Low mortality from intracranial haemorrhage in paediatric patients with haemophilia.

INTRODUCTION: Intracranial haemorrhage (ICH) in patients with haemophilia has an estimated mortality rate of 20%. Advances in haemophilia care have significantly reduced many bleeding complications but it is unclear if these advances have impacted mortality from ICH. AIM: To determine the in-hospital mortality from intracranial ICH in paediatric patients with haemophilia. METHODS: This retrospective multicentre cohort study utilized the Pediatric Health Information System administrative database with data from 43 paediatric tertiary care hospitals in the United States from January 1, 2002-December 31, 2011. Subjects included were male < 21 years of age with an ICD-9-CM code for haemophilia A or B. ICH events were identified using ICD-9-CM codes. RESULTS: There were 8325 admissions for 3133 male subjects with haemophilia. About 271 (3.3%) admissions had an ICH event in 236 (7.5%) individual subjects. The proportion of ICH events was stable over time (P = 0.13). The median age of ICH was 2 years (interquartile range 0.6-7.3). In 28.4% (77/271) of the ICH events the subject had an inhibitor. Twenty-one deaths occurred in the entire cohort (0.7%). Six (28.6%) of these deaths were in patients with an ICH for an ICH mortality rate of 2.5% (6/236). CONCLUSIONS: Mortality from ICH in paediatric patients has significantly improved from prior estimates of 20% to the current estimate of 2.5%. Unfortunately the rate of ICH events remains constant and further efforts are needed to identify alternative strategies of prevention.

Organized sports participation and the association with injury in paediatric patients with haemophilia.

INTRODUCTION: With the wide availability of factor and the routine use of prophylaxis boys with haemophilia are now able to participate in regular physical activity, including organized sports. Current guidelines vary regarding specific recommendations for sports participation and concerns remain regarding safety. AIM: To determine if participation in organized sports is associated with an increased risk for injury in paediatric subjects with haemophilia. METHODS: Retrospective single-centre cohort study from January 1, 2008 to December 31, 2010 in male subjects ages 10-18 years with a factor VIII (FVIII) or FIX level <40%. The number of injuries per subject and participation in organized sports was recorded. RESULTS: 48 male subjects with a mean age of 14.3 ± 2.6 years (range: 10-18.8) were included; 64.6% (31/48) FVIII deficiency, 54.2% (26/48) severe haemophilia, 18.8% (9/48) moderate and 27.1% (13/48) mild. The majority [62.5% (30/48)] of subjects participated in at least one season of organized sport. There were 77 injuries in 36/48 (75%) subjects. The mean number of injuries per subject was 1.6 ± 1.5. There was no statistical difference in the mean number of injuries (P = 0.44) or target joint formation (P = 0.52) between the subjects who participated in organized sports compared to those who did not. CONCLUSION: In this study, participation in organized sports by boys with haemophilia, ages 10-18 years, is common and not associated with an increased number of injuries or the development of a target joint. As injuries occurred equally in both groups, concerted efforts should be directed at reducing injuries in all patients.

Pediatric transplantation: managing bleeding.

There has been extraordinary progress over the last half-century in the field of medical transplantation in which tissue, organs, or body parts from one human are placed into another. Solid organ transplants have allowed thousands of children with otherwise devastating inherited or acquired disorders to survive. Depending upon the clinical situation, there are many specific peri-transplant issues that must be carefully addressed to optimize outcomes. Although surgical, immunologic, and infectious concerns are usually in the forefront, important aspects regarding hemostasis frequently arise. The number of solid organs that can be successfully transplanted in children has expanded over the last decades and includes kidney, liver, heart, lung, intestine, pancreas, and thymus. Bleeding complications may occur in the setting of organ failure prior to transplantation, during the surgical procedure, or in the post-transplant setting, and can results in significant morbidity. This report will focus on preventing and managing non-surgical-related bleeding complications in children undergoing liver, heart, kidney transplantation, in whom there are often unique aspects of coagulation to be considered.

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

BACKGROUND: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood. OBJECTIVES: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI. METHODS: In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. RESULTS: A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3). CONCLUSIONS: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.

Inhibition of microsomal cytochrome c reductase activity by a series of alpha, beta-unsaturated aldehydes.

alpha, beta-Unsaturated aldehydes are reactive and cytotoxic compounds which occur in the environment and are also formed in vivo. Many of these aldehydes have been reported to inhibit hepatic cytochrome P-450. Our laboratory has shown that trans,trans-muconaldehyde (a possible metabolite of benzene) as well as acrolein and crotonaldehyde, when added to hepatic microsomes, decreased cytochrome P-450 (measured spectrophotometrically). Additional studies showed that several alpha, beta-unsaturated aldehydes also inhibited hepatic microsomal NADPH-cytochrome c reductase. Acrolein, crotonaldehyde and trans,trans-muconaldehyde all decreased NADPH-cytochrome c reductase activity in vitro. Concentrations of 0.5, 1.0 and 1.5 mM acrolein decreased activity to 60, 26 and 11% of control respectively. Similar concentrations of trans,trans-muconaldehyde inhibited NADPH-cytochrome c reductase. Crotonaldehyde was a less effective inhibitor of this enzyme. Propionaldehyde, a saturated aldehyde, had no effect on NADPH-cytochrome c reductase activity. Time course experiments with acrolein over a period of 5-45 min suggest that the loss of NADPH-cytochrome c reductase activity is non-linear. The addition of reduced glutathione protected against the inhibition of reductase activity by acrolein. Formation of these aldehydes and their subsequent inhibition of these enzymes may have important consequences in xenobiotic metabolism.

Oral bioavailability of chromium from a specific site.

Analysis of soil from a specific site in New Jersey indicated a low level of sodium and chromium present as a calcium compound. Chromium was then administered orally to young, mature male rats at a level of 240 micrograms/kg for 14 days as chromium-contaminated soil, as CaCrO4, and as an equimolar mixture of the soil and calcium salts for 14 days. The rats were sacrificed 24 hr after the last dosing, and tissues were taken immediately for chromium analysis. Blood, muscle, and liver contained the highest levels of chromium in these animals, although kidney contained the highest concentration per gram of tissue. The total amount of chromium in the tissues was less than 2% of the administered chromium. In a study of the excretion of chromium, the animals were dosed orally for 8 days (with CaCrO4 or contaminated soil, each at the level of 240 mumole Cr/kg), and the chromium in feces and urine was determined on days 1, 2, 7, and 8. After cessation of dosing for 27 days, the same rats were dosed for 2 days at the same level, and chromium in urine and feces was determined for the 2 days. The animals administered the chromium in soil had higher levels of chromium in both urine and feces on all days compared to the group fed the CaCrO4. The total recovery of chromium in any of the 2-day periods was less than 50% of the chromium administered during that period.

In vivo effects of chromium.

The production of reactive oxygen species on addition of hexavalent chromium (potassium dichromate, K2Cr2O7) to lung cells in culture was studied using flow cytometer analysis. A Coulter Epics Profile II flow cytometer was used to detect the formation of reactive oxygen species after K2Cr2O7 was added to A549 cells grown to confluence. The cells were loaded with the dye, 2',7'-dichlorofluorescein diacetate, after which cellular esterases removed the acetate groups and the dye was trapped intracellularly. Reactive oxygen species oxidized the dye, with resultant fluorescence. Increased doses of Cr(VI) caused increasing fluorescence (10-fold higher than background at 200 microM). Addition of Cr(III) compounds, as the picolinate or chloride, caused no increased fluorescence. Electron paramagnetic resonance (EPR) spectroscopic studies indicated that three (as yet unidentified) spectral "signals" of the free radical type were formed on addition of 20, 50, 100, and 200 microM Cr(VI) to the A549 cells in suspension. Two other EPR "signals" with the characteristics of Cr(V) entities were seen at field values lower than the standard free radical value. Liver microsomes from male Sprague-Dawley rats treated intraperitoneally with K2Cr2O7 (130 mumole/kg every 48 hr for six treatments) had decreased activity of cytochromes P4503A1 and/or 3A2, and 2C11. Hepatic microsomes from treated female Sprague-Dawley rats, in contrast, had increased activities of these isozymes. Lung microsomes from male Sprague-Dawley rats had increased activity of P4502C11.

Mutagenicity and disposition of chromium.

Hexavalent chromium was administered to rats at doses of 20-240 mumol kg-1 for several periods of time, from 2 to 14 days. Lung, liver and blood contained the highest amounts of chromium, as detected by atomic absorption or by ICP, 24 h after cessation of treatment. A maximum of 40% of the dose was recoverable in organs along with feces and urine at this same time period, and chromium in soil (5.6% Cr) was absorbed better than equimolar amounts of the hexavalent chromates of calcium or sodium. The contaminated chromium-containing soil was found to have 30-35% of the chromium in the hexavalent state. The mutagenicity of chromium as tested in the bacterial strain of Salmonella typhimurium (strain TA 104) was decreased when tested without metabolic activation with the addition of leachate (of inexact analysis) from a waste site. When studied by alkaline elution, chromium (5-20 microM) caused single strand breaks as well as DNA-protein crosslinks in A549 lung cells, while with L1210 mouse leukemia cells, only DNA-protein crosslinks were found. Chromium(III) compounds caused no damage to DNA.