Distrust and Conflict in Sickle Cell Disease: Intersecting Narratives of Patients and Physicians

Abstract A gap in trust between patients with sickle cell disease (SCD) and medical providers is well recognized, largely originating from repetitive requests for opioid analgesics. Although expert clinical care guidelines in sickle cell disease are available, they rarely address measures by which this endemic gap in trust may be narrowed to fulfill the goals of medicine. We hypothesized that an increased familiarity with the patient as an individual through exposure of physicians to first-person narratives of the life-world of SCD may allow reformulation of perceptions and narrow the gap between physicians and patients. In a pilot study, extended first-person narratives of the illness experience elicited from patients with SCD with a history of recurrent hospitalizations (n=10) point to the individualized impact of pain, illness and stigmatizing disruptions in life-building efforts imposed by SCD together with the recurrent conflicts with medical caregivers, particularly after transition from pediatric to adult medicine. Patient-elicited narrative fragments such as "You are constantly fighting with people who are supposed to be making us feel better", "You don't know me, I am a church boy!" and "Put down your microscopes and talk to us" reveal the yearning by patients for individual integrity to be acknowledged, absorbed and interpreted by physicians. Additional narrative fragments such as "I hate myself. I hate my life", "Why am I broken?", "you don't want to be the girl with jaundice", "I had to leave work for 2 months because I was hospitalized, it killed me, it killed me", "you never know when it's going to be the last day, the last moment", exhibit the woundedness and fragility of existence experienced by patients. Narratives elicited separately from physicians caring for SCD (n=5) reveal anxiety, fear and distrust of the reported pain experience and opioid requests, and point toward deeper schisms that disparities may define: "I was very scared when I took care of my first sickle cell patient", "I came in with a bias already", "a similar frequent flier who had the same kind of behavior", "you have to be careful with empathy, people can take advantage of it", "I am not an enabler", "My grandfather told me about these people". Yet when the same physicians were invited to read and reflect on transcripts of the life-world stories of patients, reshaped perceptions of the stigmatized patient are revealed; "without knowing the story, you can't put it all together", "this would change the way I view treating them", "I will have more patience now" as examples. However, "Why can't they listen to our story? It could help them to be better patients," suggests that additional studies of the mutual intersections of patient and physician narratives are warranted and that these can offer insights and pathways toward mitigating distrust and conflict between medical care providers and patients with SCD. Disclosures No relevant conflicts of interest to declare.

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Level of Utilization and Provider-Related Barriers to Hydroxyurea Use in the Treatment of Sickle Cell Disease in Jos, Nigeria

Blood ◽

10.1182/blood-2019-128185 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1029-1029 ◽

Cited By ~ 1

Author(s):

Akinyemi Olugbenga David Ofakunrin ◽

Kehinde Adekola ◽

Edache Sylvanus Okpe ◽

Stephen Oguche ◽

Tolulope Afolaranmi ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Health Care Providers ◽

