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

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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Clinical Characteristics Associated with Survival in Adult Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.3229.3229 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3229-3229

Author(s):

Hany Elmariah ◽

Melanie E. Garrett ◽

Kenneth I. Ataga ◽

Allison E Ashley-Koch ◽

Marilyn J. Telen

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Survival Data ◽

Conflicts Of Interest ◽

Cox Proportional Hazards Model ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Cerebrovascular Events ◽

Hydroxyurea Therapy

Abstract Abstract 3229 Background: Sickle cell disease (SCD) greatly decreases survival of affected patients, and significant advances will be necessary to decrease the gap in expected survival between SCD patients and non-affected individuals. We examined the relationship of clinical differences among SCD patients to survival, in order to gain greater understanding of major contributors to early mortality. Identification of such factors could guide development of therapeutic options. Methods: Survival data were obtained for 417 adult subjects previously enrolled in a study of clinical outcome modifying genes in SCD from Duke University Medical Center and the University of North Carolina at Chapel Hill. All subjects were ≥18 years at the time of enrollment and were followed for a mean of 7.9 years (range 2.3–10 years). At enrollment, a number of clinical parameters were collected, including hemoglobin (Hb) genotype (SS, SC, Sβ0 thalassemia, or Sβ+thalassemia), baseline laboratory values (Hb, WBC, platelets, reticulocytes, fetal Hb, LDH, MCV, proteinuria), comorbidities (cerebrovascular events, pulmonary hypertension, history of acute chest syndrome, avascular necrosis, priapism, and pain crises - defined as number of hospitalizations in the past 12 months, among others), and medication status (hydroxyurea, narcotics, and others). Levels of soluble adhesion molecules (sICAM, sVCAM, sE-selectin, sP-selectin), NT-proBNP, TNF-α, and interleukins-6, -8, and -10 were measured for a subset of 87 subjects. Regression analysis based on the Cox proportional hazards model was employed to determine the effect of clinical phenotypes on survival time using PROC PHREG in SAS v9.2 (SAS Systems, Cary, NC). All models were adjusted for gender and age at enrollment. Results: Mean age at enrollment was 34 years (range 18 to 84 years). The mean age at death was 45 years (range 24 to 86 years). Subjects with HbSβ0 had the worst prognosis (p=0.0001), followed by subjects with SS, SC, and Sβ+. Lower glomerular filtration rate (GFR, hazard ratio [HR]=1.087 per each ml/min decrease in GFR, p<0.0001), incidence of pain crises (HR=2.038, p=0.005), pulmonary hypertension (HR=2.269, p=0.005), cerebrovascular events (HR=1.875, p=0.008), proteinuria (HR=1.922, p=0.011), seizures (HR=2.138, p=0.012), short-acting narcotics use (HR=1.693, p=0.033) and TIAs (HR=2.407, p=0.043) were significantly associated with decreased survival. Lower baseline Hb was also associated with decreased survival (HR=1.259 per g/dl decrease, p=0.0047), but after controlling for GFR, was no longer significant (p=0.274). Additionally, increased NT-proBNP (HR=1.617, p=0.0004) and sVCAM-1 (HR=2.032, p=0.0003) were associated with decreased survival. Fifty percent of patients were on hydroxyurea therapy, which was not associated with a change in survival (p=0.503). Conclusion: SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ0 and SS. Surprisingly, we found that Sβ0 had a significantly worse survival compared to SS. Cerebrovascular events, pulmonary hypertension, proteinuria, decreased GFR, and more frequent pain crises were also strongly associated with poorer survival. Not only were these comorbidities individually associated with decreased survival, but an additive effect was observed, such that subjects with a greater number of negative endpoints had worse survival (p<0.0001). These traits may provide some utility in predicting prognosis of SCD patients. More importantly, aggressive management of these comorbidities may produce a survival benefit. The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial. In contrast to prior studies, hydroxyurea therapy had no influence on survival. This may reflect a failure in some patients to reach the maximum tolerated dose, lack of compliance, or more severe baseline disease in those patients who were treated. Disclosures: No relevant conflicts of interest to declare.

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The Effect of Health Care Disparities on Complications and Mortality in Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-119961 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5886-5886

Author(s):

Stuthi Pavani Perimbeti ◽

Kevin Ye Hou ◽

Sabarina Ramanathan ◽

Adonas Woodard ◽

Daniel Kyung ◽

...

