FIIX-based vitamin K antagonist monitoring: the promise of improved anticoagulation stability and clinical outcomes in mechanical heart valve patients

Dear Editor,

We read with interest the case report by Luo and colleagues describing the anticoagulant management of a patient with congenital factor VII deficiency undergoing mechanical aortic and mitral valve replacement [1]. The case highlights a rare but important clinical problem: patients with a mechanical valve require lifelong vitamin K antagonist (VKA) anticoagulation, yet in congenital factor VII deficiency the conventional prothrombin time-derived international normalized ratio (INR) which reflects changes in clotting factors II, VII, and X but not IX, may be markedly abnormal at baseline and may not accurately reflect the intensity of anticoagulation [1–3].

The authors managed this problem by guiding VKA therapy using factor II and factor X activity rather than the INR [1]. This approach is physiologically attractive because the antithrombotic effect of VKA therapy appears to be mediated primarily through reduction of factors II and X [2–4]. In contrast, factor VII has a short half-life, has a major influence on the INR, and may cause substantial changes in the measured INR without proportionate changes in the more stable antithrombotic effect of VKA therapy [2, 3]. In a patient with congenital factor VII deficiency, this limitation may be magnified: the baseline INR is dominated by the pre-existing factor VII abnormality and additional VKA effects may increase INR into what may appear to be a “therapeutic” or “supratherapeutic” range which may not reflect adequate suppression of factor II and factor X activity for the prevention of thrombosis [1, 5]. Similarly, patients with other congenital or acquired factor deficiencies that affect the INR and those with lupus anticoagulant antibodies causing reagent-dependent INR abnormalities may also not be reliably monitored with INR-based VKA monitoring [6].

This case provides a useful opportunity to consider the potential role of VKA monitoring using the “FIIX assay” in settings where the INR may not reflect the true VKA anticoagulant effect [1–3]. FIIX is a modified prothrombin time assay in which the clotting time is dependent principally on the patient’s factor II and factor X activity [2, 3]. The resulting FIIX normalized ratio is calculated in a manner analogous to the INR, but unlike the conventional INR is not materially responsive to changes in factor VII [2, 3]. In practical terms, FIIX monitoring attempts to measure the components of VKA anticoagulation most closely linked to antithrombotic efficacy, while avoiding the short-term variability introduced by factor VII [2, 3].

The potential application of FIIX-based VKA monitoring may extend beyond settings in which the INR cannot be reliably interpreted [2, 3]. In a single centre randomized trial conducted in Iceland, FIIX- and INR-based VKA monitoring strategies were compared in a broad anticoagulation clinic population, most of whom had atrial fibrillation [2]. Despite high quality INR control in the conventional monitoring group, FIIX-based monitoring improved time in therapeutic range, reduced testing and dose adjustments, and was clinically non-inferior to conventional INR-based monitoring with numerically fewer thromboembolic events and no increase in major bleeding [2].

In summary, the report by Luo and colleagues highlights an important limitation of the INR as a universal measure of VKA anticoagulation, and supports the role of an alternative assay that is not affected by factor VII levels [1–3]. FIIX-based monitoring may be suitable for monitoring of patients with coagulation disorders that interfere with interpretation of the INR and its utility may extend to other settings with the potential to improve patient outcomes [1–2, 5, 6]. However, important uncertainties remain. The FIIX assay has not been prospectively validated in patients with coagulation disorders in whom INR-based monitoring may be unreliable. In such patients, individualized management using direct factor II and/or factor X activity, specialist laboratory input, and careful clinical follow-up remain essential. Furthermore, the role of FIIX-guided anticoagulation in broader VKA-treated populations, particularly patients with mechanical heart valves, both in the early post-operative phase and during long-term maintenance, requires further clinical evaluation. These patients have a high thromboembolic risk and limited alternatives to VKA therapy, making them an especially important population in whom alternative monitoring strategies should be evaluated [2, 3].

Sincerely,

Stephanie Carlin

John W. Eikelboom

Emilie Belley-Cote

Author contributions

S.C. wrote the initial draft of the commentary. J.W.E. and E.B.-C. critically reviewed and revised the commentary for important intellectual content. All authors reviewed and approved the final version of the commentary.

Funding

S.C. has received speaker and/or advisory board fees paid to her institution from: AstraZeneca, BMS/Pfizer, Fresenius Kabi, Leo Pharma, and Servier. E.B-C. has received unrestricted grants from Abbott Laboratories and consulting fees from Abbott Laboratories. She is supported by career awards from the Department of Medicine at McMaster University and the Population Health Research Institute. J.W.E. has received fees / honoraria / research support from Anthos, AZ, Bayer, BI, BMS, Fresenius Kabi, GSK, Idorsia, Janssen, JnJ, Novartis, Sanofi, Servier, Takeda and Pfizer.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors approved the final version of the manuscript for publication.

Competing interests

S.C. has received speaker and/or advisory board fees paid to her institution from: AstraZeneca, BMS/Pfizer, Fresenius Kabi, Leo Pharma, and Servier. E.B-C. has received unrestricted grants from Abbott Laboratories and consulting fees from Abbott Laboratories. She is supported by career awards from the Department of Medicine at McMaster University and the Population Health Research Institute. J.W.E. has received fees / honoraria / research support from Anthos, AZ, Bayer, BI, BMS, Fresenius Kabi, GSK, Idorsia, Janssen, JnJ, Novartis, Sanofi, Servier, Takeda and Pfizer.