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Background: Identifying perioperative bleeding risk in pediatric patients undergoing major surgery is challenging because personal history is often not sufficiently informative and laboratory tests are also more susceptible to pre-analytical variables. Children with low Willebrand add further uncertainty in the treatment options. The aim of this study was to evaluate practices to assess hemorrhagic risk and manage bleeding prophylaxis in children with low von Willebrand factor levels (30 and 50 IU/dL; low VWF), known von Willebrand disease (VWD) or healthy controls undergoing ear, nose and throat (ENT) surgery. Methods: In this retrospective observational study, data from consecutive paediatric patients undergoing ENT surgery between January 1, 2010 and December 31, 2017 at the Turin Paediatric Hospital were analysed. All statistical analyses were performed using STATA (StataCorp. 2013. Been Statistical Software: Release 13. College Station, TX: StataCorp LP). Demographic and clinical characteristics of patients were assessed using the absolute frequencies and percentages for qualitative variables and percentiles for quantitative variables. The risk of bleeding was estimated from the number of patients who experienced bleeding within 21 days as a proportion of the number of patients subjected to surgery. 90% confidence intervals (90% CIs) were estimated for the evaluation of bleeding risk, using the Jeffreys method and any differences in the risk of bleeding between patient groups were tested using a proportions test. To investigate any factors associated with the therapeutic strategy used, multinomial logistic regression models were conducted. Results: Major perioperative bleeding was seen in 6.3% (5/79) of low VWF patients, 3.0% (35/1152) of healthy controls and 20.0% (5/25) of patients with VWD. In low VWF patients, perioperative bleeding prophylaxis was given to 59.5% and included subcutaneously desmopressin (n=21) and VWF-containing concentrate (n=26). Oral or intravenous tranexamic acid was administered to all low VWF patients. Of these patients, one major hemorrhagic event occurred in patients who did not receive prophylaxis and the remaining events occurred in patients treated with VWF-containing concentrate. In patients who received a VWF-containing concentrate, lower VWF ristocetin cofactor levels were observed compared with patients who received desmopressin or were untreated during surgery. No differences in clinical and laboratory features were observed between patients with low VWF treated with desmopressin and those who were untreated. Conclusions: Patients with low VWF have a higher risk of perioperative bleeding compared with healthy controls but a significantly lower risk compared with patients with VWD. The perioperative management of these patients is complex with a high risk of overtreatment. In our experience the caution of keeping the VWF-containing concentrate in the operating room available for use in case of bleeding appears to be a balanced approach. Prospective randomized studies to identify accurate methods of assessing bleeding risk and evaluate the most effective perioperative bleeding prevention are warranted. Essential bibliography: Ruchika Sharma and Veronica H. Flood. Advances in the diagnosis and treatment of Von Willebrand disease. Hematology American Society of Hematology Education Program 2017:379-384 Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology American Society of Hematology Education Program 2009:106-112 Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010;8(9):2063-2065. Casey LJ, Tuttle A, Grabell J, et al. Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease. Pediatr Blood Cancer. 2017;64(10) Mannuccio Mannucci P, Kyrle PA, Schulman S, Di Paola J, Schneppenheim R, Cox Gill J. Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials. Blood Transfus. 2013;11(4):533-540 Disclosures No relevant conflicts of interest to declare.

