Search

Background: In sickle cell disease (SCD) abnormally shaped RBCs interact with white blood cells and the endothelium, leading to a vasculopathy and thrombotic/ prothrombotic complications such as stroke and pulmonary hypertension. About 10 % of patients with a thrombotic event in the general population will have the presence of an antiphospholipid (aPL) antibody (Andreoli et al. 2013). One proposed mechanism for the thrombophilic nature of aPL antibodies is the disruption of annexin A5. Annexin A5 is a potent anticoagulant protein that has an affinity to phospholipids. In the presence of aPL antibodies, annexin A5 is unable to form its crystallized anticoagulant shield (annexin A5 resistance). There is a paucity of data which assesses the association of aPL antibodies with vasculopathic complications of SCD, and there have been no studies investigating the annexin A5 resistance assay (A5R). We designed a pilot study assessing aPL antibody levels and A5R in a pediatric sickle cell population. Methods: Patients with a history of stroke, abnormal transcranial doppler (TCD) and elevated TR gradient by echocardiography (>25mm of Hg) were eligible. A5R, lupus anticoagulant- DRRVT, anti β2GP1, anti phosphatidylserine and anti cardiolipin antibody (IgG, IgA, IgM) assays were performed on samples obtained prospectively when patients were at a steady state (at least 4 weeks after an acute event). A5R measures coagulation times in the presence and absence of annexin A5. Resistance to the anticoagulant effects of annexin is expressed as a reduction in this ratio (Rand et al. 2004). Statistical analysis assessed multiple variables including age, gender, hemoglobin, reticulocyte count, LDH, hydroxyurea therapy, transfusion therapy, elevated TR gradient, stroke and silent stroke. Univariate analysis and multivariate logistic regression was performed with abnormal annexin A5 as the outcome variable. Results:There were a total of 39 patients: 12 patients with a history of stroke, 6 with an elevated TCD velocity and 15 patients with an elevated TR gradient. Of the 27 patients that did not have a stroke, 25 had a screening MRI in the prior year, and 9 of these patients had silent infarcts. Only 1 of 39 patients had elevated anticardiolipin IgG antibodies and 1 had an abnormal lupus coagulant (DRVVT). In contrast, 5/39 patients (12.8%) had low or abnormal annexin A5 resistance, 7/39 (18%) were in the borderline range and 27/39 (69%) were normal. This frequency of abnormality was unexpected in the antiphospolipid antibody and lupus anticoagulant negative population. None of the patients, except the one with the positive lupus anticoagulant, developed any thrombotic events in 3.5 years of follow up. None of the patients with overt stroke or abnormal TCDs had an abnormal A5R. Multivariate logistic regression analyses showed statistically significant association of hemoglobin (p= 0.037, OR 0.25, CI 0.07-0.92)), age (p =0.047, OR 1.43, CI 1.01-2.04) and silent infarct (p =0.015, OR 28.5, CI 1.9-420.5) with abnormal annexin A5 resistance. A multivariate analysis using linear regression with annexin A5 resistance as a continuous outcome variable (Table 1), showed persistence of the significant association of silent infarcts (p =0.037). Conclusion: We report an association between annexin A5 resistance and low hemoglobin, older age and presence of silent infarct in a subgroup of SCD patients. Prevalence of abnormal aPL antibody assays and lupus anticoagulant was strikingly low in this cohort. A potential role for perturbed annexin A5 resistance in the pathophysiology of silent infarction in SCD will need to be evaluated further in carefully designed prospective studies and may be a novel therapeutic target. Table 1. Hemoglobin, Age and Silent Stroke are Associated with Abnormal Annexin A5 Resistance Characteristic Odds Ratio Odds Ratio Confidence Interval p-value Hemoglobin* 0.25 0.07-0.92 0.037 Reticulocyte count 0.77 0.54-1.08 0.13 LDH 1.00 0.99-1.00 0.51 Age* 1.43 1.01-2.04 0.047 Monocyte count 1.00 1.00-1.00 0.34 Silent infarct* 28.5 1.9-420.5 0.015 Stroke 0.47 0.05-4.88 0.53 Elevated TR gradient 0.34 0.03-3.49 0.36 Gender 0.47 0.05-4.88 0.53 Allosensitization 0.56 0.05-5.86 0.63 HU vs no treatment 0.46 0.03-6.93 0.58 Transfusion vs no treatment 0.18 0.01-4.26 0.29 Disclosures No relevant conflicts of interest to declare.

