Switching from Sucrose-Formulated rFVIII to Octocog Alfa (BAY 81-8973) Prophylaxis Improves Bleed Outcomes in the LEOPOLD Clinical Trials.

Introduction: Previous clinical trials established the efficacy and safety of sucrose-formulated recombinant factor (F) VIII (rFVIII-FS/Kogenate FS®/Helixate FS®) and octocog alfa (BAY 81-8973/Kovaltry®; LEOPOLD trials). Aim: To report the results of a post hoc subgroup analysis assessing efficacy and safety outcomes in patients with hemophilia A who were receiving rFVIII-FS prior to enrolling into the LEOPOLD I Part B and LEOPOLD Kids Part A clinical trials and switching to octocog alfa. Methods: LEOPOLD I Part B (NCT01029340) and LEOPOLD Kids Part A (NCT01311648) were octocog alfa Phase 3, multinational, open-label studies in patients with severe hemophilia A aged 12-65 years and ≤12 years, respectively. Annualized bleeding rate (ABR) was the efficacy endpoint for both studies. Safety endpoints included adverse events (AEs) and development of FVIII inhibitors. Results: Of the 113 patients in both LEOPOLD trials, 40 (35.4%) patients received rFVIII-FS prophylaxis pre-study and had data available for pre-study total ABR. In LEOPOLD I Part B (n = 22, 35.5%), median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) pre-study to 1.0 (0.0; 6.8), and from 1.0 (0.0; 6.0) pre-study to 0.0 (0.0; 6.02) in LEOPOLD Kids Part A (n = 18, 35.3%). Octocog alfa was well tolerated, and no patients had drug-related serious AEs or inhibitors. Conclusion: Treatment with octocog alfa prophylaxis appeared to have a favorable risk-benefit profile compared with rFVIII-FS and thus could be an effective and improved alternative strategy for individualized treatment for children, adolescent and adult patients with severe hemophilia A currently on rFVIII-FS treatment.

Design and Usability of an Electronic Health Record-Integrated, Point-of-Care, Clinical Decision Support Tool for Modeling and Simulation of Antihemophilic Factors.

BACKGROUND: With the consequences of inadequate dosing ranging from increased bleeding risk to excessive drug costs and undesirable administration regimens, the antihemophilic factors are uniquely suited to dose individualization. However, existing options for individualization are limited and exist outside the flow of care. We developed clinical decision support (CDS) software that is integrated with our electronic health record (EHR) and designed to streamline the process for our hematology providers. OBJECTIVES: The aim of this study is to develop and examine the usability of a CDS tool for antihemophilic factor dose individualization. METHODS: Our development strategy was based on the features associated with successful CDS tools and driven by a formal requirements analysis. The back-end code was based on algorithms developed for manual individualization and unit tested with 23,000 simulated patient profiles created from the range of patient-derived pharmacokinetic parameter estimates defined in children and adults. A 296-item heuristic checklist was used to guide design of the front-end user interface. Content experts and end-users were recruited to participate in traditional usability testing under an institutional review board approved protocol. RESULTS: CDS software was developed to systematically walk the point-of-care clinician through dose individualization after seamlessly importing the requisite patient data from the EHR. Classical and population pharmacokinetic approaches were incorporated with clearly displayed estimates of reliability and uncertainty. Users can perform simulations for prophylaxis and acute bleeds by providing two of four therapeutic targets. Testers were highly satisfied with our CDS and quickly became proficient with the tool. CONCLUSION: With early and broad stakeholder engagement, we developed a CDS tool for hematology provider that affords seamless transition from patient assessment, to pharmacokinetic modeling and simulation, and subsequent dose selection.

Awareness, Care and Treatment In Obesity maNagement to inform Haemophilia Obesity Patient Empowerment (ACTION-TO-HOPE): Results of a survey of US patients with haemophilia and obesity (PwHO) and their partners and caregivers.

