Critical values for the INR.

Q Are there established critical ranges for INR (international normalized ratio) therapy? It seems that these should be standard across methods, but we have not found any reference to this issue. It does not seem logical to take the PT (prothrombin time) critical limit (e.g., 30 seconds) and simply apply the corresponding INR value to establish a critical limit. Doing that would create as much variation as simply using the PT result itself.

A Presumably in your laboratory, a PT of 30 or more seconds would be interpreted as above the upper limit for the anticoagulation of a patient. But the 30-second value on the blood specimen is method-dependent upon the instrument and/or thromboplastin being used. So, even though your method has been performed properly, the interlaboratory variability makes for uncertainty in the interpretation of the results. Also, any comparisons with definitive studies on anticoagulation of patients with clotting problems could be problematic.

There has been a need for interlaboratory comparison of this important test. This standardization of oral anticoagulation has been a long and tedious process extending over many years. The development and now general acceptance of the INR as an alternative to the PT (in seconds) has significantly improved the anticoagulation control of patients requiring such therapy. The INR system standardizes the PT to a reference point that is comparable, regardless of the instrument or thromboplastin used. Results from different laboratories using different methods are therefore comparable. It is also important for your laboratory director to confer with the clinicians about the advantages of the INR system over the formerly reported PTs in seconds with the normal control values for the control of anticoagulation therapy. (1)

Laboratories are responsible for the accurate determination of the INR levels in patients and therefore will make sure the PT determination is properly calibrated. Thromboplastins with instrument-specific assigned ISIs (international sensitivity indices) for calibration are available from manufacturers; however, you may choose to perform an in-house calibration. (2) If you do so, you should indicate that your laboratory uses an internationally standardized method directly related to international reference material, such as those materials referenced here.

The generally accepted optimal INR therapeutic range for mild anticoagulation (e.g., in atrial fibrillation) is an INR range of 1.5 to 3.0. For moderate levels of anticoagulation (e.g., post-myocardial infarction), an INR range of 2.8 to 4.8 is recommended. The 2004 edition of the PDR (Physicians' Desk Reference) summarizes the use of Coumadin (warfarin) anticoagulation in clinical medicine. (3) Your cardiologists might prefer somewhat different INR ranges than those noted in the PDR.

Results outside these limits should be called to the attention of the attending staff since changes in warfarin dosage or other measures may be indicated. The methods for such notification vary but should be agreed upon by the laboratory and the attending physicians. These methods can vary from printout flags (H, L, or *) on the computerized laboratory reports, to telephone calls to the physician. Your institution undoubtedly has an alert system in place that was developed by your clinical pathologist with the medical staff.

References

1. Koepke, JA. Role of the physician in the coagulation laboratory. In: Lewis SM, Koepke JA, eds. Hematology Laboratory Management and Practice. Oxford, UK: Butterworth-Heinemann, Ltd.; 1995:20-28.

2. Brien, WF, Crawford L, Raby A, Richardson H. In-house calibration of the International Sensitivity Index or calibration curve for the determination of the International Normalized Ratio. Arch Pathol Lab Med. 2004;128:308-312.

3. Coumadin (Warfarin). 2004 Physicians' Desk Reference. 58th ed. Montvale, NJ: Thomson Healthcare; 2003:1048-1052.

--John A. Koepke, MD

Professor Emeritus of Pathology

Duke University Medical Center

Durham, NC