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Research Applied to Clinical Practiceimgtchr1.gif (1235 bytes)
by Robert C. Knies, RN MSN CEN
Section Editor

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International Normalized Ratio (INR)
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    More than 2 million Americans are estimated to be treated with warfarin (National Center for Statistics, 1984). As with any medical treatment the weighing of risks and benefits must be carefully balanced. Anticoagulation agents have a narrow therapeutic index, and the more narrow the therapeutic index, the greater the chance for adverse effects, i.e., bleeding (Ortel, 1995). To achieve optimal effects and evaluate the patient's response to warfarin, the clinician must keep in mind several important concepts. First, the intensity and duration of the therapy depends on the identified need for treatment. Second, the dose of warfarin must be patient specific, and lastly, periodic assessment of effectiveness is necessary due to warfarin's narrow therapeutic index. Considering the aforementioned facts, the blood test chosen to monitor the patient's response to warfarin must be accurate, reliable and cost effective (Ortel, 1995).

    The traditional method of determining the efficacy of anticoagulation therapy is the prothrombin time (PT). This was first described by Armand J. Quick in 1935. He used thromboplastin derived from rabbit brains to prove his assumption that patients with bleeding abnormalities secondary to obstructive jaundice was due to a deficiency of prothrombin. This is now know to result from reduced levels of liver-produced vitamin K-dependent blood coagulation factors II, IX, and X (Florell & Rodgers, 1996).

    Today a blood sample is collected in a tube containing citrated sodium, in the laboratory the sample is spun in a centrifuge, and a specific volume of thromboplastin reagent is added to the sample. The time until a fibrin clot forms, measured in seconds, is reported as the PT (Ortel, 1995). The thromboplastin reagent can be either an extract of mammalian tissue (lungs heart or brain of animals) rich in tissue factor, or a recombinant proportion of human tissue factor in combination with phospholipids (Hirsh & Poller, 1994).

    Because thromboplastins are produced using different methods and from different sources, the sensitivity of an individual thromboplastin to another can vary greatly. The more sensitive the thromboplastin reagent the longer the resulting PT. Conversely, the less sensitive the reagent the shorter the resulting PT. Variance can even occur within a single batch depending on shelf time (Ortel, 1995). This variability in sensitivity and its effect on PT outcomes can have a major detrimental effects on the management of warfarin therapy in patients requiring anticoagulation. This variability has also caused great international debate and concern for several decades (Florell & Rodgers, 1996).

    To help standardize this difference two formats were developed, the first was the International Sensitivity Index (ISI) and the second was the International Normalized Ratio (INR). The INR was developed to incorporate the ISI values and attempt to make PT results uniformly useable. The manufacturers assign an ISI to each batch of reagent after comparing each batch to a "working reference" reagent preparation. This "working reference" has been calibrated against internationally accepted standard reference preparations which have an ISI value of 1.0 (Ortel, 1995). By definition, the more sensitive thromboplastin have an ISI of less than 1.0 and the less sensitive are greater than 1.0. The ISI value is critical for calculation of the INR, because the ISI value is the exponent in the formula. Consequently, small errors in the ISI assignment may affect the calculated INR substantially (Florell & Rodgers, 1996).

    To resolve the problem of highly variable PTs, the use of the INR has been recommended for monitoring patient's oral anticoagulant therapy. This recommendation is supported by the American College of Chest Physicians, the National Heart, Lung and Blood Institute and the British Society for Hematology (Nichols & Bowie, 1993).

    It is important to emphasize that the INR is not a new laboratory test. It is simply a mathematical calculation that corrects for the variability in PT results attributable to the variable sensitivities (ISI) of the thromboplastin agents used by laboratories.

INR = - patient PT______ ISI



Mean normal PT

PTR- is the prothrombin time ratio, which is the patient's observed PT (in seconds) divided by each laboratory's calculated mean normal PT (in seconds) (Ortel, 1995, Florell & Rodgers, 1996).

    A target INR range of 2.0 to 3.0 is recommended for most indications, such as treatment or prophylaxis of DVT, prevention of further clotting in MI's and other preventive measures for patients with atrial fibrillation. An INR of 2.5 to 3.5 is recommended for patients with prosthetic heart valves (Ortel, 1995).

    Using the INR in other medical conditions, such as coagulopathy or liver disease has not been deemed appropriate as of this time, because INR was originally developed using anticoagulated patient populations. Despite its usefulness during routine monitoring of warfarin therapy, the use of INR for monitoring during the induction phase of therapy has not been fully supported (Hirsh & Poller, 1994). Reliability is lost during the initial days of therapy because of the varying rates of plasma clearance of vitamin K-dependent clotting factors. These factors are what the thromboplastin reagents are sensitive to and in turn what the INR and PTR are actually reporting. In addition, individual thromboplastin reagents vary in their sensitivities to the vitamin K-dependent clotting factors (Ortel, 1995).

    The INR system can be precise and valid when a sensitive thromboplastin and manual method of clot detection are used. However, it loses precision and accuracy when used to convert PT ratios obtained with less-sensitive thromboplastin reagents or when automated clot detection systems are used. These problems can be avoided by using reagents with low ISI's and proper calibration of machinery.

    Although the INR system is far from perfect, it is the only practical solution currently available. With all of its faults, it is much better than an unadjusted PT system. Although the clinician would like a system with little or no variability, the goal is unattainable unless a standardized sensitive reagent is universally adopted.


Florell, S.R. & Rodgers, G.M. (December,1996). The PT and the pendulum. American Journal of Clinical Pathology, 699-700.
Hirsh, J. & Poller, L. (1994). International normalized ratio: A guide to understanding and correcting its problems. Archives of Internal Medicine, 154, 282-288.
National Center for Health Statistics, Cypress, B.K. (September, 1984). Patterns of ambulatory care in internal medicine. The National Ambulatory Care Survey, United States, January 1980-December 1981. Vital and Health Statistics, Series 13, no. 80. DHHS Pub. No. (PHS) 84-1741. Public Health Service. Washington D.C.: U.S. Government Printing Office.
Nichols, W. L. & Bowie, E. J. W. (1993). Standardization of the prothrombin time for monitoring orally administered anticoagulant therapy with use of the international normalized ration system. Mayo Clinical Procedure, 68, 897-898.
Ortel, L.B. (1995). International normalized ratio (INR); An improved way to monitor oral anticoagulant therapy. Nurse Practitioner, 20 (9), 15-22.

"Research Applied to Clinical Practice: International Normalized Ratio (INR)"
is a webarticle by  Robert C. Knies, RN MSN CEN [[email protected]]
©Robert C. Knies, RN MSN CEN
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