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Background. People with haemophilia face many treatment decisions, which are largely informed by evidence from observational studies. Without evidence-based 'best' treatment options, patient preferences play a large role in decisions regarding therapy. The shared decision-making (SDM) process allows patients and health care providers to make decisions collaboratively based on available evidence, and patient preferences. Decision tools can help the SDM process. The objective of this project was to develop two-sided decision tools, decision boxes for physicians and patient decision aids for patients, to facilitate SDM for treatment decisions in haemophilia. Methods. Development of the decision tools comprised three phases: topic selection, prototype development and usability testing with targeted end-users. Topics were selected using a Delphi survey. Tool prototypes were based on a previously validated framework and were informed by systematic literature reviews. Patients, through focus groups, and physicians, through interviews, reviewed the prototypes iteratively for comprehensibility and usability. Results. The chosen topics were: (i) prophylactic treatment: when to start and dosing, (ii) choosing factor source and (iii) immunotolerance induction: when to start and dosing. Intended end users (both health care providers and haemophilia patients and caregivers) were engaged in the development process. Overall perception of the decision tools was positive, and the purpose of using the tools was well received.Conclusions. This study demonstrates the feasibility of developing decision tools for haemophilia treatment decisions. It also provides anecdotal evidence of positive perceptions of such tools. Future directions include assessment of the tools' practical value and impact on clinical practice.

DH/DT/OHT students' comfort levels, positive attitudes and supportiveness for SND suggested positive implications for these practitioners to partake in multidisciplinary management of patients with special needs, thus indicating the need for standardised training requirements and practice guidelines in this area of care.

Background The occurrence of factor inhibitory antibodies, or inhibitors, is a significant complication in the care of individuals with congenital haemophilia A or B. Currently, immune tolerance induction is the only known intervention to successfully eradicate inhibitors. However, ideal dosing regimens, and the comparative safety and efficacy of different immune tolerance induction regimens have not yet been established. Objectives The objective of this review was to assess the effects of immune tolerance induction (different protocols of this therapy versus each other, or versus only bypassing agents) for treating inhibitors in people with congenital haemophilia A or B. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.

A B S T R A C T BackgroundThe occurrence of factor inhibitory antibodies, or inhibitors, is a significant complication in the care of individuals with congenital haemophilia A or B. Currently, immune tolerance induction is the only known intervention to successfully eradicate inhibitors. However, ideal dosing regimens, and the comparative safety and efficacy of different immune tolerance induction regimens have not yet been established. ObjectivesThe objective of this review was to assess the effects of immune tolerance induction (different protocols of this therapy versus each other, or versus only bypassing agents) for treating inhibitors in people with congenital haemophilia A or B. Search methodsWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched: MEDLINE (from 1946 to 15 July 2013); Embase (from 1980 to 15 July 2013) via the OVID platform; CINAHL (from conception to 15 July 2013); and ClinicalTrials.gov (most recent search: 15 July 2013). We also searched the reference lists of relevant articles and reviews. Selection criteriaRandomised controlled trials comparing either different immune tolerance induction regimens or immune tolerance induction versus only bypassing therapy for the eradication of factor inhibitory antibodies in patients with congenital haemophilia A or B. Data collection and analysisTwo review authors independently completed data collection, extraction and assessment of the risk of bias of trials. Main resultsOne methodologically sound randomised controlled trial met the inclusion criteria and was included in the review. One further randomised controlled trial has been recently stopped, but it has not yet been reported. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B (Review)We found one randomised trial that compared high-and low-dose immune tolerance induction, which included 115 males with haemophilia A and inhibitors. Key results and conclusionsThe single included trial was too small to be certain that both doses of immune tolerance induction were equally successful at removing inhibitors. However, the high-dose treatment destroyed all inhibitors faster and with less bleeding events than the low-dose treatment.Since there was only one available trial, further trials are needed to establish the best immune tolerance induction regimen with respect to starting time, dosing intensity and frequency. 2 Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B (Review) ]. Haemophilia 2006; 12 Suppl 2:57-69. DiMichele DM, Hay CRM. The international immune tolerance study: a multicenter prospective randomized trial in progress. Journal of Thrombosis and Haemostasis 2006;4 (10):2271-3. Hay CRM, DIMichele DM. The principal results of the international immune tolerance study: Morbidity [abstract]. Journal of Thrombosis and Haemostasis 2011;9:845...

