Hydroxyurea for Sickle Cell Disease in Children and for Prevention of Cerebrovascular Events: The Belgian Experience

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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Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience

Blood ◽

10.1182/blood-2004-07-2704 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2685-2690 ◽

Cited By ~ 100

Author(s):

B. Gulbis

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Disease ◽

Cerebrovascular Events

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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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Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events

Blood ◽

10.1182/blood.v99.9.3144 ◽

2002 ◽

Vol 99 (9) ◽

pp. 3144-3150 ◽

Cited By ~ 171

Author(s):

Scott R. Dobson ◽

Kenton R. Holden ◽

Paul J. Nietert ◽

Joel K. Cure ◽

Joseph H. Laver ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Proportional Hazards ◽

Recurrent Stroke ◽

Neuropsychological Testing ◽

Cell Disease ◽

Conventional Angiography ◽

Risk Of Recurrence ◽

Cerebrovascular Events ◽

Ischemic Attack

Abstract We conducted a retrospective study to determine whether the presence of moyamoya collaterals influenced the risk of recurrence of cerebrovascular events (CVEs: stroke or transient ischemic attack) in patients with sickle cell disease placed on chronic transfusions after a stroke. Forty-three patients with homozygous sickle cell anemia (HbSS) and 1 with HbSOArab (16 females, 28 males) who had suffered strokes while under the age of 18 were studied. All patients had been on transfusions aimed at maintaining the sickle hemoglobin (HbS) level below 30%. They were followed for a mean of 6.6 years (2.2 to 20.4 years). The presence of collaterals was diagnosed based on either magnetic resonance angiography or conventional angiography. Eighteen (41%) of the 44 patients suffered recurrent CVEs. Nineteen (43%) (6 females, 13 males) patients had moyamoya collaterals. Eleven (58%) of these 19 experienced 21 total recurrent CVEs, including 4 strokes in 4 patients (21%). In comparison, 7 (28%) of 25 patients without moyamoya collaterals experienced 9 recurrent CVEs (P < .05) with only 1 recurrent stroke (4%). Moyamoya patients were also more likely to have 2 recurrent CVEs (42% vs 8%,P < .05) as well as poorer neuropsychological testing results. A proportional hazards regression analysis indicated that patients with moyamoya were more than twice as likely to incur a subsequent CVE (hazard ratio, 2.40; 95% confidence interval, 0.85, 6.75). We conclude that up to 41% of patients with sickle cell disease experience recurrent CVEs after an initial stroke despite chronic transfusions and that the risk of recurrence is significantly higher for those who have moyamoya collaterals.

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