to DFX. Outcomes evaluated included adherence and persistence to ICT, frequency of SCD crises related hospitalizations, and overall costs. ICT adherence was evaluated using medication possession ratio (MPR) and persistence was defined as medication refill gap of ≥ 6 weeks. Multivariate linear, logistic, and Cox regression analyses were performed after controlling for demographics, number of transfusions, capitated Medicaid coverage, pre-index cost (6months prior to ICT initiation), number of hospitalizations, adherence, and risk-adjusted case-mix comorbidity. Results:A total of 484 SCD patients receiving ICTs from 2006 to 2010 within the 10 states were identified. The average age was 18.9 ±11.2 years of age, 45% (n =218) were male, and 64.7% (n=313) were African American. A total of 25.4% (n =123) patients, switched from DFO to DFX while 1.7% (n = 8) switched from DFX to DFO during one-year post-ICT initiation. Patients receiving DFX only, DFO only, or both ICTs received an average of 2.68 (±3.2), 3.54 (±3.0), 3.59 (±3.2) transfusions during the study period, respectively. Compared to pre-ICT period, the number of transfusion claims increased in all three cohorts during the study period; the mean difference was 2.7 in DFO, 3.3 in DFX, and 4.1 in the both ICT group. The Cox regression assessing long-term medication persistency indicated a 1.37 times higher likelihood of treatment discontinuation with DFO compared to DFX. Overall MPR was low in both groups; following one year of treatment, 37.4% remained on DFX compared to 15.7% on DFO (Figure 1). No differences were observed in total healthcare costs, number of hospitalizations and associated costs for SCD-related crises between the DFX only and DFO only cohorts. Meaningful differences in treatment discontinuation between the two treatment groups did not occur until 220+ days during the study period (Figure 1). Thus, a one year timeframe may be inadequate to observe complete impact of ICT adherence on sequellae of iron overload and subsequent resource use. Lengthening the study period beyond one year may be necessary to fully capture the long term impact of adherence on outcomes related to iron overload. Conclusion:This study indicated that there were more switches from DFO to DFX, higher medication persistency rate with DFX than DFO, and similar total healthcare costs, numbers of SCD crisis-related hospitalizations, and SCD crisis-related costs between DFO & DFX cohorts. Treatment discontinuation was generally high for all groups, especially for those on DFO, with a one year discontinuation rate of approximately 85%. Future research using a longer observation period than one year will be necessary to assess effects on long term clinical outcomes, resource use, and healthcare costs between different ICTs.Kaplan-Meier Graph for Treatment Discontinuation Between Deferoxamine and Deferasirox [Display omitted] Disclosures:Armstrong:Novartis Pharmaceutical Corporation: Consultancy, Research Funding. Skrepnek:Novartis Pharmaceutical Corporation: Consultancy, Research Funding. Ballas:Novartis Pharmaceutical Corporation: Consultancy. Kwok:Novartis Pharmaceutical Corporation: Employment. Snodgrass:Novartis Pharmceutical Corporation: Employment. Sasane:Novartis Pharmaceutical Corporation: Employment.

Liver Enzymes and Trace Elements in the Acute Phase of Sickle Cell Anaemia

Trace elements are required for the performance of numerous functions of immune cells. It is not clear whether levels of trace elements are elevated and whether there is a relationship between the levels of liver enzymes and trace elements in patients with sickle cell anaemia in crisis. To compare the plasma levels of liver enzymes and trace elements in non sickle cell anaemia (NSCA), sickle cell anaemia subjects in the steady state (SCASS) and sickle cell anaemia patients in crisis (SCAC). Haematological parameters, liver enzymes and trace elements were determined in 20 NSCA subjects, 20 SCASS subjects and 18 SCAC subjects. Variables studied included aspartate aminotransferase (AST) , alanine aminotransaminase (ALT), alkaline phosphatase (ALP), and the trace elements copper, zinc, and manganese. Levels of liver enzymes were higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Plasma Cu++, Zn++ and Mn++ were also higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Correlationships were high and strong between AST and ALT (r=+0.7; p=0.03), AST and ALP (r=+0.9; p=0.001), Zn++ and Fe++ (r=+0.9; p=0.001) in SCAC. During crisis in sickle cell anaemia, liver enzymes, as well as the trace elements of Cu++, Zn++ and Mn++ are increased; levels of aspartate aminotransaminase are strongly correlated with those of ALT and ALP. Levels of liver enzymes do not appear to be related to those of the trace elements in painful sickle cell crisis.

Mandibular osteomyelitis associated with paroxysmal nocturnal hemoglobinuria

A case of osteomyelitis in a 71-year-old woman with paroxysmal nocturnal hemoglobinuria (PNH) is reported. Osteomyelitis of the jaw is a well known condition of the oral and maxillofacial region that may cause severe morbidity. It is well documented that vaso-occlusive crises in sickle cell anaemia, a hemolytic blood disorder, can make the jaw bone susceptible to osteomyelitis. The authors report a case proposing an association between PNH and osteomyelitis of the mandible.

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.