Keyword(s):

Sickle Cell Disease ◽

Healthcare Cost ◽

Sickle Cell ◽

Significant Role ◽

Conflicts Of Interest ◽

Acute Chest Syndrome ◽

Insurance Status ◽

Cell Disease ◽

Splenic Sequestration ◽

Increased Risk

Abstract Introduction: Sickle cell disease (SCD) is a chronic and debilitating disorder that affects approximately 100,000 Americans and results in the development of significant complications, leading to high numbers of hospitalizations, healthcare cost and mortality. Despite the advent of newer therapies, the overall rate of complications has continued to rise. We aimed to study the prevalence of complications in SCD as well as its relation to differing insurance status. Methods: Patients with SCD were identified using ICD-9 codes 2826, 28260, 28261, 28262, 28263, 28264, 28268 and 28269 from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample from 1999 to 2014. Admission with acute chest syndrome, acute myocardial infarction (AMI), avascular necrosis of the hip (AVN), end stage renal disease (ESRD), pneumococcal infections, splenic sequestration and stroke. Univariate and bivariate analyses were performed using the Chi square test. Cox proportional hazard regression was used to control for multiple confounders in calculating the hazard ratios of an event occurrence and mortality. Results: A total of 216,438 (Weighted=1,066,536) observations were identified from the years 1999 to 2014. The median age for male patients was 25 years and that for females was 27. Observing the trends from 1999 to 2014, the prevalence of acute chest syndrome increased from 1.22% to 8.82% (p=0.002), splenic sequestration from to 0.08 % to 1% (p=0.01) and AVN from 1 % to 8.8% (p=0.001). The prevalence of stroke and ESRD were unchanged over the interval studied. After controlling for confounding factors such as race, age, sex, income, comorbidities and insurance status, the hazard ratio of mortality for various complications is significantly elevated. Also, after controlling for multiple confounders, the patient's insurance status plays a significant role in the risk of developing a complication and subsequent mortality (Table 1). Discussion: The data indicates that the rate of complications from SCD have risen since 1999. With newer therapies and better understanding, the life expectancy of SCD patients has risen over time, nearly doubling from 1951 to 2018. The increased frequency of complications may be attributed to better survivorship and a rising number of older SCDs patients. However, our data also suggests that insurance status plays a significant role in the complication rate of SCD. The uninsured and patients with Medicaid have significantly increased risk of developing disease complications and resultant mortality. This could be the result of reduced access to care and health disparities due to race, socioeconomic status and insurance status. Disclosures No relevant conflicts of interest to declare.

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Low Sickle Cell Disease Mortality In Belgium and Benefit From Hydroxyurea Therapy

Blood ◽

10.1182/blood.v122.21.2231.2231 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2231-2231 ◽

Cited By ~ 2

Author(s):

Phu-Quoc Lê ◽

Laurence Dedeken ◽

Beatrice Gulbis ◽

Christiane Vermylen ◽

Anna Vanderfaeillie ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Death Rate ◽

