Little discrepancy between one-stage and chromogenic factor VIII (FVIII)/IX assays in a large international cohort of persons with nonsevere hemophilia A and B.

BACKGROUND: Accurate measurements of coagulation factor activity form an essential part of hemophilia management and are performed by the one-stage or chromogenic assay. Current literature suggests that approximately one-third of persons with nonsevere hemophilia A exhibit assay discrepancy, albeit with a high variability between studies. Such data are scarce in nonsevere hemophilia B. OBJECTIVES: To investigate the extent of factor VIII/IX one-stage and chromogenic assay discrepancy in moderate and mild hemophilia A and B. METHODS: Persons with previously diagnosed nonsevere hemophilia A and B with a factor level of 2 to 35 IU/dL were included from the international DYNAMO cohort study. Central measurements of the factor VIII and IX activity levels were performed by the one-stage and chromogenic assay. Relative and absolute discrepancy definitions were used, with the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee proposed ratio of >2.0 or <0.5 being the primary outcome. Discrepancy was also evaluated in a subgroup of 13 persons with mutations previously associated with discrepancy (≥3 cases reported in literature). RESULTS: A total of 220 persons were included, of whom 3 (1%) showed assay discrepancy: 2/175 hemophilia A and 1/45 hemophilia B. Six persons (3%) exhibited an absolute difference >10 IU/dL between the assay results. In addition, with more lenient definitions, over 90% of participants (n = 197) had no discrepant results. Only 1 out of 13 persons with a mutation previously associated with discrepancy had significant assay discrepancy. CONCLUSION: Little assay discrepancy was observed despite the presence of mutations previously associated with discrepancy, suggesting that the presence and magnitude of assay discrepancy are largely determined by laboratory variables.

Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency.

Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP.Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency. Patients received their routine FVII product (30 IU/kg plasma-derived FVII [pdFVII] or 25 µg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 µg/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48 hr after administration. FVIIa activity was determined using a one-stage clotting assay. PD parameters were derived from thrombin generation testing, using the Nijmegen hemostasis assay.Results: rVIIa-FP showed improved PK compared to rFVIIa, with 2- to 3-fold longer t1/2 and 4- to 8-fold lower clearance. Analysis of PD data showed a sustained suppression of lag time below 4.5 min (upper limit of healthy people) for rVIIa-FP compared to rFVIIa. AUEC and ECmax were similar across the two dose groups of rVIIa-FP and rFVIIa.Discussion: rVIIa-FP was well tolerated in patients with congenital FVII deficiency, showed a longer half-life and lower clearance compared to rFVIIa, and lag time remaining within healthy ranges for ≥8 hr.Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients.

The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL-1) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients' and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, intercompartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing.