The International Normalized Ratio during Concurrent Warfarin and Argatroban Anticoagulation: Differential Contributions of Each Agent and Effects of the Choice of Thromboplastin Used

Abstract

Oral anticoagulants such as warfarin induce depletion of vitamin K-dependent coagulation factors, causing prolongation of the prothrombin time (PT) and the PT-International Normalized Ratio (INR). The available thromboplastins used for measuring the PT vary in their sensitivity to coagulation factor depletion, and each is assigned an International Sensitivity Index (ISI) that is used when calculating the INR. Traditional monitoring of oral anticoagulant therapy using the INR is confounded during concurrent therapy with direct thrombin inhibitors, such as argatroban, that also prolong the INR (1)(2)(3). Although alternative monitoring methods have been suggested for use in this setting (2)(3), guidelines allowing for refined interpretation of the INR would also be useful. To facilitate the development of such guidelines, we have characterized in vitro the differential effects of warfarin and argatroban, as well as the choice of thromboplastin used, on the INR during anticoagulation with both agents. For this study, plasma specimens were obtained from 10 healthy donors (laboratory personnel) and 35 patients on warfarin therapy, in accordance with policies of the institution’s responsible committee. Blood was collected into evacuated tubes (38 g/L sodium citrate), and plasma was prepared by the centrifugation of the blood within 30 min of collection. The only selection criterion for the patient group was that each was on warfarin therapy, and both inpatients and outpatients were included. In addition, four plasma pools (each prepared from at least 10 individuals) were obtained from Harris Laboratories. One plasma pool was from healthy donors, and three pools were from patients on warfarin therapy exhibiting generally similar levels of oral anticoagulation. Plasma specimens were stored at −30 °C for up to 2 weeks and thawed rapidly immediately before testing. The PT of each individual or pooled plasma specimen was determined in the absence and presence of …