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Introduction The development of anti-factor VIII inhibitors is the main complication of modern therapy of hemophilia A (HA) occurring in 25%-30% of severe forms. Inhibitors affect the possibility of a primary prophylaxis and regular physiotherapy, which is an important therapeutic tool to preserve joint function. In patients with severe HA with inhibitors, a prospective randomized study (Konkle et al J Thromb Haemost 5:1904, 2007) and the PRO-PACT retrospective multicenter observational study of a large case series (Young et al Thromb Res 130:864, 2012) have demonstrated the feasibility and effectiveness of secondary prophylaxis with recombinant activated factor VII (rFVIIa, NovoSeven®) in reducing hemarthrosis. Aim of the study: This study describes the unique experience of Hemophilia Pediatric Center of Turin (Italy) in a case series of 4 children with severe hemophilia A, history of high-titer inhibitor and mild or severe artropathy, who underwent to regular rehabilitation programme despite presence of inhibitors. Methods Postural evaluation and gait analysis have been performed for each patient to assess posture and gait performance and plan a tailored therapeutic-rehabilitative treatment. Each physiotherapy session lasted about 45 minutes. rFVIIa at a dose of 90-180 mcg/kg in a preparation for rehabilitative treatment was administered immediately prior to each session. During physiotherapy sessions, children carried out both active and passive rehabilitation exercises to maintain adequate muscle strength and preserve joint range of movement (ROM). Basal and final joints angles (in degree) were measured with a goniometer. Manual Muscle Testing (MMT) was applied for grading muscle strength. Results Clinical characteristics and individual physiotherapy program are listed below: Patient 1 A 10-years-old African child with 2 target joints (knees) and 1 bleeding episode/month, has performed 102 sessions of active and passive rehabilitation treatment (November 2010 to November 2012) while on immune tolerance therapy (ITI). Patient 2 A 12-years-old Caucasian child with 3 target joints (left elbow, knees) has performed a total of 16 sessions (February 2011 to April 2011). Patient 3 A 2-years-old Caucasian child with a target joint (knee) has performed a total of 20 sessions (February 2011 to August 2012) while on ITI. Patient 4 A 8-years-old Caucasian child with 4 target joint (elbow, 2 ankles) has performed a total of 149 sessions (November 2009 to November 2012) after failed ITI. Within 72 hours after each session, no joint nor muscle bleeding have been observed as evidence of the potential role of rFVIIa in preventing bleeding. The 4 children had a total of 287 physiotherapy sessions, each of them preceded by a single administration of rFVIIa. Treatment provided adequate hemostasis in all patients; no bleeding was observed during the sessions and in the following 3 days. The rehabilitative program obtained a gain of ROM in most of the 9 joints assessed and an improvement in muscle strength was also observed, as described in table. Postural evaluation and gait analysis confirmed these results. We did not observe thrombotic events nor infectious episodes. Conclusion Combination of rFVIIa and physiotherapy improved joint ROM and muscle strength in hemophilic children with inhibitors. The rehabilitation program has not given rise to safety issues in these young patients. Disclosures: Messina: Pfizer: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Baxter: Honoraria; Bayer: Honoraria. Forneris:Novo Nordisk: Honoraria, the autor has received reimbursement for attending a symposium and fees for speaking by Novo Nordisk Other. Off Label Use: rFVIIa is not licensed for nonsurgical prophylaxis in Italy. The use of rFVIIa in prophylaxis as a preparation for physiotherapy treatment currently is considered off label in Italy.

In a multicenter case-control study we investigated the impact of prenatal/perinatal events and early FVIII exposure on the inhibitor risk in hemophiliacs. Patients: 102 children (age:13–196 months) with hemophilia A (FVIII≤2%) exclusively treated with recombinant FVIII and evaluated for inhibitors every 3 months were included. Forty-seven patients who developed inhibitors at the median age of 26 months (4–80) after a median of 16 exposure days (ED, 5–150), 37 high-responders (6–500 BU/mL) and 10 low-responders (200 ED). Results: by univariate analysis, family history of inhibitors, intron 22 inversion and prophylaxis started after the first 20 ED were significantly associated with an increased risk of inhibitor development (OR 9.5, 95%CI 1.1–79.9; OR 2.7, 95%CI 1.1–6.6; OR 3.7, 95%CI 1.1–12.1, respectively). No statistically significant differences were found for variables such as villocentesis/amniocentesis, premature/caesarian birth, breast-feeding, surgery, central venous devices and FVIII infusions associated with infections/vaccinations. By multivariate analysis, the inhibitor risk was 2.8-folds (95%CI 1.1–7.3) in children with intron 22 inversion and 4.5-folds (95%CI 1.1–17.5) in patients who started prophylaxis after the first 20 ED. By univariate and multivariate analysis, there was not a linear trend in the inhibitor development according to the age at first FVIII exposure (≤6, 7–12, 13–18, 19–24, >24 months). Conclusions: this study showed that starting prophylaxis within the first 20 ED had a favourable impact on the inhibitor risk independently from the age at first FVIII exposure.