Treatment of Non-Hemophiliac Disorders in Children with Recombinant FVIIa - A Review of Dosing, Safety, and Efficacy.

Recombinant FVIIa (rFVIIa) is approved for use in hemophilia in the presence of inhibitors, thus bypassing the internal cascade of coagulation. It promotes thrombin generation on activated platelets, providing another mechanism of hemostasis. The use of rFVIIa has expanded to include patients with hemorrhage due to other etiologies, especially when refractory to other products enhancing coagulation. Aim: Faced with the question of cost, efficacy, and potential for adverse events such as thrombosis, we reviewed the use of rFVIIa in pediatric patients at our institution to document dosing, efficacy, and side effects following administration. Methods: rFVIIa was released for use from the Transfusion Service upon request by the treating physician, following a review of the indication by the Medical Director or the Hematology faculty member. A retrospective chart review was performed for 16 children that received the drug during their inpatient hospital stay. Data was collected for indication and severity of hemorrhage, dosing based on weight, side effects during and after infusion for 48 hours, and efficacy (presence and timing of control of hemorrhage). Results: Between September 2002 and July 2005, 16 children, aged between 7 weeks and 20 years, received rFVIIa. Four were treated prior to December 2003. Indications for use included FVII deficiency and elective surgery (2), trauma (2), coagulopathy of malignancy with cerebellar hemorrhage, GI hemorrhage secondary to GVHD of skin, liver and/or gut (3), post-operative hemorrhage (3) (cardiac or abdominal surgery, 2 on ECMO), uncontrolled hemorrhage due to systemic disease or DIC (gut/lung) (6). The number of doses ranged between 1 and 17 per patient (median 2.5). Dosing ranged between 20 and 90 mcg/kg (median 50 mcg) and was often adjusted by the size of the product and stability. In the very young (n=5), the remaining product was wasted secondary to the packaging size and short half life (3 hours). All patients with hemorrhagic symptoms also received platelets, FFP, cryoprecipitate and PRBCs. rFVIIa was used for poor efficacy after these interventions. Efficacy, noted by clinical improvement or resolution of hemorrhage, coagulation parameters, and a dramatic decrease in the need for blood products was documented in all but one recipient, who had fulminant sepsis and DIC who continued to bleed. Recurrent hemorrhage was present in 1 patient with traumatic hemorrhage, 15 days after initial doses. No thrombotic events were encountered following administration, even in the presence of an extracorporeal circuit. Twelve of the 16 patients treated died 1–36 days after treatment. The cause of death was non-hemorrhagic in all but one. Conclusions: rFVIIa was used for refractory hemorrhage and was effective in controlling bleeding complications when other interventions had failed. Therapy lowered transfusion requirements. Though the suggested dosing for hemophilia is 90 mcg/kg, efficacy was noted with doses as low as 20 – 30 mcg/kg. Recurrent hemorrhage was seen in only one patient following second instrumentation 2 weeks later. No thrombotic complications were encountered even in the presence of pro-thrombotic states such as DIC and the use of ECMO. rFVIIa, though expensive, is a valuable hemostatic agent with minimal side effects. It can reduce risk of exposure to blood products and cost is offset by reduced transfusions. Smaller dose packaging would further reduce cost in children. This drug can be safely considered an early therapeutic option in children with severe hemorrhagic complications.