Conflicts Of Interest ◽

Sampling Technique ◽

P Value ◽

Care Providers ◽

Cell Disease ◽

Cross Sectional ◽

Inadequate Knowledge

Background: Hydroxyurea is one of the currently approved medications capable of modifying the pathogenesis of sickle cell disease (SCD), and its use has transformed the management of this disease worldwide.However, available evidences suggest that hydroxyurea is underutilized by sickle cell health-care providers in Nigeria despite the huge burden of the disease. Objectives: This study assessed the level of utilization and provider-related barriers to the use of hydroxyurea in the treatment of SCD patients in Jos, Nigeria. Methods: A cross-sectional study conducted among 132 medical doctors providing care for SCD patients in four tertiary hospitals in Jos using a multistage sampling technique. In this setting, SCD patients are cared for by the Hematologists, Pediatricians, Family Physicians and General Practitioners. Data on socio-demographics of the respondents, knowledge, utilization and barriers to the utilization of hydroxyurea were obtained using an interviewer-administered questionnaire. The data were processed and analysed using SPSS version 23. Hydroxyurea was adjudged utilized if a provider has prescribed hydroxyurea to any SCD patient within the last 12 months. Chi square test was used to test the association between the demographic, provider-related barrier variables and the level of utilization of hydroxyurea. The barriers were fed cumulatively into logistic regression model as predictors of utilization of hydroxyurea. Adjusted odds ratio and 95% confidence interval were used as point and interval estimates respectively. A P-value of <0.05 was considered statistically significant. Results: Of the 132 respondents, 88 (67%) had been in medical practice for upward of six years while 80 (60.6%) of them affirmed that they have attended to more than 10 SCD patients in the last 6 months. Sixty-seven (50.8%) of the participants had inadequate knowledge of hydroxyurea use in SCD management while the level of utilization of hydroxyurea in SCD treatment was 24.2%. The odds of non-utilization of hydroxyurea was 5.1 times higher in providers with no expertise in its use (OR =5.1; 95% CI =2.65-9.05; P<0.0001). Other barriers that predicted its non-utilization included inadequate knowledge (OR =0.17; 95% CI =0.29-0.71; P=0.017), fear of side-effects (OR =0.50; 95% CI =0.22-0.68; P=0.019) and doubt about the effectiveness of the medication (OR =0.30; 95% CI =0.20-0.90; P=0.002). Conclusion: The level of utilization of hydroxyurea in the treatment of SCD among the sickle cell care-providers is sub-optimal with the lack of expertise in its use identified as the most prominent barrier. Therefore, training of Nigeria sickle cell care-providers to attain and maintain competence in the use of hydroxyurea for the treatment of SCD is required. Keywords: Sickle cell disease, hydroxyurea, utilization, barriers, Jos, Nigeria Disclosures No relevant conflicts of interest to declare.

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Neonatal Screening for Sickle Cell Disease in Belgium for More than 20 Years: An Experience for Comprehensive Care Improvement

International Journal of Neonatal Screening ◽

10.3390/ijns4040037 ◽

2018 ◽

Vol 4 (4) ◽

pp. 37 ◽

Cited By ~ 1

Author(s):

Béatrice Gulbis ◽

Phu-Quoc Lê ◽

Olivier Ketelslegers ◽

Marie-Françoise Dresse ◽

Anne-Sophie Adam ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Health Care Providers ◽

Neonatal Screening ◽

Clinical Care ◽

Care Providers ◽

Cell Disease ◽

Clinical Registry ◽

Birth Prevalence ◽

Screening Programs

Our previous results reported that compared to sickle cell patients who were not screened at birth, those who benefited from it had a lower incidence of a first bacteremia and a reduced number and days of hospitalizations. In this context, this article reviews the Belgian experience on neonatal screening for sickle cell disease (SCD). It gives an update on the two regional neonatal screening programs for SCD in Belgium and their impact on initiatives to improve clinical care for sickle cell patients. Neonatal screening in Brussels and Liège Regions began in 1994 and 2002, respectively. Compiled results for the 2009 to 2017 period demonstrated a birth prevalence of sickle cell disorder above 1:2000. In parallel, to improve clinical care, (1) a committee of health care providers dedicated to non-malignant hematological diseases has been created within the Belgian Haematology Society; (2) a clinical registry was implemented in 2008 and has been updated in 2018; (3) a plan of action has been proposed to the Belgian national health authority. To date, neonatal screening is not integrated into the respective Belgian regional neonatal screening programs, the ongoing initiatives in Brussels and Liège Regions are not any further funded and better management of the disease through the implementation of specific actions is not yet perceived as a public health priority in Belgium.

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Barriers and Resident Attitudes Surrounding Care of Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-142986 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-22

Author(s):

