Search

INTRODUCTION The contribution of coagulation activation to the pathogenesis of sickle cell disease (SCD) remains incompletely defined. We evaluated the efficacy and safety of rivaroxaban, an oral direct factor Xa inhibitor, in subjects with sickle cell anemia. MATERIALS AND METHODS In this pilot, single-center, randomized, double-blind, placebo-controlled, crossover study, eligible subjects with sickle cell anemia received rivaroxaban or placebo. The effect of rivaroxaban on coagulation activation, endothelial activation, inflammation, and microvascular blood flow was evaluated. RESULTS Fourteen patients (HbSS - 14; females - 9) with mean age of 38 ± 10.6 years were randomized to receive rivaroxaban 20 mg daily or placebo for 4 weeks and, following a 2-week washout phase, were "crossed-over" to the treatment arm opposite to which they were initially assigned. Mean adherence to treatment with rivaroxaban, assessed by pill counts, was 85.6% in the first treatment period and 93.6% in the second period. Treatment with rivaroxaban resulted in a decrease from baseline of thrombin-antithrombin complex versus placebo (-34.4 ug/L [95% CI: -69.4, 0.53] vs. 0.35 ug/L [95% CI: -3.8, 4.5], p = .08), but the difference was not statistically significant. No significant differences were observed in changes from baseline of D-dimer, inflammatory, and endothelial activation markers or measures of microvascular blood flow. Rivaroxaban was well tolerated. CONCLUSIONS Rivaroxaban was safe but did not significantly decrease coagulation activation, endothelial activation, or inflammation. Rivaroxaban did not improve microvascular blood flow. Adequately powered studies are required to further evaluate the efficacy of rivaroxaban in SCD. Clinicaltrials.gov Identifier: NCT02072668.