BACKGROUND: The ACTION study identified barriers to initiating and maintaining weight loss in patients with obesity; however, joint-related issues (pain, mobility and bleeding) may affect perceptions of patients with haemophilia and obesity (PwHO). AIM: To identify patient and caregiver insights on the unique challenges of PwHO. METHODS: Following IRB approval, adults who self-identified as PwHO, spouses/partners of adult PwHO, and caregivers of adolescent PwHO (aged 12-17 years) completed an online survey between December 2017 and April 2018. RESULTS: Respondents included 124 adult PwHO, 45 spouses/partners and 42 caregivers. By calculated BMI, most adults were overweight (43%) or had obesity (51%); this differed from self-reported weight category. PwHO goals were improving health conditions (60%), having more energy (54%), reducing risks of weight (46%), and losing any weight (44%). Issues related to joint health were secondary for PwHO but frequently reported by spouses/parents. Most perceived weight loss to be a high priority (66%) and their responsibility (64%) but required a complete lifestyle change (63%). Most anticipated that weight loss would reduce joint pain (62%), bleeding (58%) and factor use (52%) and increase mobility (62%). Weight discussions with healthcare providers (HCPs) were commonly reported (51%). HCP discussions targeted improving health conditions (46%), achieving any weight loss (44%), being more active (73%) and improving eating habits (72%). Most PwHO (65%) perceived obesity as a disease and believe that 10% weight loss would be extremely beneficial (78%). In the past 5 years, 80% discussed being overweight and 68% losing weight; a minority reported being successful (9%) or somewhat successful (38%) with weight loss. More realistic or specific (51%/47%) goals, resources (46%), referrals to weight-loss programmes (41%) or dietitians (38%), meals or recipes (54%/50%), local or national (42%/41%) programmes for PwHO and success stories of PwHO (40%) are needed or would be helpful. CONCLUSIONS: PwHO, spouse/partners and caregivers exhibited awareness of general and haemophilia-specific consequences of excess body weight. Most have tried general approaches to improve eating and increase activity with little success and desire more education on weight management and more details on specific actionable recommendations distributed through existing haemophilia channels. These insights will better inform the creation of weight-loss programmes for this community.

Hereditary spherocytosis: a risk factor for thigh pressure myonecrosis in posterior spine surgery.

The objective of this study was to make surgeons aware of a potential pressure complication in posterior spine surgery for patients with hereditary spherocytosis (HS) and to present a plausible hypothesis for injury. Posterior spine surgery is common practice for adolescent idiopathic scoliosis (AIS). Common, less severe surgical risks include pressure ulcers; while rare, more severe pressure complications include rhabdomyolysis and compartment syndrome. In patients with HS, a familial hemolytic disorder with altered red cell deformability, it is unknown if their red cell disorder is an additional risk factor for pressure-related surgical injuries. Two patients with HS, an 18-year-old male and a 17-year-old female, were both post-splenectomy and underwent revision posterior spinal fusion and instrumentation for progressive AIS. Surgery lasted 9 hours and 7 hours respectively, with no intraoperative complications other than prolonged surgical time due to revision nature of the deformities. Thigh redness and swelling was noted in both patients directly deep to the thigh pads. Thigh myonecrosis was diagnosed with eventual recovery in both cases. Patients with HS may be at inherent more risk of pressure complications during posterior spine surgery. We propose that thigh myonecrosis occurs with decreased perfusion and hemolysis from HS erythrocytes' inherent fragility, decreased deformability within capillaries, and prolonged microvasculature compression from positioning, causing poor microvascular perfusion, tissue ischemia, and reperfusion injury. Level of veidence: IV.

The impact of thromboelastography on resuscitation in pediatric liver transplantation.

