PB1323 - Impact on thrombin generation of direct oral anticoagulants in a FVIII deficient plasma spiked with emicizumab and human FVIII.

Background: Haemophilia A (HA) therapeutic landscape has evolved in the past few years with the bispecific monoclonal antibody emicizumab. The aging of HA population and the development of aged-related diseases, like atrial fibrillation or thrombotic events, unveiled new haemostatic challenges for HA patients. Some cardiovascular events will require an anticoagulant therapy by direct oral anticoagulant (DOAC) and could be antagonistic with emicizumab. The evaluation of this new complex balance is challenging, especially as FVIII infusions are required to undergo a surgery act or to treat a bleeding event.

Aims: To analyse this new coagulation balance, we assessed the simultaneous effect of DOAC, emicizumab and FVIII on routine coagulation assays and thrombin generation assay (TGA).

Methods: We simultaneously spiked a deficient FVIII plasma with a range of emicizumab (0, 12.5, 25, 50, 100 µg/ml), FVIII (0, 5, 15, 50, 100%) and DOAC (apixaban, edoxaban, rivaroxaban and dabigatran; 0, 50, 100, 200, 400 ng/ml) concentrations. Routine coagulation assays (PT, aPTT) and thrombin generation assay (PPP and PPPlow reagents) for all possible conditions.

Results: At low dose of DOAC, emicizumab and FVIII had additional effect on thrombin generation which is lost with higher FVIII concentrations. Introduction of DOAC showed different thrombin generation profiles depending on the drug used. For example, apixaban (50 ng/ml) rapidly inhibits thrombin generation on plasma spiked with 100% FVIII and 100 µg/ml with peak thrombin dropping from 2.15 fold to 0.50 fold of non-spiked plasma (Figure 1). At the same dose of 50 ng/ml, dabigatran (FIIa inhibitor) failed to inhibit thrombin generation as peak is increased by 2.71 fold.

Conclusion(s): Our study provides a cartography of haemostatic balance in complex plasmas and showed the variable efficacy of FVIII substitution on patients receiving emicizumab and DOAC. TGA appears as a promising tool for monitoring patients with complex haemostatic balance.