Introduction : Chronic kidney disease is common in patients with sickle cell disease (SCD) and is associated with increased mortality. As albuminuria and changes in estimated glomerular filtration rate (eGFR) occur well after substantial structural and functional tissue damage have ensued, biomarkers that predict the development of CKD are needed. Metabolite profiling and the bioinformatics tools to study them may aid in the discovery of novel associations and uncover pathophysiological pathways in SCD-related glomerulopathy. In this study, we have performed an exploratory study to identify urinary biomarkers, which may be predictive of kidney damage in children with SCD. Methods: Consecutive patients with SCD seen at a pediatric chronic care clinic at Kamuzu Central Hospital in Lilongwe, Malawi, between January and May 2015 were evaluated. Patient urine samples were analyzed for metabolites using NMR-based methodologies. Spot urine measurements for albumin/creatinine ratio (UACR) were required to ascertain the degree of albuminuria (normal albuminuria [UACR < 30 mg/ g creatinine] or albuminuria [UACR ≥ 30 mg/ g creatinine]). Descriptive statistics (mean and standard deviation for continuous variables, and count and percentage for discrete variables) were calculated for each of the baseline variables. T-test and Fisher's exact test were performed to compare the baseline measurements between those with and without albuminuria for continuous and discrete variables, respectively. Metabolite measurements were Pareto scaled and quantile normalized. To detect differential metabolites between the normal albuminuria and albuminuria groups, Wilcoxon rank sum test was performed. Results: Spot urine samples were obtained in 92 children, 32 (46.4%) of whom were female, average age of 40.6 (±0.98) months, and 23 (25%) patients with normal albuminuria. The patients in both categories were generally similar (age, sex, WBC count, hemoglobin, bilirubin and serum creatinine), except for higher baseline levels of lactate dehydrogenase (p < 0.05) in patients in the albuminuria category. From 1078 bins, we deleted those with low measurements across the majority (>95%) of samples and applied the differential metabolite analysis to 723 bins. Among these bins, 43 metabolites were different in both albuminuria categories (p ≤ 0.05). Although none of the metabolites were significantly different after adjustment for multiple comparisons, the top list is preliminarily identified as ethylmalonic acid, an acidogenic and a metabotoxic branched fatty acid, as an important urinary metabolite differentiating the two groups. High levels of ethylmalonic acid are also found in the urine of patients with short-chain acyl-coenzyme A dehydrogenase deficiency, a fatty acid metabolism disorder. The results remain largely unchanged after important covariates, age, sex, WBC count, hemoglobin, lactate dehydrogenase, bilirubin and creatinine were adjusted. In addition, principal component analysis (PCA) and partial least square discrimination analysis (PLS-DA) were performed (Figures 1A and 1B). Despite the lack of distinct clusters on the score plots, 15 metabolites were identified as "important features" in PLS-DA, based on their variance of importance projection (VIP) score (Figure 2). Conclusion: Our exploratory study shows that urinary ethylmalonic acid is a potentially important biomarker for the early detection of kidney damage in children with SCD. More studies of larger patient populations with SCD are required to identify urine metabolites which may predict the development of albuminuria. Disclosures Key: UniQure BV: Research Funding. Ataga:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Essentials Sickle cell disease is increasingly being recognized as a chronic hypercoagulable state. Thrombin generation is elevated in the whole blood, but not the plasma of sickle cell patients. Whole blood thrombin generation inversely correlates to erythrocyte phosphatidylserine exposure. Acquired protein S deficiency is likely explained by binding of protein S to sickle red cells. Click to hear Dr Hillery discuss coagulation and vascular pathologies in mouse models of sickle cell disease. SummaryIntroduction Sickle cell disease (SCD) is a hypercoagulable state with chronic activation of coagulation and an increased incidence of thromboembolic events. However, although plasma pre-thrombotic markers such as thrombin-anithrombin complexes and D-dimer are elevated, there is no consensus on whether global assays of thrombin generation in plasma are abnormal in patients with SCD. Based on our recent observation that normal red blood cells (RBCs) contribute to thrombin generation in whole blood, we hypothesized that the cellular components in blood (notably phosphatidylserine-expressing erythrocytes) contribute to enhanced thrombin generation in SCD. Methods Whole blood and plasma thrombin generation assays were performed on blood samples from 25 SCD patients in a non-crisis ‘steady state’ and 25 healthy race-matched controls. Results Whole blood thrombin generation was significantly elevated in SCD, whereas plasma thrombin generation was paradoxically reduced compared with controls. Surprisingly, whole blood and plasma thrombin generation were both negatively correlated with phosphatidylserine exposure on RBCs. Plasma thrombin generation in the presence of exogenous activated protein C or soluble thrombomodulin revealed deficiencies in the protein C/S anticoagulant pathway in SCD. These global changes were associated with significantly lower plasma protein S activity in SCD that correlated inversely with RBC phosphatidylserine exposure. Conclusion Increased RBC phosphatidylserine exposure in SCD is associated with acquired protein S deficiency. In addition, these data suggest a cellular contribution to thrombin generation in SCD (other than RBC phosphatidylserine exposure) that explains the elevated thrombin generation in whole blood.

Women living in rural areas of the U.S. face disparities in screening mammography and breast cancer outcomes. We sought to evaluate utilization of mammography, awareness of screening guidelines, and attitudes towards screening among rural insured U.S. women. We conducted a cross-sectional self-administered anonymous survey among 2000 women aged 40-64 insured by the National Rural Electric Cooperative Association, a non-profit insurer for electrical utility workers in predominantly rural areas across the U.S. Outcomes included mammographic screening in the past year, screening interval, awareness of guidelines, and perceived barriers to screening. 1588 women responded to the survey (response rate 79.4 %). 74 % of respondents lived in a rural area. Among women aged 40-49, 66.5 % reported mammographic screening in the past year. 46 % received annual screening, 32 % biennial screening, and 22 % rare/no screening. Among women aged 50-64, 77.1 % reported screening in the past year. 63 % received annual screening, 25 % biennial screening, and 12 % rare/no screening. The majority of women (98 %) believed that the mammography can find breast cancer early and save lives. Less than 1 % of younger women, and only 14 % of women over age 50 identified the recommendations of the U.S. Preventative Services Screening Task Force as the current expert recommendations for screening. Screening practices tended to follow perceived guideline recommendations. When rural U.S. women over age 40 have insurance, most receive breast cancer screening. The screening guidelines of cancer advocacy groups and specialty societies appear more influential and widely recognized than those of the U.S. preventative services taskforce.