Daniela Anderson ◽

Erin Hickey ◽

Sharjeel Syed ◽

Jacobi Hines ◽

Nabil Abou Baker

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Health Care Providers ◽

Asian American ◽

Residency Program ◽

Barriers To Care ◽

Conflicts Of Interest ◽

Care Providers ◽

Cell Disease ◽

Resident Attitudes

Introduction Patients with sickle cell disease (SCD) commonly experience negative attitudes from health care providers, leading to significant barriers to care and management of pain (Haywood 2009). Incidence of SCD is high on the South Side of Chicago and the University of Chicago Medical Center (UCMC) is among the primary systems in the area caring for these patients. Based on the results of a small pilot study conducted at UCMC in 2019, providers can hold biased beliefs that lead to inadequate delivery of analgesia (Nelson 2019). Because internal medicine (IM) and emergency medicine (EM) residents are often at the frontline of caring for patients with SCD, we sought to explore attitudes and beliefs amongst IM and EM residents at our institution in order to address biases with future interventions. Methods We conducted anonymous surveys using validated questions (Haywood 2011) for UCMC IM and EM residents. The surveys were administered in paper form during conferences in July 2019 to IM and EM residents and January 2020 to IM residents. The surveys, which included questions that assess barriers to care of patients with SCD and attitudes amongst providers, utilize the 4-point Likert scale in which higher scores correspond to stronger agreement with the statement. Participants were asked to provide non-identifiable demographic information including sex, ethnicity, age range, training year (PGY-1- PGY-3), and residency program. Responses were pooled and analyzed to assess for differences in attitudes by residency program (EM vs. IM), sex, age, year of training, and ethnicity. Statistical analysis was performed using the student's t-tests to identify differences in average responses and ANOVA to examine for confounding variables. Results Sixty-six residents were included in this study: 44 IM and 22 EM. Residents were 41% female and 58% male, ranging in age from 20-39 (median 25-29 yrs). Forty-eight percent of residents were White, 20% Asian/Asian American, 11% Black/African American, 9% Latinx, and 12% unidentified/other. Resident training level included 20% PGY-1 (13), 53% PGY-2 (35), and 29% PGY-3 (19). In terms of attitudes, 38% of IM and EM residents overall believed that patients with SCD over-report pain and are "drug-seeking" (N=66). IM residents (84% N=44) were more likely to consider patients to be frustrating to work with compared to EM residents (23% N=22, p<0.0001). While 83% of residents overall said patients with SCD are easy to empathize with, only 50% of IM residents (N= 44) believed they could be friends with SCD patients compared to 82% amongst EM residents (N=22, p=0.001) (Figure 1). When comparing these responses by year of training, attitudes generally became more negative with increased training, with advanced residents more likely to believe that SCD patients over-report pain (p=0.011), feel more frustrated caring for patients (p<0.001), consider themselves less likely to be friends with the patients (p=0.004), and feel less satisfied about going into medicine in general (p=0.012). No significant differences were observed when comparing resident ethnicity or age group. Considering barriers to SCD pain management, 100% of IM residents (N=23) believed opioid tolerance was a significant barrier, followed by 92% reporting opioid dependence, 83% side effects, 79% addiction, and 67% regulatory oversight. Conclusion This study highlights gaps in resident understanding of SCD and reveals biases held amongst IM and EM residents. Biases are augmented amongst IM residents and tend to become more exaggerated with increased level of training. The latter result may be confounded by burnout, which was not directly assessed in this study. The differences observed between IM and EM residents may be due to variation in education, workflow, or program diversity (although effect of ethnicity was not statistically significant). Resident-perceived barriers also seem to be focused on negative patient-centered factors (dependence, addiction, tolerance) rather than systemic limitations (availability, training, efficacy), likely reflecting negative resident attitudes as seen in previous studies (Haywood 2009). These data demonstrate an unmet need, underlining the importance of developing education, training, and potentially wellness programs to confront biases, build positive attitudes toward patients with SCD and ultimately remove barriers to care of patients with SCD. Disclosures No relevant conflicts of interest to declare.

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Demographic and Socio-Economic Features of a Cohort of Adult Sickle Cell Disease Patients.

Blood ◽

10.1182/blood.v114.22.4616.4616 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4616-4616 ◽

Cited By ~ 1

Author(s):

Syed N Haider ◽

Jun Tang ◽

Raymond U. Osarogiagbon

Keyword(s):

Sickle Cell Disease ◽

Marital Status ◽

Sickle Cell ◽

Health Care Providers ◽

Catchment Area ◽

Conflicts Of Interest ◽

Categorical Variables ◽

Continuous Variables ◽

Care Providers ◽

Cell Disease

Abstract Abstract 4616 Introduction Despite improvements in diagnosis, preventive care and treatment, care of sickle cell disease (SCD) patients remains difficult. The majority are from lower socio-economic strata, poorly educated and from single parent households. The racial divide between patients (who tend to be almost all black) and their health care providers (who tend to be predominantly non black) can adversely affect the quality of care when stereotypes are assumed. We examined the demographic and socio-economic features of patients in our adult sickle cell disease program. Patients and Methods We retrospectively reviewed data on 118 patients that entered our program between February 2005 and October 2008. Our catchment area included parts of rural Mississippi, Tennessee and Arkansas as well as a major urban community. We reviewed the following demographic characteristics: age, gender, patient's marital status, parent's marital status, employment status, highest level of education, health insurance status and referral source. We then contrasted the characteristics of those with SC (which tends to be milder) with SS/Sβ0 sickle cell disease (which is phenotypically more severe). Continuous variables were evaluated using t-test. Chi-square test was used to assess categorical variables. Results The results are depicted in the table. Conclusions We describe the demographic and socio-economic features of a cohort of 118 patients seen in an academic center with a diverse catchment area. In spite of adverse family circumstances, relatively high proportion of the cohort was college educated (32%) or graduated from high school/GED (55%). 61% of the patients are either currently employed or current students. These results are quite contrasting to the general perception about the adult sickle cell disease population. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2020-134202 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-13