Conflicts Of Interest ◽

Outcome Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Data Set ◽

Aplastic Crisis ◽

First Contact

Abstract In Western countries, mortality among patients with sickle cell disease (SCD) has decreased in the last decades by means of neonatal screening (NS), infectious prophylaxis and care improvements. The major causes of death in children include acute chest syndrome, sepsis, splenic sequestration, stroke, aplastic crisis while in adults end-stage organ failure contributes also to premature death. Hydroxyurea (HU) and stem cell transplantation (SCT) are used in Belgium for more than 20 years but their possible influences on survival have not been yet analyzed. The Belgian SCD Registry was created in 2008 including patients of 8 centres. All available data in 2008 were retrospectively encoded in the database. After 2008 and until 2012, all data were recorded prospectively for already registered patients as well as newly diagnosed subjects. Data were registered from NS or from diagnosis (first contact) until last follow up (FU) visit, SCT or death. Data included diagnosis, demography and outcome data. After SCT, only vital status and cause of death were recorded. Up to date, data from 470 pts are recorded (224 males), 412 are HbSS, 14 HbSβ0, 7 HbSβ+ and 37 HbSC. The median age at diagnosis and at last FU was respectively 0.7 year (y) and 9.9 y. The FU for the whole cohort was 3810 patient-years (PY) and with 136 patients aged over 18y, their FU during adulthood accounted for 520 PY. Thirteen patients died (2.8%). The mortality per 100-PY was 0.34 and the median age at death was 14.5 y (range, 1.5-23.7 y). All deaths occurred in HbSS patients, 5 after SCT and 8 due to an acute event. Complete data set is missing for 3 of the 8 patients. For the 5 well documented SCD related deaths, causes were: hemorrhagic stroke (2), sepsis due to S. pneumoniae (1), aplastic crisis (1) and infection during stay in homeland (1). At last FU, 91 patients were transplanted, 182 were on HU, 7 on HU + chronic transfusion (CT), 19 on CT (4 after HU treatment). The remaining 171 patients never had disease modifying therapy (DMT). Compared with the latter, mortality rate for those on HU was significantly reduced (0.1 vs 0.5/100-PY) while patients on HU have longer FU and are older at last FU (Table 1). Among 91 patients transplanted at a median age 6.9 y, 5 died: 3 from acute transplant related toxicity, 1 from secondary acute myeloblastic leukemia after cGVHD, and 1 is unexplained more than 7 years post SCT. The data issued from the most recent NS cohorts report a low death rate during childhood ranging from 0.13 to 0.52. Even if our Belgian cohort is not exclusively issued from neonatal diagnosis, the observed death rate is low (0.34/100-PY). Several methodological biases are present in this partially retrospective study (incomplete or unavailable data, lost of FU, no information if death occurred before the first contact in a center, …). Nevertheless our low mortality is not underestimated since 1) most patients were followed since infancy and during a long period (3810 PY); 2) the FU during adulthood (period of increased mortality) accounted for 520 PY; 3) our cohort represents a very large part of the Belgian SCD population since a national inquiry performed in 2007 estimated the whole SCD population to 500. The effect of HU on mortality has been reported in adults and more recently in children. Despite longer FU and older age at last FU, our data confirms those previously results With only one case, death by infection is rare while SCT complications contributed to about 40 % of deaths. Even if SCT is the only curative option for SCD, it encompasses a risk of mortality. As life expectancy of SCD patients has been extended which is confirmed by our results (especially for patients on HU), SCT should be reserved for clinically severe cases. Population-based prospective studies evaluating the survival in transplanted and non transplanted patients are needed. Disclosures: No relevant conflicts of interest to declare.

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A case of severe multi-system disease in a sickle cell SC patient caused by parvovirus B19 infection

Journal of Clinical Images and Medical Case Reports ◽

10.52768/2766-7820/1314 ◽

2021 ◽

Vol 2 (5) ◽

Author(s):

Mohamed Almuqamam ◽

◽

Swetha Madhavarapu ◽

Nataly Apollonsky ◽

◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Parvovirus B19 ◽

Acute Infection ◽

Organ Injury ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Splenic Sequestration ◽

Increased Risk ◽

Parvovirus B19 Infection

Sickle Cell Disease (SCD) is an inherited hemoglobinopathy, which results in production of abnormal hemoglobin S. HbSC disease is a variant of SCD, which shares a similar clinical complication profile to HbSS disease, but often thought to be a milder condition. In patients with SCD, Hb S in deoxygenated state undergoes polymerization, leading to hemolysis, vaso-occlusive events, and eventually end-organ damage. Among other complications in patients with SCD is increased risk of complications caused by parvovirus B19. We present a case of a 14-year-old female with HbSC disease who presented to the emergency room with complaint of abdominal pain and found to have splenic sequestration. Splenic sequestration progressed rapidly, Hemoglobin (hb) dropped to 4.6 g/dl and acute chest syndrome (ACS) developed. She was treated following the ACS protocol, received 4 units of Packed Red Blood Cells (PRBC) and subsequently underwent a single volume PRBC exchange transfusion. Considering her unusual presentation, with severe ARDS from alveolar hemorrhage requiring mechanical ventilation and multi-organ injury, several autoimmune and infectious conditions with a cytokine storm component including COVID-19 disease, were considered. Results of viral testing revealed parvovirus B19 IgM antibodies signifying an acute infection. She fully recovered with supportive care and was discharged home. Multisystem involvement simulating connective tissue disorders or malignancies with acute parvovirus B19 infection has been reported and is considered extremely rare. To our knowledge, there were no reports of pediatric patients with SC disease presenting with splenic sequestration and ACS in the setting of parvovirus B19 multisystem disease. Keywords: sickle cell disease; acute respiratory distress syndrome; acute chest syndrome; parvovirus B19.

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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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Identification of Clinical and Laboratory Parameters Associated with the Development of Acute Chest Syndrome during Vaso-Occlusive Episodes in Children with Sickle Cell Disease: A Preliminary Step before Assessing Specific and Early Treatment Strategies

Journal of Clinical Medicine ◽

10.3390/jcm8111839 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1839

Author(s):

Madhi ◽

Kamdem ◽

Jung ◽

Carlier-Gonod ◽

Biscardi ◽

...

