A retrospective analysis of the safety and effectiveness of recombinant von willebrand factor in children with von willebrand disease undergoing surgery

Abstract Background: Von Willebrand disease (VWD) is a bleeding disorder caused by deficient or defective von Willebrand factor (VWF) that can result in increased perioperative bleeding. Currently, there are limited treatment options for perioperative management of bleeding in pediatric patients with VWD, with only plasma-derived VWF concentrates approved for use as replacement therapy. Recombinant VWF (rVWF) is currently under phase 3 investigation for perioperative use in pediatric patients with severe VWD (NCT02932618). Aims: To evaluate the real-world effectiveness and safety of rVWF in the prevention or treatment of surgical bleeding in pediatric (aged <18 years) participants with VWD. Methods: Pediatric participants with VWD identified from the ATHNdataset were included in this retrospective analysis if they experienced at least 1 surgical procedure in which rVWF was used for perioperative treatment. The American Thrombosis & Hemostasis Network (ATHN) is the steward of the ATHNdataset, a Health Insurance Portability and Accountability Act compliant, limited dataset containing data from individuals with bleeding disorders receiving care through ATHN affiliates who opt in to contribute. Participants were required to have 6 months of clinical data before and 14 days of clinical data after the surgical procedure. A subgroup analysis in participants with severe VWD (VWF ristocetin cofactor assay levels <20 IU/dL) was completed. The primary objective was to describe the safety and effectiveness of rVWF in a perioperative setting. Secondary objectives included collection of demographic and clinical characteristics, coagulation/hematological disease markers, hemostatic control, and concomitant medications. Results: Nine participants were included in the full cohort (subgroup: 4), including 6 with Type 1 VWD (subgroup: n=1) and 3 with Type 2A VWD (subgroup: n=3). Mean (SD) age at the time of first surgical procedure was 12.8 (4.0) years (subgroup: 13.3 [4.8]). Most participants were female (full cohort: n=6; subgroup: n=2), White (full cohort: n=7; subgroup: n=3), and not of Hispanic, Latino, or Spanish origin (full cohort: n=7; subgroup: n=3). Laboratory measurements prior to surgery were available in 2 participants with severe VWD; mean (SD) VWF activity, VWF antigen, and factor VIII (FVIII) measurements were 4.0 (0) IU/dL, 33.5 (11.8) IU/dL, and 64.8 (51.9) IU/dL, respectively. Twelve surgical procedures, including 4 in the subgroup, were evaluated. Eight (67%) procedures in the full cohort and 2 (50%) procedures in the subgroup were reported as successful; outcomes were not reported for the remaining procedures. All surgeries were treated with an rVWF infusion either within 1 day before (full cohort: 9 procedures; subgroup: 2 procedures) or on the same day as the procedure. While 5 procedures, including 3 in the subgroup, required postoperative rVWF infusions, there were no postoperative bleeds reported. There were no reported adverse events defined by the European Haemophilia Safety Surveillance program, including treatment-emergent side effects, hypersensitivity/allergic reactions, thrombotic events, or events of VWF inhibitor development. Concomitant use of antifibrinolytics was reported in 2 separate procedures, once on the one day before or on the same day as the procedure, and once during the postoperative period. Plasma-derived VWF was used in 1 procedure during the postoperative period. There were no reports of perioperative FVIII, tranexamic acid, desmopressin, anemia treatment, or need for transfusion. Conclusions: Results from this study suggest that off-label use of rVWF is effective for the perioperative management of surgical bleeding in pediatric individuals with VWD undergoing major and minor procedures, including those with severe disease. No new safety events were observed. These results lend further support for the positive benefit-risk profile for rVWF in a pediatric population.