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.

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.).

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.