Keyword(s):

Sickle Cell Disease ◽

Pain Score ◽

Sickle Cell ◽

Multivariate Model ◽

Red Blood Cell Transfusion ◽

Predictive Score ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Laboratory Parameters ◽

Increased Risk

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (±2.3) vs. 3.3 (±1.8) days, p < 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion (p < 0.0001). The multivariate model retained pain score (≥9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (≥260 × 109/L) and neutrophil (>10 × 109/L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74–0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS.

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Clinical Complications in Adult Patients with Sickle Cell Anemia and β-Thalassemia-Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4767.4767 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4767-4767

Author(s):

Giovanna Graziadei ◽

Alessia Marcon ◽

Martina Soldarini ◽

Ilaria Gandolfi ◽

Luisa Ronzoni ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Acute Chest Syndrome ◽

P Value ◽

Cell Disease ◽

Transfusion Therapy ◽

Clinical Complications ◽

Significant Difference ◽

The Mean

Abstract Abstract 4767 Background. Sickle-Cell Disease (SCD) is one of the most common severe monogenic inherited disorders worldwide, due to hemoglobin S (HbS), with reduced affinity for the oxygen. HbS polymerization, leading to erythrocyte rigidity, vaso-occlusion and hemolytic anemia, is central in the pathophysiology and crucial for the clinical outcome. The term SCD refers to Sickle Cell Anemia (SCA) due to homozygosis for βS allele, HbS/β-thalassemia (T-SCD) due to compound of β-thal and βS allele, and HbSC disease, owing to the coinheritance of βS and βcalleles. SCD is a multiorgan disease characterized by recurrent acute events and progressive organ damage, worsening during the life. Aims. This is a retrospective monocentric study aimed to assess and compare the clinical complications among 59 adult SCD patients, followed at the Hereditary Anemia Centre of the Foundation IRCCS “Ca Granda” Ospedale Maggiore Policlinico, in Milan, Italy. Methods. Mutation analysis of the b globin gene was established by direct DNA sequencing on the ABI Prism 310 genetic analyzer. Clinical and hematological features were evaluated by routine tests and physical examination, with special attention to the erythropoiesis stress parameters as LDH values and extramedullary erythropoietic (EE) masses. Results. Fifty-nine adult SCD patients, 16 SCA and 43 T-SCD, were evaluated. In T-SCD patients detected b-mutations were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2%. The mean age of SCA patients was 36±9 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years, while the mean age at the presentation in our Centre was 32±8 years in SCA patients and 31±10 years in T-SCD ones. Five out of 16 (31.2%) SCA patients and 16/43 (37.2%) T-SCD patients were male. HbF mean levels were 6.9±5.1% and 10.1±7.2%, respectively in SCA and T-SCD group; surprisingly Hb mean levels were lower in SCA (9.3±1.3 g/dl) than in T-SCD (9.9±1.4 g/dl) patients. Comparing SCA and T-SCD, there was statistically significant difference in splenic features: splenectomy was performed in 2/16 (12.5%) SCA patients vs 21/43 (48.8%) T-SCD patients (p-value < 0.01). Splenomegaly was absent in SCA, while was detected in 11/22 (50%) T-SCD (p-value < 0.0001); all SCA patients had functional asplenia, not observed in T-SCD patients; splenic infarctions were absent in SCA patients and were detected in 7/22 (31.8%) T-SCD patients, of whom 5 had splenomegaly and 2 had normal spleen size (pvalue <0.001). On the other side, there was not statistically significant difference in the prevalence of stroke, acute chest syndrome (ACS), bone pain crisis, sepsis, leg ulcers and priapism. However, we observed some clinical differences, even if not statistically significant. Cholecistectomy was performed in 4/16 (25%) SCA patients vs 17/43 (39.5%) T-SCD patients, and gallstones were detected respectively in 5/12 (41.7%) and in 14/26 (53.8%) of SCA and T-SCD patients. Thrombotic events were absent in SCA patients, compared to 4/43 (9.3%) T-SCD patients. Furthermore, we detected EE in 3/16 (18.6%) SCA and in 3/43 (7%) T-SCD, all carrying b° thal mutations. We underlie that Hb levels and LDH values were higher in SCA than in T-SCD patients (823±295 vs 689±209 U/L). About the treatment, 14/16 (87.5%) SCA and 31/43 (72%) T-SCD underwent to top-up transfusion; 5/43 (11.6%) T-SCD were regularly transfused. Seven out of 16 (43.8%) SCA and 18/43 (41.8%) T-SCD patients were treated with Hydroxycarbamide (HU). Criteria for transfusion therapy were: painful crisis not responsive to HU, major clinical complications, such as stroke or ACS, extramedullary erythropoietic masses associated with high LDH levels and low Hb values. Conclusions. These data suggest that SCA and T-SCD patients have similar clinical course. Splenomegaly is present only in T-SCD patients, probably due to the increased amount of extravascular hemolysis. Surprisingly, SCA patients showed EE and lower Hb levels with higher LDH values compared to T-SCD ones. This could be related to the prevalence of intravascular hemolysis, that can lead to erythropoietic stress in SCA, even if tissues are better oxygenated in these patients because of biochemical characteristic of HbS in terms of decreased oxygen affinity. These observations could be important to evaluate transfusion and HU treatment. Disclosures: Cappellini: Novartis: Research Funding.

