Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (p<0.0001), including vaso-occlusive pain (p<0.01) and acute chest syndrome (ACS) (p<0.01), and more than four times the odds of admission for fever (p<0.001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1,000×106/L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared to healthy controls, SCD patients exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with TNFα. Additionally, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, uPAR and αMβ2 integrin expression in SCD patient neutrophils compared to healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in SCD patients.

Tick paralysis is a rare condition which can be treated easily but if undiagnosed can lead to significant morbidity and mortality. It is prevalent in certain areas especially in North America and Australia. It is characterized by acute onset symmetric lower extremity weakness and if not diagnosed early the weakness involves the upper extremities, cranial nerves, respiratory musculature leading to respiratory failure requiring mechanical ventilation. The clinical picture is often confused with other causes of acute onset paralysis eg., Guillain-Barre syndrome, the Miller Fisher variant, leading to unnecessary investigations and interventions complicating the clinical picture. The condition can be easily diagnosed by careful history and physical examination. Tick removal will lead to early and complete recovery of the condition.It is very important for the clinicians to be aware of this condition so that it can be recognized early to avoid unnecessary and expensive investigations, interventions, morbidity and mortality.

Background : Serious morbidity and mortality in sickle cell anemia (SCA) begins early in life during the physiologic decline of fetal hemoglobin (HbF) and its replacement with sickle hemoglobin (HbSS). In older children (>5 years), hydroxyurea (HU) is safe and provides similar laboratory benefits as in adults when escalated to a mean (standard deviation, SD) maximal tolerated dose (MTD) of 25.6 ± 6.2 mg/kg/day (Kinney, Blood 1999). In infants, a fixed-dose of 20 mg/kg/day is safe, improves hematologic parameters and provides substantial clinical benefits (Wang, Lancet 2011). However, the hematologic benefits of intensifying HU to MTD in young children have not been evaluated. We aimed to describe the initial and long-term hematologic changes provided by initiation of HU and escalation to MTD in young children (<5 years of age) who have not yet completed their physiologic decline of HbF. Methods: The Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) is a prospective observational evaluation of HU in children with SCA. After enrollment, all children were escalated to MTD, defined by an absolute neutrophil count goal of 2,000-4,000x106/L or other hematologic toxicity. Medication possession ratios (MPR) were calculated as [(days medication in family's possession ÷ days for which medication was prescribed) x 100] and MPR values >80% were used as a surrogate for good adherence (Estepp, Pediatr Blood Cancer 2014). Children who initiated HU prior to 5 years of age (younger group) were compared to those who initiated at ≥5 years of age (older group) at three time points: prior to initiation of HU (baseline), when MTD was established, and 5 years after MTD was reached. Laboratory parameters for the two groups (means and SD) were compared using the two sample t-test or Wilcoxon Rank Sum test based on the normality of the data. Correlation between changes in HbF and age at baseline was tested using Spearman correlation test. P-values <0.05 were considered statistically significant, and all statistical tests and tables were performed with SAS version 9.3 (Cary, N.C.). Results: In total, 151 children provided nearly 700 patient-years of follow up with a mean MPR of 106% (0.9) (median [IQR]; 100% [84.8-107.1%]). The young group (n=49) initiated HU at a mean (SD) of 2.6 (1.1) years old, and the old group (n=102) at 11.1 (3.7) years (p<0.001). The young group was escalated over a longer time period (13.6 versus 10.6 months; p=0.04) and achieved a higher average MTD compared to the older group (28.8 versus 24.7 mg/kg/day; p<0.001). At baseline, the young group had a higher mean HbF level (14.9 versus 7.5%; p<0.001), absolute reticulocyte count (ARC) (300 versus 270 x103, p=0.02)and white blood cell count (WBC) (15.6 versus 12.6 x103/μL, p<0.001), and similar relationships were observed at MTD (Table 1). No differences between the two age groups were observed in the direction or magnitude of changes after escalation of HU between groups (Table 1). For example, the young group had an average increase of 13.3% in HbF compared to 13.4% in the older group (p=0.87) (Table 1; Figure 1). Following 5 years of therapy at MTD, the mean (SD) age of the young group was 9.1 (1.0) years and 15.7 (3.7) in the older group. At this time, only hemoglobin levels differed between groups (slightly higher in the old group), but HbF levels were similar between groups as HbF declined with age (Table 1). Figure 1. Increase in fetal hemoglobin (HbF) at maximal tolerated dose (MTD) from baseline versus age (years) at the time hydroxyurea was initiated. The solid green line stands for linear regression line; the solid and dash read lines stand for nonparametric regression and its smoothed conditional spread lines, respectively. Conclusions: Intensifying HU to MTD in young children with SCA is safe and efficacious, providing stable long-term improvement in numerous hematologic parameters. At young ages, there appears to be a short-term additive effect of HU to the elevated baseline HbF, but this is not sustained. Thus, initiating HU at an early age does not prevent the normal physiological decline of HbF. The clinical impact of intensifying HU to MTD in very young children warrants further exploration and is to be addressed by the recently NHLBI-funded pilot HUGKISS trial (hydroxyurea management in kids: intensive versus stable dosage strategies trial). Figure 1 Figure 1. Disclosures Hankins: Novartis: Research Funding. Estepp:Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Health: Research Funding.