High resource hospitalizations among children with vaso‐occlusive crises in sickle cell disease

Vaso-occlusive crises (VOCs) contribute to frequent hospitalizations among children with sickle cell disease (SCD). The objective of this study was to identify factors associated with high resource utilization during hospitalizations for VOC. We analyzed pediatric discharges 0-18 years of age with a primary diagnosis of SCD with crisis from the 2006 Kids' Inpatient Database, a nationally representative sample of pediatric hospital discharges. High resource hospitalizations were defined as those in the highest decile for total charges. We conducted sample-weighted regression analyses to determine associations between independent variables (patient demographics, hospital characteristics, illness severity) and high resource use. There were 9,893 (0.371%) discharges for children with VOCs. Median total hospitalization charges were $10,691. In multivariate analysis, children 15-18 years of age (odds ratio [OR] 3.39, 95% confidence interval [CI] 2.54-4.53), 10-14 years of age (OR 2.72, 95% CI 2.07-3.59), and 5-9 years of age (OR 1.74, 95% CI 1.30-2.34) had higher odds of high resource hospitalizations compared to children 0-4 years of age. Care in a children's hospital had three times the odds of high resource use compared to care in a general hospital. Discharges with secondary diagnoses including pneumonia (OR 2.46, 95% CI 1.96-3.09) and constipation (OR 1.78, 95% CI 1.31-2.40) were also associated with high resource use. Older age and secondary diagnoses were associated with high resource use during VOC hospitalizations. These findings suggest the need to improve adherence to comprehensive care among older children to prevent VOCs and standardize protocols to manage VOC complications.

Can Pain Studies Influence Regulatory Policy?

Pain has a way of clipping our wings and keeping us from being able to fly … and if left unresolved for very long, you can almost forget that you were ever created to fly in the first place.William Paul Young The Shack , published 2007 In April, 1907, the young man reported that he had been laid up in a hospital from December 26, 1906, to February 26, 1907, with what he called muscular rheumatism. His illness had begun with malaise, pain in the back, the muscles of the legs and arms.J.B. Herrick Arch Intern Med 1910;5:517 … relentless and repetitive gnawing pains in the bones and joints characteristic of the disease.F.I.D. Konotey-Ahulu Arch Intern Med 1974;133:611 Pain, the symptom that typifies sickle cell disease, has the frightful capacity to strip life of all aspirations. Those who experience the inveterately painful existence of sickle cell disease often lead lives defined by their relationship with their pain; those with inadequate coping skills have lives filled with frustration, dissocial adaptations, isolation, and depression [1]. The pain crises of sickle cell disease have been described as rather brief episodes that last from hours to a few days [2] and occur relatively infrequently [3,4]. This notion differs greatly from the 2-month ordeal experienced by patient Walter Clement …

Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia?

Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia?

Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia?

Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia?

Pilot study of omega-3 fatty acid supplements in sickle cell disease

In a previous retrospective study, it was observed that the greater the amounts of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the blood, the lesser the number of complications of sickle cell disease (SCD) and the higher the steady state haemoglobin level. SCD causes ischaemia-reperfusion injury and inflammation; which can be ameliorated by a metabolite of DHA that down-regulates expression of pro-inflammatory genes. The objectives of this prospective pilot study were to evaluate the effects of DHA and EPA supplements in SCD, and test the hypothesis that these effects are mediated partly by reducing inflammation. Oral DHA and EPA supplements were given to 16 SCD patients for 6 months. We then compared pre- and post-supplementation values of number of crisis, steady state Hb, plasma unconjugated bilirubin and three indices of inflammation: plasma interleukin-6, blood neutrophil and platelet counts. There was a significant reduction in the plasma level of unconjugated bilirubin, and the number of sickle cell crisis; but not in the markers of inflammation. The pilot data suggest that DHA and EPA supplements reduce the number of crisis and steady state haemolysis in SCD; but provide no evidence that these effects are mediated by reducing inflammation.

Changes in Platelet Count as a Predictive Tool in Sickle Cell Acute Vaso-Occlusive Crises: A Pediatric Study

Studies have shown that platelets play an important role in the pathophysiology of vaso-occlusive crises (VOC) in sickle cell disease. This study investigates whether changes in platelet indices from baseline can be predictive of complications during acute pain crisis. Data were obtained from pediatric sickle cell patients in the well-clinic setting and compared with data gathered during VOC (n = 67). Primary outcome was complicated (admission, acute chest syndrome, transfusion, etc) versus uncomplicated (discharge from emergency department without subsequent return) course. Patients with uncomplicated courses had larger platelet declines (53.7) than those with complicated courses (14.8, P = .005). The study suggests that patients with uncomplicated VOC are more likely to experience a larger decline in platelets. The predictive value is limited by the need to have preexisting steady-state data and relatively small decline. Ongoing studies are needed to identify useful laboratory data to help predict severity of VOC.

Erythrocyte membrane sulfatide plays a crucial role in the adhesion of sickle erythrocytes to endothelium

Enhanced adhesion of sickle erythrocytes to the vascular endothelium and subendothelial matrix is fundamental to the development of vascular occlusion in sickle cell disease. Erythrocyte membrane sulfatide is implicated in the pathogenesis of vasoocclusive crises in sickle cell disease (SCD) patients. Because previous evidence linking sulfatide to cell adhesion has largely been circumstantial due to a lack of reagents that specifically target sulfatide, we used two sulfatide-specific strategies to address the role of erythrocyte membrane sulfatide in sickle cell adhesion to the vascular endothelium: a single-chain fragment variable chain (scFv) antibody against sulfatide as well as cerebroside sulfotransferase-deficient mice incapable of synthesising sulfatide. The sickle erythrocytes from mice and humans adhered at a greater extent and at higher shear stresses to activated endothelium than normal erythrocytes, and approximately 60% of the adhesion was prevented by the anti-sulfatide scFv. Similarly, the extent of adhesion of sulfatide-deficient erythrocytes was lower than normal erythrocytes. These findings suggest an important role for membrane sulfatide in sickle cell disease pathophysiology.