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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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Microparticles As Biomarkers Of Osteonecrosis Of The Hip In Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.2226.2226 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2226-2226

Author(s):

Anne M Marsh ◽

Raymond Schiffelers ◽

Ginny Gildengorin ◽

Frans A Kuypers ◽

Carolyn Hoppe

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Vascular Occlusion ◽

Predictive Biomarker ◽

Acute Chest Syndrome ◽

Mobility Limitations ◽

Cell Disease ◽

The Past ◽

D Dimer

Abstract Introduction Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) in children. ONFH is a debilitating condition that is associated with mobility limitations, chronic pain, and an impaired quality of life. While the mechanisms that cause ONFH remain unknown, ischemia from recurrent microvascular occlusion is likely to play a role. Vascular occlusion may result directly from obstruction by sickled cells, or indirectly via complex interdependent pathways characterized by sustained endothelial activation, chronic inflammation, and coagulation. Microparticles (MP) are small, cell membrane-derived vesicles generated in response to cellular activation, injury or apoptosis. MPs have emerged as potential modulators of inflammation and thrombosis and have been found to be elevated in patients with ONFH in the general population. Objective This pilot study examined whether microparticle levels in patients with SCD who have ONFH differ from SCD patients without ONFH, as well as healthy African American (AA) controls. Methods Subjects were recruited at their baseline status and were excluded if they had been transfused within the past 30 days, hospitalized for a vaso-occlusive pain episode, acute chest syndrome, fever or surgery within the past 30 days, or had bony lesions of the femur or hip due to causes unrelated to SCD. For MP analysis, whole blood was collected in sodium citrate tubes and centrifuged for 15 minutes at 1500 x g at 20° C to generate platelet poor plasma. Aliquots of the plasma were immediately frozen and stored at -80° C until the time of MP analysis. 300 μl samples were diluted in PBS and centrifuged at 10000 x g for 1hr and the supernatant was centrifuged at 100,000 x g for 2 hr. The pellet was re-suspended in 1 mL of PBS and subjected to nanoparticle-tracking analysis to determine concentration and size. Additional laboratory biomarkers of inflammation and coagulation, including highly-sensitive C-reactive protein (hs-CRP), von Willebrand factor antigen (vWF Ag), tissue factor (TF), and D-dimer were analyzed for differences between groups. Analysis of variance was used to compare MP and biomarker levels between the three groups. The institutional review board at Children's Hospital & Research Center Oakland approved the study protocol and written informed consent was obtained from all participants. Results Characteristics of the 30 subjects enrolled are shown in Table I. Total microparticle levels in ONFH(+) patients were 2.3-fold higher than in ONFH(-) patients, and 2.5-fold higher than in AA controls (Figure 1). Mean MP levels for ONFH(+) patients, ONFH(-) patients, and AA controls were 4.55 x 1010, 1.99 x 1010, and 1.85 x 1010, respectively. Microparticle levels in ONFH(-) SCD patients did not differ from AA controls. There were no statistically significant differences in hsCRP, vWF Ag, TF, or D-dimer levels between the ONFH(-) and ONFH(+) groups. Conclusions The results of this study demonstrate significantly elevated MP levels in individuals with SCD who have ONFH. Additional studies are needed to better understand the mechanistic effects of MPs on the development of ONFH and to determine whether MP levels may be useful as a predictive biomarker for early disease detection. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Disclosures: No relevant conflicts of interest to declare.

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