Abstract 4276 Introduction: Hematopoietic stem cell transplantation (HSCT) from an HLA matched donor is the only curative therapy for sickle cell disease (SCD), with sibling donor survival rates approaching 95%. Referral from the primary hematologist for transplant evaluation is a key step in the process. Study aims were to assess pediatric SCD providers for: 1) Current perspectives and referral patterns; 2) Whether perspectives differ for those practicing at a transplant center. Methods: All pediatric hematology providers at the designated newborn screening hemoglobinopathy centers within the seven state New York-Mid-Atlantic Consortium (NYMAC) were anonymously surveyed. Descriptive statistics and chi squared test or Fisher's exact test were used for analysis. Results: Of 197 pediatric SCD providers contacted through the NYMAC listserv, 104 (53%) responded, predominantly hematologists. Half (53%) of responders practice at sites performing HSCT for pediatric SCD. Overall, transplant centers had larger SCD patient populations (p Provider referral pattern: Most providers (89%) had referred at least one child with SCD for transplant evaluation within the past two years. A higher proportion of practitioners at a transplant center had referred at least 3 patients for transplant evaluation, 84% vs. 53% (p=0.001). Patient demographics for transplant eligibility: Overall, 77% would limit HSCT to children with HbSS or HbS-β° thalassemia. Nearly half (44%) were less likely to refer a child for evaluation with SCD than with β-thalassemia major (no significant difference (NS) by practice setting). Those practicing at transplant centers were more certain of 6–16 years as an optimal transplant age (100% vs. 84%; p=0.004). Indications: Single disease indications for transplant referral were stroke, acute chest syndrome or family request. Less commonly cited were abnormal TCD (31%) or clinically silent stroke (34%). Commonly listed treatment indications were a new stroke despite chronic transfusion (82%) or poor response to hydroxyurea (71%), not iron overload (22%) (NS by practice setting). Donor: Most would offer HSCT to a child with multiple SCD complications with (95%) or without (66%) a sibling match; 37% would refer a child with limited disease despite a sibling donor (NS by practice setting). Acceptable outcomes: The majority (78%) agreed that HSCT can improve health. Risk of mortality, lack of sibling match, and infertility were most commonly cited as barriers to referral. Most identified acceptable overall survival rates as 90–100% (divided between ≥90% or 95–100%). Providers at transplant centers were more likely to accept event-free survival rates of 75–90% (87% vs. 63%; p=0.002), rather than 95–100%. Limitations: While only one U.S. region was surveyed, NYMAC collectively diagnoses approximately 25% of all newborns with SCD (genes-r-us.uthscsa.edu). Actual referral patterns could not be verified. No adjustments were made for size of each practice site, nor were providers queried about perceived influence of payer mix or other patient demographics. Conclusions: Most pediatric SCD providers accept HSCT as a treatment option, especially for children with severe disease complications or inadequate response to other therapies. Practitioners at transplant centers reported making more referrals for evaluation, having a stronger preferred age and accepting a broader range of event-free survival. Overall, only one third of providers deem eligible those patients with a sub-clinical stroke or stroke risk, or those with a sibling donor if without major disease complications. Most providers prefer transplant for children with a limited sickle hemoglobinopathy type, and almost half favor transplantation for β-thalassemia major. These findings suggest varying enthusiasm for HSCT for pediatric SCD beyond donor availability or current survival outcomes. The SCD provider is a critical conduit for ushering families towards transplantation and weighing difficult risk-benefit ratios. Informed decisions and referral may benefit from provider education, especially for those not practicing at transplant centers, as well as professional guidelines about current indications and research comparing outcomes of SCD versus HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 171 Background: The BABY HUG trial was a multi-center double-blinded randomized comparison of hydroxyurea (HU) versus placebo in infants (mean age 13.6 mo. at entry) with HbSS/Sβ° thalassemia who were followed for 2 years [Lancet 377(2011):1663–1672; Clinical Trials #NCT00006400]. Hydroxyurea therapy was associated with less pain, dactylitis, acute chest syndrome (ACS), hospitalization (HSN), and transfusion (TX) and with improved hematologic values; toxicity was limited to mild-moderate neutropenia. On the basis of the safety and efficacy data from this trial, it was concluded that hydroxyurea therapy can be considered for all very young children with sickle cell anemia (SCA). With anticipated broader use of hydroxyurea in this population, we examined estimated medical costs of care (based on Medicaid reimbursement) in treated versus placebo subjects. Methods: The BABY HUG database (C-TASC, Baltimore, MD) was utilized to compare inpatient