Population-Based Surveillance of Pneumococcal Infections in Children with Sickle Cell Disease before and after Prevnar 7® and Prevnar 13® Licensure: Implications for Expanded Vaccination

Abstract Before prophylactic antibiotic use, approximately 1/10 children <5 years old with sickle cell disease (SCD) developed invasive pneumococcal disease (IPD) with a high risk of meningitis and death. Although the emergence of penicillin-resistance in IPD threatened benefits of penicillin prophylaxis, after licensure of the 7-valent pneumococcal polysaccharide vaccine (PCV7) in 2000, IPD rates in children with SCD decreased by over 2/3. In 2010, PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F) was licensed in children, and in 2021, two additional conjugated vaccines were approved for use in adults: PCV15 (VAXNEUVANCE®, PCV13+: 22F, 33F) and PCV20 (PREVNAR20®, PCV13+: 8, 10A, 11A, 12F, 15B, 22F, 33F). IPD rates in children with SCD over 24 years in Atlanta were evaluated to describe trends in age of infection, frequency of antibiotic resistance, non-vaccine IPD serotype distribution after vaccine licensures, and estimates for serotype coverage by newer vaccines. IPD among children with SCD, ages 0 to 4 years and 5 to 9 years, residing in the Metropolitan area of Atlanta, Georgia, USA, from 1/1/1994 through 7/31/2018, were compared to the general population. The Centers for Disease Control and Prevention (CDC)-funded Georgia Emerging Infections Program (GA EIP) Active Bacterial Core Surveillance network included initially 8 counties in 1994 and from 1997 onward, 20 counties (total populations of approximately 3.8 and 5.1 million, respectively). Two registries of patients with SCD seen at least once at one of 3 pediatric hospitals serving the region were merged and matched with GA EIP data. The serotyping and antibiotic susceptibility testing were conducted at the CDC. The study was approved by the Emory University Institutional Review Board. Data from 3 periods: pre PCV period (94-99), PCV7 period (00-09) and PCV13 period (10-18) were analyzed. Compared to the pre PCV period, overall, IPD rates decreased in children with SCD vs 91% in the RP for 0-4 years; and 80% in children with SCD vs 78% in the RP for 5-9 years (table1). The difference in IPD rates between patients with SCD and the general population increased over time: pre PCV period, relative risk (RR)=24.22 (95 % Confidence Interval [CI] 17.43,32.88), P<.001; PCV 7 period, RR=32.17 (95 %CI 22.17,45.37), P<.001; PCV 13 period, RR=39.18 (95 %CI 22.35,64.69) P<.001. Meningitis and deaths from IPD decreased significantly in all populations examined but remained significantly higher in patients with SCD compared to RP (table 2). The mean age at IPD diagnosis for the 3 periods examined increased both in SCD and in the RP. For those with SCD (n=50), pre-PCV7 period mean age was :2.7 standard deviation (+/-) 2.3 years; for the PCV 13 period: n=19; 3.7 years +/-2.2 years p= 0.0877; for the RP: Pre-PCV period: n=1025; 1.3 +/-1.6 years; PCV 13 period: n=213; 2.2 +/-2.3 years. Overall absolute IPD rates declined for all age groups examined (table 1). Prior to PCV7 licensure, IPD in patients with SCD were significantly less likely to be penicillin susceptible (MIC <0.06 µg/mL) compared to the RP: 41.9% (18/43) vs 60.0% (476/793) RR=0.70 (95% CI 0.49,1.00), p=0.025. This difference was no longer present after PCV licensure (PCV 13 period , SCD 52.9% [9/17], vs RP 48.6% [70/144]). Non PCV serotypes IPD rates increased after PCV7 licensure but remained stable after PCV13 licensure; 16% of non PCV13 serotypes during all time periods are included in PCV15, whereas PCV20 may cover between 29% and 50% depending on related serotypes cross protection (table3). Although significantly less frequent compared with pre-PCV-era, IPD can be severe in patients with SCD. Increase in IPD age was seen in both SCD and RP. Lower rates of penicillin non-susceptibility may may reflect lower exposure to penicillin prophylaxis. Newer vaccines may offer expanded coverage for children with SCD. Ongoing surveillance will help determine their effect. Vaccines that cover all serotypes are needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Alloantibody Formation In Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.2395.2395 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2395-2395 ◽

Cited By ~ 1

Author(s):

Joep Sins ◽

Saurabh Zalpuri ◽

Marjon Cnossen ◽

Anita W. Rijneveld ◽

Jean-Louis Kerkhoffs ◽

...

