INR and Vitamin K Dependent Coagulation Factor Fluctuation during Warfarin Initiation and Stable Therapy in Patients Dosed with the Fiix-Prothrombin Time or the Quick Prothrombin Time. the Fiix Trial
Authors: Gudmundsdottir Brynja R. , Jonsson Petur I. , Onundarson Pall T. 
Published: October 2019

Abstract
Introduction: The Quick prothrombin time (PT) is equally sensitive to the influence of factors (F) II, VII and X but experiments suggest that it is mainly the influence of warfarin on factors (F) II and X that cause its anticoagulant effect. The new Fiix prothrombin time (Fiix-PT) differs from the PT in it being sensitive only to factors (F) II and X and not being sensitive at all to FVII activity in the test plasma. The Fiix-trial has demonstrated increased stability of warfarin anticoagulation and possibly improved efficacy when monitored with Fiix-PT compared to PT monitoring (unpublished data). However, as very low levels of vitamin K dependent (VKD) factors not measured with the Fiix-PT could possibly have deleterious effect on anticoagulation (AC) outcome, we measured the VKD coagulation factors in plasma obtained from patients on stable warfarin anticoagulation and during the first 30 days of warfarin treatment monitored either with the Fiix-PT or the PT.
Methods: In order to define stable anticoagulation in terms of coagulation factor activity, samples from patients enrolled in the Fiix trial and monitored either with Fiix-PT or PT were used. Frozen samples from 20 patients were obtained from each monitoring group. All the samples had been drawn from patients during very stable warfarin treatment (INR within range 2-3 for over 10 months by serial monitoring). Serial samples were also obtained from 10 patients in each group during days 1-30 of warfarin initiation. PT, Fiix-PT and VKD coagulation factors were measured. An INR was calculated for both PT and Fiix-PT.
Results: During stable AC, the median INR (range) was 2.5 (2.1-3.0) in the Fiix-group vs 2.4 (2.0-3.0) in the PT group (p=ns). The median (95% range) VKD factor percent coagulant activity was as follows in the stable Fiix-group vs the stable PT-group: FII 28 (19-40) vs 25 (18-40), FVII 48 (30-88) vs 42 (23-85), FIX 66 (41-85) vs 61 (36-79), and FX 15 (11-17) vs 15 (10-22). Although the medians tended to be higher in the Fiix group except for FX, p was n.s. for all. In patients starting on warfarin a stable Fiix-INR (defined as two INRs within target range) was reached on day 14 (median) in the Fiix group vs a stable PT-INR on day 11 in the PT controls. Following this, however, the PT-INR fluctuates more out of the INR target range than the Fiix-INR does. As shown in the figures, the earlier rise in INR in the PT group is mainly a reflection of a rapid fall in FVII activity. The FVII level decreases to a nadir of 20% in the Fiix group compared to a nadir of 30% in the PT monitoring group. Subsequently FII, FVII and FX fluctuate less in the Fiix-PT group than in the PT group. During the first 30 days 46% of Fiix-INRs in the Fiix-group were within target range vs 29% of INRs in the controls (p=0.06). Also during the initiation period FII was 47% vs. 30% within the 95% stable range established for the PT method (p=0.06), FVII 60% vs. 73% (p=0.13), FIX 41% vs 36% (p=0.69), and FX 51% vs 38% (p=0.20), respectively. The more fluctuating INR in the PT group is also reflected by a rollercoaster like pattern of warfarin dosing as opposed to the more cascade like pattern that is observed in the Fiix group.
Figure 1 Figure 1. Figure 2 Figure 2.
Conclusion: During stable warfarin AC VKD factors are similarly reduced with Fiix-PT or PT monitoring.During initiation of warfarin monitored with the Fiix-PT, FVII decreases initially more than with PT monitoring but subsequently stabilizes and fluctuates less. Fiix-PT leads to smoother reduction in FII and X which stabilize faster than during PT monitoring. The smoother anticoagulant effect is also reflected by the warfarin dose pattern during initiation. The results may suggest that the Quick-PT confounds warfarin management during initiation and dose changes.

Disclosures
Gudmundsdottir: Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.