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Background Thrombocytopenia is common in children receiving cancer chemotherapy. In addition, children with cancer are also at increased risk of acute thrombotic events (TE). When these two complications occur simultaneously, TE management with anticoagulants (ACT) poses a unique challenge, as ACT use in thrombocytopenic patients increases their bleeding risk. Current guidelines provide only best practice recommendations on how to manage this treatment conundrum, and even these recommendations vary on optimal management due to the lack of evidence to guide treatment. To date, no systematic literature review summarizing the available paediatric data on treatment of TE in the presence of thrombocytopenia has been conducted. The aim of our systematic review was to summarize the data available to evaluate the safety of ACT for management of TE in paediatric oncology patients during periods of thrombocytopenia. Methods We systematically searched MEDLINE and EMBASE from the OVID platform from inception to April 15th 2016 for studies that included children aged less than 18 years with diagnosis of cancer complicated by an objectively confirmed TE, whose anticoagulation therapy was complicated by a period of thrombocytopenia (as defined by the study author). We included all study designs. Two authors (LB and AA) screened the data at title then full-text level to select eligible studies. Disputes were arbitrated by a third author (UA) until a consensus was reached. Our primary outcome was haemorrhagic complications, categorized as minor or major according to paediatric ISTH criteria. Bleeding episodes were divided according to anticoagulation intensity (age-appropriate, agent-specific full dose vs. half-dose, as per CHEST guidelines) and degree of thrombocytopenia (i.e. severe </=50 x109/L, moderate 51-99 x109/L, mild >/=100 x109/L). Our secondary outcome was the identification of platelet transfusion triggers according to degree of anticoagulation intensity. Results Our search yielded 244 articles, of which 13 were screened at a full text level. Four manuscripts were selected for inclusion, as follows: case report (n=1), case series (n=2), and prospective cohort study (n=1). Details of included studies are described inTable 1 and patient information in table 2. The studies included 39 patients with malignancies, of which the most common were acute lymphoblastic leukaemia (n=13), CNS malignancies (n=6), non-hodgkinlymphoma(n=4). All patients had venous TE. Type and regimen of ACT, and author definitions of thrombocytopenia and bleeding were variable. Thirty-five patients received low-molecular weight heparin (LMWH), of whom 33 received therapeutic dose, and no dose was recorded for two. Three patients received unfractionated heparin (UFH) with antithrombin(AT) supplementation; however, UFH wasstopped in periods of low platelet counts, and one received a reduced dose UFH. According to our definition, 36/39 (92.3%) experienced severe thrombocytopenia, 1 (2.6%) developed moderate thrombocytopenia, platelet count was not stated in 2(5.1%). Using the ISTH bleeding criteria, one patient (2.6%) developed major bleeding, and seven (17.9%) developed minor bleeding (n=2 intestinal bleeding, n=5 injection site/port bleeding). Only one study reported our secondary outcome, which used a platelet transfusion trigger of <40x109/L if receiving therapeutic LMWH and <20x109/L if receiving prophylactic LMWH. Given the heterogeneity, we were unable to statistically aggregate any data. Discussion The results of this systematic review highlight the paucity of high-quality data to assess the use and safety of ACT for TE in paediatric cancer patients during periods of thrombocytopenia. We identified only observational studies- one prospective and three retrospective in design. These studies included very few patients (total n=39), and had variable patients, disease and treatment-related factors. Evidence-based recommendations cannot be generated to guide an optimal ACT management in such situations. Further research using standardized definitions is needed to identify optimal strategies for treating thrombotic events during periods of thrombocytopenia. Such research will help on the development of evidence-based clinical practice guidelines to improve patient care. Disclosures Brandão: Boehringer Ingelheim: Consultancy.

Purpose: Concomitant administration of asparaginase (ASP) and steroids, the backbone of front line acute lymphoblastic leukemia (ALL) therapy, are shown to increase the risk of thromboembolism (TE). On Dana-Farber Cancer Institute (DFCI) ALL Consortium studies TE is frequent during ASP intensification phase (Consolidation II) where pulse steroids are administered for 5 days at commencement of 3-week multiagent chemotherapy cycles (Grace et al, 2011). These observations indicate that combination therapy with ASP and steroids leads to a hypercoagulable state. However, there are no in vivo or in vitro data to support these clinical observations. Hence we undertook a study to evaluate the impact of concomitant administration of ASP and steroids on markers of endogenous thrombin generation namely prothrombin activation fragment 1.2 (F1.2) and, activated coagulation factor VII (FVIIa) and antithrombin (AT) complex (FVIIa-AT). Hypothesis: ASP administered with steroids results in increased levels of endogenous thrombin generation when compared to baseline or with ASP only therapy. Methods: Children (>1 to ≤18 yrs. of age) treated according to DFCI ALL 05-001 therapy protocol who are in remission following consolidation I therapy, without prior TE or ASP allergy, were eligible. Blood samples collected at 3 time points: prior to the first post-induction dose of E. Coli ASP ("baseline"), prior to Week 2 therapy (effects of ASP and Dex therapy) and prior to subsequent Week 1 (effect of ASP only) of three week cycle of Consolidation II therapy, were analyzed for F1.2 and FVIIa-AT complex. F1.2 levels were estimated by enzyme-linked immunosorbent assay (ELISA). FVIIa-AT levels were analyzed using the Asserachrome FVIIa-AT ELISA kits (Diagnostica Stago). Baseline parameters [time point (TP) 1] were compared to parameters after ASP and Dex (TP2), and after ASP only (TP3) therapy, using paired t-tests. Pearson correlation was used to evaluate the relationship between FVIIa-AT complex and F1.2. Results: This exploratory study included 9 patients (7 boys; 2 with high-risk ALL). The average age was 4.7 yrs. (range 1 to 8 yrs.). All patients received weekly E. Coli ASP during Consolidation II phase. As shown in Table 1, compared to baseline both F1.2 and FVIIa-AT complex levels were significantly increased at TP2 (ASP and Dex) and TP3 (ASP alone). In all but one patient the FVIIa-AT levels were higher following Dex therapy (TP2) compared to ASP alone (TP3). However this difference was not statistically significant [mean difference 83.4 (SD152.1), 95% CI -33.5, 200.4; p=0.138]. Similarly F1.2 levels were higher at TP2 compared to TP3 in all but 2 patients, but the difference was not statistically significant [mean difference -5.9 (SD 38.2), 95% CI-35.2, 23.4; p=0.656]. Following ASP alone therapy F1.2 and FVIIa-AT were significantly correlated (Pearson correlation coefficient 0.716, p=0.046). Conclusions: E. Coli ASP and Dex therapy is associated with significantly increased levels of F1.2 and FVIIa-AT levels compared to baseline, indicating activation of the coagulation cascade with increased endogenous thrombin generation. In the majority of patients combination of ASP and Dex had increased levels of F1.2 and FVIIa-AT compared to ASP alone therapy. However as a group this comparison was statistically insignificant. This may explain the increased risk of TE with concomitant ASP and Dex therapy as in Consolidation II phase on DFCI ALL therapy protocol. Small sample size is a limitation of our study. Hence we recommend a larger study to confirm our findings. Table 1. Variable TP1 Mean(SD) TP2 Mean (SD) Mean Difference TP1/TP2 (SD)[95% CI] P value TP3 Mean (SD) Mean Difference TP1/TP3 (SD)[95% CI] P value FVIIa-AT (pmol/L) 77.4 (25.7) 296.4 (132.3) -291.0 (133.9)[-322.0,-116.0] 0.001 213.0 (131.4) -135.6 (117.6)[-226.0, -45.1] 0.009 F1.2 (nmol/L) 110.7 (45.9) 153.0 (78.8) -42.3 (50.4) [-81.1,-3.6] 0.036 158.9 (80.4) -48.2 (61.3)[-95.3,-1.1] 0.046 Disclosures No relevant conflicts of interest to declare.