Keyword(s):

Sickle Cell Disease ◽

General Population ◽

Sickle Cell ◽

Cumulative Incidence ◽

Cox Regression ◽

Conflicts Of Interest ◽

Cumulative Number ◽

Cell Disease ◽

Cox Regression Analysis ◽

Increased Risk

Abstract Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent complications in sickle cell disease (SCD). However, frequent transfusions may lead to erythrocyte alloimmunization, thereby complicating donor matching procedures and posing patients at risk for hemolytic transfusion reactions. Little information is available about the risk of alloimmunization of sickle cell patients living in European countries. In the Netherlands extensive matching procedures to prevent alloimmunization were introduced a decade ago, but the effect on alloimmunization has not been evaluated yet. Aims The primary aim of this study is to evaluate the cumulative incidence of first alloantibody formation in a Dutch cohort of transfused SCD patients, and to compare this with a general Dutch RBC-transfused population. In addition, the effect of extended RBC matching protocols on the incidence of alloantibody formation in SCD and potential clinical determinants of alloimmunization will be assessed. Methods We conducted a retrospective cohort study and collected data on SCD patients (genotypes HbSS, HbSC, HbSβ0 and HbSβ+ thalassemia), diagnosed in three Dutch Sickle Cell Treatment Centers that received non-extended matched (ABO, RhD) RBC transfusions between 1984-2004 and extended matched (at least ABO, Rhesus phenotype, Kell) RBC transfusions between 2004-2011. In addition, we compared this population with a general population of 3 042 patients that received non-extended matched (ABO, RhD) RBC transfusions between 2005-2009 in the Leiden University Medical Center (Zalpuri et al. 2012). Cohorts were not matched for ethnicity. Alloimmunization risk was calculated as Kaplan-Meier incidence with cumulative number of transfusions as time variable. The association with the clinical determinants gender, SCD-phenotype and ethnicity was analyzed with Cox-regression analysis. Results A total of 291 SCD patients received 7 957 RBC units. Alloantibody formation occurred in 52 (17.9%) patients. The cumulative incidence of alloimmunization was 9% after 5 RBC units, 15% after 10, 24% after 20 and 34% after 40 RBC units. Multivariate analysis, correcting for the cumulative number of transfusions, demonstrated a significantly increased risk of alloantibody formation in our SCD cohort when compared to a general population of transfused patients (HR 7.5 (95% CI: 5.06-11.14), where the cumulative incidence of alloimmunization was 1.1% after 5, 2.4% after 10, 3.4% after 20 and 6.5% after 40 RBC units. No association could be demonstrated between alloantibody formation and clinical determinants such as gender, SCD-phenotype or ethnicity. However, a significant reduction in alloimmunization was observed in SCD patients that received their first transfusion from the year 2004 onwards, after preventive matching for Rhesus phenotype and Kell was introduced for SCD patients (HR 0.48 (95% CI: 0.24-0.97)). Conclusion The overall rate of first RBC alloantibody formation in our cohort was 17.9% and the risk of alloimmunization increased substantially with an increasing number of RBC transfusions. A unique comparison with a general cohort of Dutch transfused patients demonstrates a significantly higher risk of alloantibody formation in SCD, acknowledging earlier findings. This may partially be explained by differences in RBC antigens between patients of African descent and the predominantly Caucasian donors. Besides the number of RBC units, no other clinical risk factors for allo-immunization in SCD could be identified. The effectiveness of extended RBC matching protocols in the prevention of alloimmunization for chronically transfused patients in the participating centers was confirmed. Disclosures: No relevant conflicts of interest to declare.

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COVID Vaccination Rates in Children and Adults with Sickle Cell Disease in British Columbia, Canada

Blood ◽

10.1182/blood-2021-152141 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3034-3034

Author(s):

Hayley Merkeley ◽

Marlee McGuire ◽

Lillian Ding ◽

Heather McCartney ◽

Ali Amid ◽

...

Keyword(s):

British Columbia ◽

Sickle Cell Disease ◽

General Population ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Vaccine Hesitancy ◽

