OC 17.2 - The measurement of a next-generation FVIII Mimetic, Mim8, using tissue factor triggered calibrated automated thrombography

Background: Mim8 is a next-generation bispecific antibody that mimics the action of factor VIIIa in patients with haemophilia A (HA). Mim8 complexes with factor X and factor IXa to accelerate activation of factor X. Previous studies have mostly assessed thrombin generation using activated factor XI or tissue factor as a trigger (1).

Aims: To assess the thrombin generation capacity of severe HA plasma spiked with Mim8 using low concentration of tissue factor as a trigger.

Methods: Severe HA plasma (HRF) was spiked with Mim8 0-20 µg/mL (Novo Nordisk). Calibrated Automated Thrombography (CAT) was performed using Stago PPP-reagent low (low concentration of tissue factor) on Fluoroskan Ascent. Pooled normal plasma (PNP, Precision Biologic) was used as a normal comparison. Samples were tested on 4 times on different days.

Results: The mean Endogenous thrombin potential (ETP) and mean peak thrombin of unspiked, severe HA plasma were 234.6nM/min and 10.8nM respectively. The addition of 1 µg/mL Mim8 increased the mean ETP to 713.3nM/min and peak thrombin to 39.1nM. At 2 µg/mL Mim8, all parameters, except time to peak (TTP), were within normal limits (data shown in table 1 and figure 1); the mean ETP was 1440.1nM/min and peak thrombin was 118nM. TTP was normal in at 5 µg/mL Mim8. Plateaux were observed at 5-20 µg/mL Mim8 for all parameters (Kruskal-Wallis P>0.05).

Conclusion(s): The addition of 5µg/mL Mim8 to HA plasma normalised all CAT parameters however, higher concentrations of Mim8 did not further increase thrombin generation. Mim8 restored the thrombin generation of severe HA plasma to normal levels in a low tissue factor-triggered thrombin generation assay.