Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Dalle Carbonare L, 2015, Blood (Link to abstract)                                                          

Using a SCD mouse model, the authors showed that these mice [JB1] have reduced osteoblasts while osteoclasts were increased compared to healthy mice. Simulating vaso-occlusive crises with hypoxia-reperfusion events, osteoclast recruitement was seen and osteoblast activity was reduced. Zolendronic acid, a bisphosphonate, reduced bone loss in SCD mice with hypoxia-reperfusion damage.

* This study on SCD mice supports further evaluation of bisphosphonates in SCD patients to reduce sickle cell bone disease.

Free hemoglobin increases von Willebrand factor–mediated platelet adhesion in vitro: implications for circulatory devices

Da Q, 2015, Blood (Link to abstract)   

Patients on extra-corporeal life support (ECMO) are prone to hemolysis. This report analyzed the effect of free hemoglobin on thrombus formation in vitro. The authors found that free hemoglobin ≥50mg/dl induces thrombus-formation through GPIbα-vWF interaction. GPIbαantibodies inhibited platelet deposition.  Heparin insufficiently inhibited thrombus formation in this setting.

* Hemolysis and resulting free hemoglobin ≥50mg/dl are involved in thrombus formation in an ECMO model through GPIbα-vWF interaction. Inhibition of this process might decrease thrombus formation.

Erythropoietin Stimulates Tumor Growth via EphB4

Pradeep S, 2015, Cancer Cell (Link to abstract)

In the adult world, recombinant erythropoietin had been used to treat anemia associated with cancer until several studies showed an association with poorer survival. However, this association has been tenuous without a clear mechanism (the Epo receptor isn’t present in many tumor cells). This group hypothesized that Epo binds to another receptor and found one using an in-silico analysis – EphB4. They then showed in vitro and in vivo that this ligand-receptor interaction leads to cell proliferation and migration. Finally, they found that women with ovarian or breast carcinoma treated with Epo whose tumors expressed EphB4 had worse survival than those whose tumors had low expression.

* Now that there’s a mechanism it seems pretty solid that Epo is not a good choice for treating anemia associated with cancer. We hadn’t used it before in pediatrics but now we probably never will (pending better evidence).

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Barazia A, (2015), Blood (Link to Abstract)              

Hydroxyurea (HU) is the established mainstay of chronic treatment in sickle cell disease (SCD). HU was shown to stimulate HbF production, serve as an NO donor, and inhibit tissue factor expression in leukocytes. HU was also effective as acute vaso-occlusive crisis (VOC) treatment in SCD mouse models. The authors of this manuscript showed that co-administration of hydroxyurea and Akti XII, an AKT2 inhibitor, did have beneficial effect and prolonged survival in SCD mice with VOC. AKT2 plays an important role in neutrophil-erythrocyte and neutrophil-platelet interaction and its inhibition led to increased blood flow in affected areas of VOC.

* AKT2 inhibition might be a novel target in the acute VOC of SCD patients improving perfusion of affected tissues.

IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy

Van Vulpen LFD, (2015), Blood (Link to Abstract)                                                          

Joint bleeds from various causes can induce cartilage remodeling and apoptosis after a single event. In this article, the authors used in vitro analyses to study the effect of cytokine inhibition on cartilage damage. Postmortem human cartilage was extracted and cells were cultured. IL-1β inhibition within 24hrs from blood exposure led to dose-dependent recovery of cartilage dysfunction markers. TNFα inhibition did not show the same effect.

*IL-1β inhibition might be a target for prevention of blood-induced cartilage damage in joint bleeds.

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

Antun A (2015), Hemostasis and Thrombosis (Link to Abstract)

Immune tolerance induction (ITI) is successful in about 70% of cases in patients with Hemophilia A who develops inhibitors, but little is known about the rate and predictors of recurrence. This is a retrospective, multicenter (12 US center) cohort study of patients with Hemophilia A (levels 1% or less) after successful ITI. Sixty-four patients were included with a median follow up of 3.4 years. Probability of recurrence was 12.8% at 1 year, 26% at 3 years, and; 32% at 5 years.  Amongst them, 10 restarted ITI and 10 used bypassing agents.  Predictors of recurrence were: use of concurrent immune therapy during ITI (4/5 recurred), and recovery less than 85% (3 fold increase in risk). Lack of adherence to post ITI prophylaxis was not predictive of recurrence.

* There is a high rate of recurrence after successful ITI. Immune therapy and incomplete recovery are predictive of recurrence, but lack of adherence is not.



Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women

Moretti, D (2015), Blood (Link to Abstract)                                                             

54 non-anemic young women (aged 12-49y) with plasma ferritin ≤20 µg/L were recruited and subsets of 13-25 individuals were given labeled iron (FeSO4) at different single doses orally on 1 or on 2 consecutive days, or three 60-mg Fe doses (twice-daily dosing) within 24 hours.

In the single dose administration, 24 hours after doses ≥60 mg, serum hepcidin was increased and the fraction of the iron being absorbed was decreased by 35% to 45%. With increasing dose, fractional absorption decreased whereas absolute absorption increased. Total iron absorbed from 3 doses (2 mornings and an afternoon) was not significantly greater than that from 2 morning doses. Providing lower dosages (40-80 mg Fe) and avoiding twice-daily dosing maximized fractional absorption. The duration of the hepcidin response supported alternate day supplementation.

*Current dosing recommendations giving iron multiple times a day seem to reduce the iron absorption of subsequent doses by increasing hepcidin with negative feedback on iron absorption from the guts.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone–treated donors in neutropenic patients with infection

Price TH (2015), Blood (Link to abstract)                                                              

Granulocyte transfusion therapy has been used for 20 years without demonstrating clear efficacy in treating infections in neutropenic patients. This report from a multicenter randomized controlled trial included patients with neutropenia and proven/probable/presumed infection. Subjects were randomized to receive either standard antimicrobial therapy (n=56) or standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone (n=58). The primary end point was a composite of survival plus response to antimicrobials, at 42 days after randomization. Transfused subjects received a median of 5 transfusions. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection

* There is no evidence for superiority of giving granulocyte transfusions in addition to standard care with antimicrobials in subjects with neutropenia and infection.

Comparison Of Long-Term Outcomes Between Children With Aplastic Anemia And Refractory Cytopenia Of Childhood Who Received Immunosuppressive Therapy With Antithymocyte Globulin And Cyclosporine

Hama A (2015) Haematologica  (Link to Abstract)            

The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood (RCC). However, it is unclear whether this morphological classification reflects clinical outcomes. This study is a review on the outcome among 186 children who had received immunosuppressive therapy (IST, horse ATG / cyclosporine) for acquired aplastic anemia. Patients were divided into 3 groups after re-classification by bone marrow pathology: aplastic anemia (AA), refractory cytopenia of childhood (RCC), refractory cytopenia with multilineage dysplasia (RCMD). The AA group had significantly lower leukocyte/neutrophil/reticulocyte/platelet counts compared to the RCC and RCMD groups. No difference in response rates to IST among the 3 groups was seen. Cumulative incidence of total clonal evolution showed no significant difference among the groups. However incidence of development of monosomy 7 was higher in the AA group. Longer duration of G-CSF administration was associated with development of monosomy 7 in AA patients. 10-year failure-free survival did not differ significantly among the 3 groups. 10-year overall survival was significantly lower in the AA group (85%) vs. the RCC group (97%) and the RCMD group (100%).

* The 3 groups did not appear to be distinctly different in terms of biology[NW1]  and outcome in this study. Clonal evolution is still seen in the AA group. This hints that the current morphological classification may not be reliable enough to distinguish aplastic anemia from hypocellular MDS.


Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomized, multicenter, placebo-controlled trial

Grainger JD (2015), Lancet (Link to Abstract)         

Eltrombopag is a thrombopoietin receptor agonist, which is used effectively in adults with chronic immune thrombocytopenia. This study involved a randomized, multicenter, placebo-controlled, double blinded study looking at the safety and efficacy of eltrombopag in pediatric patients with chronic ITP. 92 patients: 63 in the treatment arm and 29 in the placebo arm. 40% of patients achieved platelet counts of greater than or equal to 50 during the initial 12 weeks of the study, while only 3% of the placebo treated group achieved these counts. 80% of patients achieved a platelet count of greater than 50 in the 24 weeks following the randomized portion of the study, when all patients were treated with Eltrombopag. There was no significant difference in adverse events between the two groups.

* Eltrombopag, a thrombopoietin receptor agonist, is a suitable therapeutic option to consider in pediatric patients with chronic ITP.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children.

Brousseau D (2015) Blood  (Link to Abstract)           

Multicentre, randomized, parallel, double blind, placebo-controlled trial comparing: intravenous Magnesium 40 mg/Kg q8 hourly versus normal saline plus standard therapy for the treatment of pain crisis for patients with Sickle cell anemia. Hypothesis it would reduce length of stay (LoS), opioid use and improve QoL.

204 children eligible: n=101 magnesium and n=103 placebo. The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis.

* IV Magnesium doesn’t help children with SCD pain crisis.

Red blood cell transfusion is associated with increased hemolysis and an acute phase response in a subset of critically ill children

L’Acqua C (2015) American Journal of Hematology

Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/26183122

In this prospective study of critically ill children, the effect of RBC storage duration on extent of hemolysis was examined by comparing laboratory measurements obtained before, and 4 hours after RBC transfusions in 100 patients. They identified a subset of 21 patients with considerable extra-vascular hemolysis accompanied by an acute phase response. Storage duration of the RBC did not correlate with hemolysis and inflammation indicators, suggesting that other recipient and donor factors are more important in the induction of post transfusion hemolysis.

Hydroxyurea treatment does not increase blood viscosity and improves red blood cell rheology in sickle cell anemia

Lemonne N (2015) Hematologica

Link to abstract: http://www.haematologica.org/content/100/10/e383

Study on 24 adult patients in Guadeloupe with Sickle Cell Anemia: 50% had 1 a-gene deletion, who were given hydroxyurea treatment including escalating doses for history of frequent VOC and or ACS or frequent subclinical VOC and anemia in the preceding year. Outcomes measures: hematocrit (Hct), blood viscosity, red cell deformability and RBC disaggregation threshold as well as clinical VOC and ACS. Blood samples were taken at 1,3,6 and 12 months of HU. Hemoglobin and Hct increased from 3rd month of therapy; RBC deformability increased from 1 month onwards - effects more pronounced in non a-gene deletion. The blood viscosity did not change in SCA patients receiving HU therapy, which is important as increased viscosity increases the frequency of VOC in SCA.  Also implications for possible use of HU in other sickle syndromes e.g. SC disease, which have increased blood viscosity compared to SCA.

Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia

Gerrits AJ, 2015 Blood                                                   

Link to abstract: http://www.bloodjournal.org/content/126/11/1367

Platelet activation measured by flow cytometry in 9 Wiskott-Aldrich Syndrome/ X-linked Thrombocytopenia (WAS/XLT) patients and 8 age-matched healthy controls, showed that reduced platelet activation found in WAS/ XLT was directly due to microthrombocytopenia.  GP IIb-IIIa and P-selectin were less expressed due to smaller platelet size. Eltrombopag treatment resulted in an increased platelet count in 5 out of 8 patients with WAS/ XLT and 6/8 had reduced clinical bleeding severity. Although the eltrombopag-induced increase in platelet production in WAS/XLT is less than in ITP (sample cohort compared to 7 age-matched ITP patients), it has beneficial effects on platelet counts but not platelet activation in the majority of WAS/XLT patients.

Changing practice: red blood cell typing by molecular methods for patients with sickle cell disease

Changing practice: red blood cell typing by molecular methods for patients with sickle cell disease

Casas et al, 2015 Transfusion

Link to abstract: http://onlinelibrary.wiley.com/doi/10.1111/trf.12987/abstract


Retrospective study of RBC antigen phenotypes and genotypes, as per pre-transfusion samples done routinely at 1 year of age. Compared RBC antigen phenotypes obtained by hemagglutination methods and by genotyping predictions.

Genotyping was done using DNAbased assays targeting SNP associated with blood group Ag expression for 35 antigens. 494 patients (single-institution (CHOP), 2008-2014), total 6360 antigen comparisons; Results: 77 discrepancies (1.1%): 16 Fyb, 13 Jkb, 10 M, 10 N, 7 S. Serologic assays were redone for 66; 64 in concordance with genotyping –> concordance 0.9997. 34 false-positive serologic testing; 33 false-negative serologic testing and 15 false negative serologic results associated with alleles encoding weak antigens or single-dose Fyb expression.