Cell Disease ◽

Vaccination Rates ◽

Phone Calls ◽

To Receive

Abstract Background: Persons with Sickle Cell Disease (SCD) infected with the SARS CoV-2 virus have significantly increased risks of hospitalization and death and are strongly recommended to be fully vaccinated. Vaccine hesitancy has previously been described in the SCD population and uptake of other recommended vaccines has been reported to be low in some studies. The goal of this study was to assess how vaccination rates amongst eligible pediatric and adult SCD patients in British Columbia (BC), Canada, compared to those of the general population and other "clinically extremely vulnerable" (CEV) groups. Methods: Persons age 12 and over with SCD in BC were identified as a CEV population and prioritized for immunization. A comprehensive process was undertaken to find and identify all CEV patients in BC and notify them of their priority status. Individuals diagnosed with SCD in the province were identified in the shared pediatric and adult patient registry (iCHIP), which tracks demographics, diagnoses and therapies, and added to the CEV patient list. SCD patients were notified of their priority status through standard mail from the provincial health officer, as well as emails and phone calls from the pediatric and adult SCD programs. Those aged 16+ were invited to register for immunization beginning in March 2021 while those 12-15 years were permitted to register starting in May 2021. Adult patients were eligible to receive mRNA vaccines from Pfizer and Moderna as well as the Astra-Zeneca (AZ) COVISHIELD vaccine, while those aged 12-17 were eligible only for Pfizer vaccines. The provincial immunization registry (PIR) was interrogated to confirm vaccine administration. The main outcome measure was the proportion of SCD patients who received 1st and 2nd dose COVID vaccines. Results: 138 individuals age 12+ with SCD were identified in the iCHIP database. 71.0% had Sickle Cell Anemia (SCA), 25.4% had Hemoglobin SC (Hb SC) and 3.6% had other genotypes. Participants ranged in age from 12-69 years with a median of 28 years. 67.4% were receiving disease-modifying therapy (76 were on hydroxyurea, 11 on regular red cell exchange, 1 was receiving crizanlizumab, and 5 with Hb SC were phlebotomized). None were treated with gene therapy or transplant. 7 individuals had a PCR-confirmed SARS CoV-2 infection prior, but none following immunization. As of July 30, 2021: 68.8% of persons with SCD received a 1st and 55.1% received a 2nd dose of COVID vaccine. Almost all doses were mRNA-based vaccines with the exception of a single 1st dose administration of AZ. Vaccination rates amongst different age ranges and genotypes are displayed in Table 1. Patients with SCA did not have significantly different vaccination rates compared to those with Hb SC/other genotypes: 64.3% versus 80.0% for 1st dose (p=0.0703) and 48.0% versus 62.5% (p =0.12114) for 2nd dose. Vaccination rates amongst the SCD group were compared to other age matched CEV populations as well as the general provincial population and are detailed in Tables 2 and 3. A higher proportion of persons with SCD under the age of 20 received 1st dose (70.8% versus 31.1%; p<0.00001) and 2nd dose (50.0 versus 15.3%; p <0.00001) of vaccines compared to the general population. However, a lower proportion age 20-49 and 50+ years old received a 1st dose as demonstrated in Table 2. In addition, lower proportions of persons with SCD of all age ranges were vaccinated in comparison to other CEV groups. As demonstrated in Table 3, SCD was not associated with receiving a 1st dose vaccine compared to the general BC population (OR 0.8, 0.56 to 1.16 95% CI, p=0.2481). In contrast, persons in other CEV groups were twice as likely to receive a first dose COVID immunization compared to the general BC population (p<0.0001). No severe vaccine-related complications including vaccine-induced immune thrombotic thrombocytopenia (VITT) were reported. There were 7 presentations to hospital for vaso-occlusive crises (VOC) within 21 days of immunization. Conclusion: Despite an active CEV process to find and invite persons with SCD to be vaccinated, these data demonstrate that vaccination rates amongst persons with SCD in BC are below those of other CEV age-matched groups. Vaccination rates amongst adults are also lower than the general population, however there is a high vaccination rate in persons under 20 years old. A subsequent qualitative study exploring COVID vaccine hesitancy amongst persons with SCD in BC is being explored. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Hematological and Biochemical Reference Ranges for the Population with Sickle Cell Disease at Steady State in Tanzania

Hemato ◽

10.3390/hemato3010007 ◽

2022 ◽

Vol 3 (1) ◽

pp. 82-97

Author(s):

Anna Daniel Fome ◽

Raphael Z. Sangeda ◽

Emmanuel Balandya ◽

Josephine Mgaya ◽

Deogratius Soka ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

General Population ◽

Sickle Cell ◽

Age Groups ◽

Mean Corpuscular Hemoglobin ◽

Reference Ranges ◽

Cell Disease ◽

Laboratory Reference ◽

Males And Females

Hematological and biochemical reference values in sickle cell disease (SCD) are crucial for patient management and the evaluation of interventions. This study was conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania, to establish laboratory reference ranges among children and adults with SCD at steady state. Patients were grouped into five age groups and according to their sex. Aggregate functions were used to handle repeated measurements within the individual level in each age group. A nonparametric approach was used to smooth the curves, and a parametric approach was used to determine SCD normal ranges. Comparison between males and females and against the general population was documented. Data from 4422 patients collected from 2004–2015 were analyzed. The majority of the patients (35.41%) were children aged between 5–11 years. There were no significant differences (p ≥ 0.05) in mean corpuscular hemoglobin concentration (MCHC), lymphocytes, basophils, and direct bilirubin observed between males and females. Significant differences (p < 0.05) were observed in all selected parameters across age groups except with neutrophils and MCHC in adults, as well as platelets and alkaline phosphatase in infants when the SCD estimates were compared to the general population. The laboratory reference ranges in SCD at steady state were different from those of the general population and varied with sex and age. The established reference ranges for SCD at steady state will be helpful in the management and monitoring of the progress of SCD.

