Do You Report an Accurate International Normalized Ratio? Find Out Using Local Verification and Calibration

Abstract

The current method for monitoring vitamin K antagonist (AVK) anticoagulant therapy is the international normalized ratio (INR) that provides consistency and standardization for the prothrombin time (PT) assay value. Even after the standardization of the INR, inaccuracies of this value have still been reported. To make the INR even more accurate, better local assessments of INR parameters are becoming available. These new methods use plasmas with certified INR values to locally verify and, if necessary, recalculate the international sensitivity index (ISI) for the local laboratory’s reagent and instrument system. This CE Update will discuss the concepts of local verification and calibration to better define the manufacturer’s assigned ISI value, thus reporting more accurate INR results. * INR : international normalized ratio; ISI : international sensitivity index; PT : prothrombin time; aPTT : activated partial thromboplastin time; IRP : international reference preparation; DTI : direct thrombin inhibitor; MNPT : mean normal prothrombin time; AVK : vitamin K antagonists; WHO : World Health Organization; CLSI : Clinical and Laboratory Standards Institute; CAP : College of American Pathologists * Activated partial thromboplastin time (aPTT): : The time in seconds required for a fibrin clot to form in a plasma sample after a negative surface activator and optimal amount of phospholipid and calcium ions have been added to the sample. The aPTT measures the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (factors X and V, and prothrombin and fibrinogen). Calibration: : Set of operations that establishes, under specified conditions, the relationship between values of quantities indicated by a measuring instrument or measuring system, or values represented by a material measure or a reference material, and the corresponding values realized by standards. Certified plasma: : Normal or abnormal plasma samples assigned a PT/INR value by a manufacturer, using a manual method based on a WHO-accepted protocol determined against an appropriate thromboplastin international reference preparation (IRP) (or manufacturer or standard reference reagent) that has been calibrated against the appropriate WHO standard in a multicenter study. Direct thrombin inhibitor (DTI): : A class of drugs (either oral or intravenous) directly inhibiting the enzyme thrombin (without the need for a cofactor). Generic ISI: : An ISI determined for a thromboplastin that is not instrument specific (ie, determined for a group of instruments using the same general method for endpoint detection, such as manual, photo-optical, or mechanical methods). International normalized ratio (INR): : The patient’s prothrombin time (PT) test result expressed as a ratio to a mean normal prothrombin time (MNPT), which has been standardized (or normalized) for the potency of the thromboplastin used in the assay. International reference preparation (IRP): : A thromboplastin with defined biological activity used to calibrate other reference preparations and secondary or manufacturer’s standards. The thromboplastin reagent is a commercially prepared, lyophilized reagent packaged in individual 1 mL vials available from the WHO. It is usually purchased for a nominal fee by commercial manufacturers of PT reagents. Its shelf life is between 3 to 8 years. International sensitivity index (ISI): : A quantitative measure, in terms of the IRP of Human Thromboplastin, of the responsiveness of a prothrombin-time system to the defect induced by oral anticoagulants. Instrument-specific ISI: : A thromboplastin ISI generated by the reagent manufacturer specific for the particular reagent/instrument combination. Mean normal prothrombin time (MNPT): : The geometric mean of the PTs of the healthy adult population. Prothrombin time (PT): : The time in seconds required for a fibrin clot to form in a plasma sample after tissue thromboplastin and an optimal amount of calcium chloride have been added to the sample. Verification: : Confirmation through the provision of objective evidence that specified requirements have been fulfilled. Vitamin K antagonists (AVK): : A class of compounds that, when taken orally, act as AVK and, depending on the dose administered, result in diminished levels of functional factors II, VII, IX, and X, creating an in vivo anticoagulant effect. World Health Organization (WHO): : A specialized agency of the United Nations acting as a coordinating authority on international health. In regard to INR, it accepts and maintains the IRP for the standardized thromboplastin reagent for ISI assignment.