Although TEG directs effective resuscitation in adult surgical patients, pediatric data are lacking. We performed a retrospective comparative review of the effect of TEG on blood product utilization and outcomes following pediatric liver transplantation in 38 patients between 2008 and 2014. Diagnoses, laboratory values, fluid and blood product use, and outcomes were examined. Nineteen patients underwent liver transplantation prior to the implementation of TEG, and 19 had perioperative TEG. The most common indications for transplant were BA (n = 14), HB (n = 7), and metabolic disorders (n = 7). Intraoperative blood loss, urine output, fluid and blood product use were similar between groups. However, the use of fresh frozen plasma decreased significantly in TEG patients within the first 24 hours (29 vs 0 mL/kg, P < .01), and between 24 and 48 hours (12 vs 0 mL/kg, P = .01) post-operatively. The total use of fresh frozen plasma during hospitalization was markedly reduced (111 vs 17 mL/kg, P < .01). Four patients in the TEG group had thromboembolic graft complications, including portal vein or hepatic artery thrombosis, and underwent retransplantation. The decreased use of fresh frozen plasma since implementation of TEG is an important finding for resource utilization and patient safety. However, the increased incidence of thromboembolic complications requires further investigation.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Prophylactic versus reactive transfusion of thawed plasma in patients undergoing surgical repair of craniosynostosis: a randomized clinical trial.

BACKGROUND: Surgical repair of craniosynostosis in young children is associated with copious bleeding and often coagulopathy. Typically, a reactive transfusion strategy is used to treat coagulopathy whereby fresh frozen plasma (FFP) is given only after clinical manifestation of clotting abnormality. This prospective, randomized clinical trial was designed to test the hypothesis that prophylactic FFP during craniofacial surgery reduces blood loss and blood transfusion requirements compared to a reactive FFP transfusion strategy. METHODS: Eighty-one patients less than 2 years of age requiring primary repair of craniosynostosis were randomized to receive FFP using either a prophylactic or reactive strategy. Laboratory values were measured at four standardized time points. The volume of blood products transfused, length of stay in the pediatric intensive care unit (PICU), hospital length of stay, and number of donor exposures were recorded for each patient. RESULTS: The prophylactic FFP group received a significantly greater average volume of FFP compared to the reactive group (29.7 ml·kg(-1) vs 16.1 ml·kg(-1) ; P < 0.001), which was associated with improvement in coagulation values at multiple time points. However, there was no difference in blood transfusion requirements or blood loss between the two groups. The two transfusion strategies resulted in similar median donor exposures. There was no difference in PICU or hospital length of stay. CONCLUSION: A reactive FFP transfusion strategy required less plasma transfusion and was associated with similar rates of blood loss and PRBC transfusion as prophylactic FFP despite improvement in coagulation values in the prophylactic FFP group.

Bleeding and clotting disorders in pediatric liver disease.

The coagulopathy of liver disease in pediatric patients presents an unusual set of challenges. Little pediatric data have been published, so this review is based largely on adult studies. There is a precarious balance between deficiencies of clotting factors and anticoagulation factors in liver disease that result in abnormal prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests that would suggest a bleeding tendency, yet the patients can form a clot and are at risk of thromboembolic disease. Attention has centered on thromboelastography and thrombin-generation assays to clarify the patient's ability to control bleeding, but these tests are not routinely available to many treating physicians.

Off-label use of rFVIIa in children with excessive bleeding: a consecutive study of 153 off-label uses in 139 children.

BACKGROUND: Recombinant factor VIIa is a general hemostatic agent. Randomized trials have demonstrated effectiveness in adults; however, data in children are confined to case reports and series subject to publication bias. PROCEDURES: A consecutive cohort of children treated with rFVIIa was identified via inspection of pharmacy records. Data collected included demographic data, underlying disorders, reason for rFVIIa use, dosing, thrombotic events, and mortality. Efficacy was scored subjectively on a 3-point scale (complete, partial, or no response) and supported by a measurement of transfusion of red cells, platelets, fresh frozen plasma, and cryoprecipitate in the 3 days prior to and following use of rFVIIa. Patients with hemophilia and congenital factor VII deficiency were excluded. RESULTS: Sixty-five percent had a complete response and 26% had a partial response. Following treatment, there was a mean reduction in transfusions of 14.2 ml/kg for red blood cells, 10.9 ml/kg for platelets, 9 ml/kg for fresh frozen plasma, and 4.6 ml/kg for cryoprecipitate. Thrombosis occurred in 4.3% of patients with the highest rate being in neonates (17.6%). CONCLUSIONS: rFVIIa is an effective general hemostatic agent for management of excessive bleeding in children and that with the exception of neonates has excellent safety.