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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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A Novel Connection Between Stress Erythropoiesis and Coagulation Activation in Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.905.905 ◽

2009 ◽

Vol 114 (22) ◽

pp. 905-905

Author(s):

Julia E. Brittain ◽

David Manly ◽

Leslie V. Parise ◽

Nigel Mackman ◽

Kenneth I. Ataga

Keyword(s):

Flow Cytometry ◽

Sickle Cell Disease ◽

Tissue Factor ◽

Sickle Cell ◽

Whole Blood ◽

Conflicts Of Interest ◽

Cell Disease ◽

Coagulation Activation ◽

Monocytic Cells ◽

Stress Erythropoiesis

Abstract Abstract 905 Introduction: Sickle cell disease (SCD) is associated with a hypercoagulable state. Multiple studies show that plasma from these patients exhibit: 1) increased thrombin generation; 2) decreased levels of natural anticoagulant proteins; and 3) a defect in the activation of fibrinolysis. The mechanism of coagulation activation in SCD is presumed to be multi-factorial, with contributions from abnormal erythrocyte phospholipid asymmetry and induction of tissue factor (TF) following hemolysis. In addition, hemolysis in SCD leads to elevated levels of erythropoietin (EPO) in patients, increased reticulocyte counts and the presence of stress (or shift) reticulocytes in circulating blood. These stress reticulocytes retain expression of the α4b1 integrin and are demonstrably adhesive to vascular factors in SCD. We have previously reported that these stress reticulocytes bind to blood monocytes in SCD patients via the α4b1 integrin, but the effect of this interaction on either cell remained unknown in SCD. Objective: With the increasing evidence that hemolysis and subsequent stress erythropoiesis associates with coagulation activation, we sought to evaluate the role of erythropoietin and the effect of stress reticulocyte adhesion to monocytes on coagulation activation in SCD patients. Methods: Coagulation activation in plasma samples was examined by evaluating TF activity on microparticles derived from patients with SCD. Stress reticulocytes were visualized and enumerated from these same patients using Wright Giemsa stained blood smears counter stained with new methylene blue to detect reticulocytes. Reticulocytes were scored as a stress reticulocytes based on the amount of punctuate reticular material, cell size, and presence of nuclear material. Stress reticulocyte induction of monocyte tissue factor expression was measured by flow cytometry after incubation of THP-1 monocytic cells with purified SS RBCs or control RBCs. To determine if induced THP-1 TF expression was due stress reticulocyte binding, THP-1 TF expression was examined in the presence or absence of known inhibitors of the monocyte/stress reticulocyte interaction. TF expression on CD14+ monocytes was examined in whole blood from SCD patients using flow cytometry. Plasma erythropoietin levels were quantified by ELISA. Results: We found that direct binding of the stress reticulocyte increased THP-1 TF expression 2.5 fold. This increase in TF expression was completely ablated by function blocking antibodies against the α4 integrin, but not by an isotype-matched control IgG. In whole blood samples, we also found increased TF expression on CD14+ monocytes with stress reticulocytes directly bound, compared to those monocytes in the same patient without stress reticulocytes bound (p = 0.002, n =3).We noted a strong correlation between stress reticulocyte count and TF activity on plasma microparticles in SCD (rspearman = 0.8656, CI = 0.5382 – 0.9660, p = 0.0006, n=11). Furthermore, we found that EPO induced α4b1 activation on the stress reticulocyte. This activation may promote both adhesion to the monocyte and an increase in TF expression. Consequently, we noted a strong trend towards an association of EPO with microparticle TF activity in SCD (rspearman = 0.5740, CI=-0.06 – 0.8780, p=0.068, n= 11) suggesting that EPO, by promoting the interaction between the stress reticulocyte and the monocyte, may contribute to TF activity in SCD. Conclusion: Taken together, we find that stress reticulocyte adhesion to monocytes and monocytic cells induces TF expression and may promote TF activity in patients. These data suggest a novel connection between stress erythropoiesis and coagulation activation in SCD. Disclosures: No relevant conflicts of interest to declare.

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