Background: International normalized ratio (INR) is an in vitro blood test designed to measure the clotting time of blood. The INR represents the activity of several clotting factors including fibrinogen, prothrombin (factor II), factor V, factor VII, and factor X. As a global measure of coagulation, the INR is unable to delineate the contributions of individual clotting factors. The thrombotic effect of factor VII is considered to be of negligible importance compared to the activity of factor II and factor X. (1) Understanding the contribution of individual clotting factors to INR is crucial for the interpretation of non-steady-state INR values, such as those measured following warfarin overdose or when re-warfarinising a patient after surgery.
Aim: The aim of this work is to evaluate the sensitivity of INR to a reduction in individual clotting factors.
Methods: A previously developed mathematical model of the coagulation network was used for deterministic simulations of INR. (2) A single clotting factor deficiency of the vitamin K-dependent clotting factors (factor II, factor VII, and factor X) was simulated one-at-a-time. Subsequently, multiple clotting factor deficiencies were simulated two-at-a-time and finally simulated using the clinical example of a patient initiated on warfarin therapy with reduced production of factor II, factor VII, and factor X, simultaneously. Local INR sensitivity was quantified by taking the partial derivative of INR with respect to the individual clotting factor concentration. Interactions between clotting factors that could lead to non-additivity were explored graphically by using isobolograms.
Results: The model simulations showed that the INR was sensitive to changes in factor II, factor VII, and factor X, with increasing sensitivity at low clotting factor levels. Time series of INR sensitivity for warfarin initiation suggested that the non-steady-state INR is most sensitive to changes in factor VII (maximum sensitivity ratio VII:II 2.3), followed by factor X (maximum sensitivity ratio X:II 1.4) and then factor II. In contrast, steady-state INR appeared to be equally sensitive to all clotting factors that were assessed (sensitivity ratio 1). Subsequent isobologram analysis showed that simultaneous reduction in two clotting factors was antagonistic in nature with respect to INR. Of clinical importance, it was demonstrated that INR can be driven by the clotting factor that is the most deficient (e.g. factor VII during warfarin initiation), which makes other clotting factor levels of limited additional relevance to changes in INR.
Conclusion: Non-steady-state INR is the most sensitive to variations in factor VII, followed by factor X and factor II, while steady-state INR is equally sensitive to these clotting factors. Factor VII is influential on non-steady-state INR despite reported playing a modest role in thrombosis. INR values may have different interpretations under steady state and non-steady state conditions.
1. Gudmundsdottir BR, Francis CW, Bjornsdottir AM, Nellbring M, Onundarson PT. Critical role of factors II and X during coumarin anticoagulation and their combined measurement with a new Fiix-prothrombin time. Thromb Res. 2012;130(4):674-81.
2. Wajima T, Isbister GK, Duffull SB. A comprehensive model for the humoral coagulation network in humans. Clin Pharmacol Ther. 2009;86(3):290-8.