Author(s):

Oladipo Cole ◽

Asia Filatov ◽

Javed Khanni ◽

Patricio Espinosa

Keyword(s):

Case Report ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Moyamoya Disease ◽

Conflicts Of Interest ◽

Acute Chest Syndrome ◽

African American Female ◽

Moyamoya Syndrome ◽

Cell Disease ◽

Radiographic Findings

Moyamoya disease, well described in literature, is a chronic cerebrovascular occlusive disorder. It is characterized by progressive stenosis/occlusion of the terminal portions of the internal carotid arteries (ICA) and the proximal portions of the middle cerebral arteries (MCA). Less frequently described is Moyamoya syndrome, the name given to radiographic findings consistent with Moyamoya disease, but with an identifiable cause. The diseases associated with Moyamoya Syndrome include Sickle Cell Disease (SCD), Thalassemias, and Down's Syndrome to name a few. Common complications of Moyamoya include both ischemic and hemorrhagic strokes. Upon literature review, Moyamoya syndrome caused by SCD is not well described. When it is, the discussion is centered around the pediatric patient population and surgical management. Our case report describes a 22-year-old African American female with SCD who initially presented with Acute Chest Syndrome. Her hospital course was complicated by development of overt debilitating neurologic deficits. Subsequently, she was found to have Moyamoya Syndrome on neuroimaging. She was successfully treated with medical management without any surgical intervention. This case highlights the necessity of thorough examination, differential diagnosis, imaging findings, and consideration of predisposing syndromes in the work-up for Moyamoya syndrome; especially individuals with Sickle Cell Disease. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2020-143454 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Satish Maharaj ◽

Simone Chang ◽

Karan Seegobin ◽

Marwan Shaikh ◽

Kamila I. Cisak

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Complete Blood Count ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Acute Chest Syndrome ◽

Adult Males ◽

Cell Disease ◽

Unequal Variances ◽

Recorded Data

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

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Interferon Induction By HbS, SERINC5 Upregulation and Reduction of HIV-1 Nef and AP2 Contribute to HIV-1 Restriction in Sickle Cell Disease

Blood ◽

10.1182/blood-2020-142699 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Namita Kumari ◽

Marina Jerebtsova ◽

Songping Wang ◽

Sharmin Diaz ◽

Sergei Nekhai

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Mononuclear Cells ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Interferon Response ◽

Cell Disease ◽

Restriction Factors ◽

Peripheral Blood Mononuclear ◽

Hiv 1

Concerted action of numerous positively acting cellular factors is essential for Human immunodeficiency virus type 1 (HIV-1) replication but in turn is challenged by anti-viral restriction factors. Previously we showed that ex vivo one round HIV-1 replication and replication of fully competent T-tropic HIV-1(IIIB) is significantly reduced in peripheral blood mononuclear cells (PBMCs) obtained from patients with Sickle Cell Disease (SCD). Further, we identified and confirmed CDKN1A (p21) and CH25H as host restriction factors expressed in SCD PBMCs that may contribute to the HIV-1 inhibition, in addition to the previously reported SAMHD1 and IKBα. Since CH25H is an interferon stimulated gene (ISG), we analyzed IRFs and interferon expression in SCD PBMCs. Higher levels of IRF7 and IFNβ mRNA were observed in SCD PBMCs compared to controls. We probed further to ascertain if hemin or sickle Hb was responsible for interferon response. We found upregulation of IFNβ in THP-1 - derived macrophages treated with lysates of HbSS RBCs or purified HbS as compared to untreated or HbA treated controls. HbSS RBCs lysates and purified HbS inhibited HIV-1 gag mRNA expression in monocyte-derived macrophages infected with HIV-1(Ba-L). Recent clinical study showed increased levels of CD4 in HIV-1 infected SCD patients in Africa. Thus we analyzed CD4 levels in HIV-1 IIIB infected SCD PBMCs, and found them to be higher compared to controls. Levels of HIV-1 nef mRNA, that controls CD4 expression was lower in HIV-1 IIIB infected SCD PBMCs. As Nef counteracts SERINC3/5 restriction factor, we analyzed its expression as well as the expression of AP2 clathrin adaptor that is required for Nef mediated internalization of CD4. AP2 expression was lower and SERINC5 expression was higher in SCD PBMCs. CONCLUSIONS: SCD PBMCs could resist HIV-1 infection because of the increased IFNβ production by macrophages exposed to HbSS or sickle cell RBCs. SCD PBMC have increased levels of SERNIC5 and lower levels of HIV-1 Nef and host AP2 expression that, culumlatively, can increased CD4 levels and lead to the overall improved immunological health of SCD patients. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 1SC1HL150685, 5U54MD007597, 1UM1AI26617 and P30AI087714). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures No relevant conflicts of interest to declare.

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American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support

Blood Advances ◽

10.1182/bloodadvances.2019001143 ◽

2020 ◽

Vol 4 (2) ◽

pp. 327-355 ◽

Cited By ~ 22

Author(s):

Stella T. Chou ◽

Mouaz Alsawas ◽

Ross M. Fasano ◽

Joshua J. Field ◽

Jeanne E. Hendrickson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Guideline Development ◽

Practice Research ◽

Evidence Based ◽

Red Cell ◽

Cell Disease ◽

American Society

Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

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

Blood ◽

10.1182/blood.v114.22.1540.1540 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1540-1540 ◽

Cited By ~ 1

Author(s):

Latorya A Barber ◽

Allison E Ashley-Koch ◽

Melanie E. Garrett ◽

Karen L Soldano ◽

Marilyn J. Telen

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Umbilical Vein ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Data Set ◽

Clinical Complications ◽

Cerebrovascular Events ◽

Increased Risk

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

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Measurement of Urine Pyridinoline and Deoxypyridinoline as Markers of Increased Bone Degradation in Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.2572.2572 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2572-2572

Author(s):

Erfan Nur ◽

Willem Mairuhu ◽

Dees P. Brandjes ◽

Ton van Zanten ◽

Bart J. Biemond ◽

...

Keyword(s):

Sickle Cell Disease ◽

Bone Resorption ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Healthy Controls ◽

Cell Disease ◽

Skeletal Involvement ◽

Asymptomatic Patients ◽

Bone Degradation ◽

Painful Crisis

Abstract Abstract 2572 Poster Board II-549 Introduction: Sickle cell disease (SCD) is commonly manifested through skeletal involvement. Besides the characteristic acute musculoskeletal pain, SCD is also associated with chronic skeletal complications such as osteopenia and osteoporosis. During bone resorption, the collagen cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) are released into circulation with subsequent urinary excretion. Measurements of urinary PYD and DPD could serve as valuable tools in detecting osteoporosis in the follow-up of SCD patients but perhaps also in determining the severity of bone infarction during painful crises. Therefore we compared urinary concentrations of PYD and DPD of SCD patients during asymptomatic state and painful crisis with those of race- and age-matched healthy controls. Methods: Urinary concentrations of PYD and DPD, adjusted for urine creatinine, were measured in SCD patients both during asymptomatic state (n=38) and painful crisis (n=27) and healthy controls with normal HbA hemoglobin (n=25) using high performance liquid chromatography (HPLC). Results: PYD and DPD concentrations were higher in asymptomatic SCD patients compared to controls ((54.8 (41.5–68.6) vs. 44.1 (37.7–49.9),P=0.005 and 11.6 (9.3–15.2) vs. 8.5 (6.8–10.4),P=0.004 respectively), with further increments during painful crisis (63.3 (51.8–76.0),P=0.041 and 15.3(13.0–21.5),P=0.003 respectively). In the asymptomatic patients levels of PYD and DPD were significantly correlated to the degree of hemolysis. Conclusion: In sickle cell patients bone resorption is increased and significantly correlated to the degree of hemolysis, compatible with their susceptibility to osteopenia and osteoporosis. Measurement of pyridinoline and deoxypyridinoline could have additional value as biomarkers of osteoporosis in SCD. During painful crises a further increment in bone degradation was observed. Disclosures: No relevant conflicts of interest to declare.

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