events in subjects receiving hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 Thomson Reuters MarketScan® Multi-state Medicaid Database for children with HbSS (ICD-9 codes 282.61 or 282.62), ages 1–3 years. Inpatient costs included emergency department (ED) costs for admissions from an ED in about 80% of the 748 admissions in the database. Inpatient cost estimates were based on length of stay (LOS) modified by a diagnosis of ACS or splenic sequestration (SpS) or a procedure code for a TX. Outpatient expenses were estimated based on the schedule required for BABY HUG (and recommended for clinical use) and a “standard” schedule for 1–3 year-olds with SCA based on management protocols at 3 pediatric sickle cell centers in the US. Results: 96 subjects were randomized to hydroxyurea (83 completed the trial); 97 received placebo (84 completed the trial). In the full study, there were 232 hospitalizations (for any cause) in those receiving hydroxyurea and 324 in those on placebo; inpatient data were captured for only the final 77% of admissions (between 2/06 and 9/09). The LOS for subjects receiving hydroxyurea (mean 3.7, median 3, range 1–9 days) did not differ from those receiving placebo (3.6, 3, 1–13). Estimated inpatient and outpatient costs are shown in Tables 1 and 2. When inpatient and outpatient expenses were combined, the annual cost for 1–3 year-old children with SCA was $11,345 on hydroxyurea and $14,815 on placebo, a difference of $3,470. Discussion/Conclusion: Despite increased outpatient care expenses from clinic visits, laboratory monitoring, and hydroxyurea, savings on inpatient care resulted in an overall reduction in estimated annual per patient expenditure of approximately 23%. A limitation of our analysis was the dependence on MarketScan Medicaid data in lieu of the availability of specific expenses of the subjects participating in the BABY HUG study. Medicaid data may understate costs of care; based on prior analyses, we estimate that costs to private payers may be 20–30% greater than Medicaid reimbursements. We conclude that increased use of hydroxyurea treatment in children with SCA can lead to significant medical cost savings. Disclosures: Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.

Hydroxyurea therapy is associated with reduced morbidity among patients with sickle cell disease (SCD). Avascular necrosis of the femoral head (AVN) is one potentially debilitating complication of SCD. In this study, we examined the relationship between hydroxyurea use and the prevalence of AVN among children with SCD. We performed a retrospective chart review of 202 children with SCD, aged 10–21 years, followed in the pediatric hematology program at the Children’s Hospital at Montefiore (Bronx, NY) between July 2007 and 2008. Abstracted data included age, ethnicity, SCD genotype, frequency of hospitalization, hip radiograph results, laboratory data and hydroxyurea use. Hip radiographs were performed prospectively as part of SCD health maintenance from 2005–2008. Forty-four patients were excluded because they did not have a screening hip radiograph. Descriptive statistics were calculated for independent variables. T-tests and chi-square tests were used to compare clinical and demographic characteristics of children with and without AVN. Multivariate logistic regressions were used to estimate the odds ratio of having AVN among SCD patients. Our final sample consisted of 158 patients whose demographic characteristics are listed in Table 1. The prevalence of AVN was 16.5% (n=26). Of the clinical variables analyzed, we identified significant associations between the presence of AVN and hydroxyurea use (p=.005), as well as older age (p=.013) (Table 1.) Children with AVN had significantly lower mean lactic dehydrogenase levels (LDH) (p=.04) and higher mean corpuscular volumes (MCV) (p=.012). (Table 2.) After controlling for gender, ethnicity, sickle cell genotype, and frequency of hospitalizations, age was also found to be associated with AVN (OR 1.15, 95% confidence interval (CI): 1.01,1.31, p=0.033). SCD patients on hydroxyurea had higher odds of having AVN compared to non-users (OR 3.51, 95% CI: 1.31, 9.38, p= 0.013). Laboratory values (MCV, Hemoglobin, LDH and Hematocrit) had a high degree of collinearity and were removed from the final model. In summary, the prevalence of AVN in our sample was 16.5%. This is substantially higher than the prevalence of approximately 6% reported by the Cooperative Study of Sickle Cell Disease for comparative age groups in a prospective study1. SCD patients exposed to hydroxyurea were three times more likely to have AVN than those not exposed to this drug. Vaso-occlusive pain crisis is a recognized risk factor for AVN, thus we could expect a higher rate of AVN among patients on hydroxyurea. However, the odds ratio of 3.5 is unexpectedly high and warrants further investigation into the role of hydroxyurea as a risk factor for AVN. Nonetheless, these preliminary results suggest that more stringent screening regimens for AVN may be indicated among this subset of patients. Table 1. Clinical characteristics of patients with and without avn *p5 8 (6%) 2 (8%) Table 2. Mean Laboratory Values for Patients With And Without AVN No AVN AVN *p