Download PDF
Semin Thromb Hemost 2008; 34(7): 593-603
DOI: 10.1055/s-0028-1104538
© Thieme Medical Publishers

Standardization of the INR: How Good Is Your Laboratory's INR and Can It Be Improved?

Emmanuel J. Favaloro1 , Dorothy M. Adcock2
  • 1Department of Haematology, ICPMR, Westmead Hospital, Westmead, Australia
  • 2Medical/Laboratory Director, Esoterix Coagulation, Englewood, Colorado
Further Information

Publication History

Publication Date:
15 December 2008 (online)

    Permissions and Reprints

ABSTRACT

The prothrombin time (PT) assay is the most clinically ordered coagulation test and is most often used for monitoring of vitamin K antagonist (VKA) therapy (e.g., warfarin), where results are expressed as an international normalized ratio (INR). The INR is in essence the patient's PT “mathematically adjusted” to a standardized value by taking into account the peculiarities of the test system through applying two “correction factors” defined by an international sensitivity index (ISI) and mean normal prothrombin time (MNPT). Although some manufacturers provide assigned ISI values for specific PT reagents and instrumentation, it is still recommended practice that laboratories check or locally validate these ISIs, as well as estimate the MNPT based on the population being tested. Where a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. Current recommendations suggest the use of commercial reference-plasma calibration sets, but there is limited information to validate their performance in laboratory practice. We report our personal experience with use of some of these materials, as well as review alternate or supplementary procedures for calibration and/or validation of ISI and for determination and validation of MNPT. In brief, our data and experience suggests that further verification checks should be performed prior to acceptance of ISI and MNPT estimates generated from commercial reference-plasma calibration sets. We detail various strategies to ensure that laboratory practices are optimized to provide INRs that accurately reflect a patient's true anticoagulant status and to thus assist their clinical therapeutic management.

KEYWORDS

Prothrombin time - international normalized ratio - international sensitivity index - mean normal prothrombin time - standardization

REFERENCES

  • 1 Gallus A S. Management options for thrombophilias.  Semin Thromb Hemost. 2005;  31 118-126
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa.  Semin Thromb Hemost. 2008;  34 39-57
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Medicare Australia .Australian Medicare statistics. Available at: http://www.medicareaustralia.gov.au/statistics/dyn_mbs/forms/mbs_tab4.shtml Accessed May 4, 2008
    Google Scholar
  • 4 Australian Bureau of Statistics .Australian population statistics. Available at: http://www.abs.gov.au/ Accessed May 4, 2008
    Google Scholar
  • 5 Kitchen S, Preston F E. Standardisation of prothrombin time for laboratory control of oral anticoagulant therapy.  Semin Thromb Hemost. 1999;  25 17-25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Guidelines on oral anticoagulation: third edition.  Br J Haematol. 1998;  101 374-387
    CrossrefPubMedGoogle Scholar
  • 7 Baglin T P, Keeling D M, Watson H G. British Committee for Standards in Haematology . Guidelines on oral anticoagulation (warfarin): third edition – 2005 update.  Br J Haematol. 2006;  132 277-285
    CrossrefPubMedGoogle Scholar
  • 8 Adcock D M, Brien W F, Duff S L et al.. Procedures for Validation of INR and Local Calibration of PT/INR Systems; Approved Guideline. Nt H54-A, Vol. 25, No. 23 (replaces H54-P, Vol. 24, No. 30). Wayne, PA; Clinical and Laboratory Standards Institute 2005
    Google Scholar
  • 9 Adcock D M, Duff S. Enhanced standardization of the international normalized ratio through the use of plasma calibrants: a concise review.  Blood Coagul Fibrinolysis. 2000;  11 583-590
    CrossrefPubMedGoogle Scholar
  • 10 McGlasson D L. A comparison of INRs after local calibration of thromboplastin international sensitivity indexes.  Clin Lab Sci. 2002;  15 91-95
    PubMedGoogle Scholar
  • 11 Kearon C, Kahn S R, Agnelli C, Goldhaber S, Rascob G, Comerota A J. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Practice Guidelines; 8th edition.  Chest. 2008;  133 454S-545S
    CrossrefPubMedGoogle Scholar
  • 12 Stevenson K J, Craig S, Dufty J MK, Taberber D A. System ISI calibration: a universally acceptable scheme is possible only when coumarin plasma calibrants are used.  Br J Haematol. 1997;  96 435-441
    CrossrefPubMedGoogle Scholar
  • 13 Expert WHO Committee on Biological Standardization .Requirements for Thromboplastins and Plasmas Used to Control Oral Anticoagulant Therapy. 33rd report, WHO Technical Report Series. Geneva, Switzerland; World Health Organization 1983 687: 81-105
    Google Scholar
  • 14 Adcock D M, Johnston M. Evaluation of frozen plasma calibrants for enhanced standardization of the international normalized ratio (INR): a multicenter study.  Thromb Haemost. 2002;  87 74-79
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Fareed J, Hoppensteadt D A, Fareed D et al.. Survival of heparins, oral anticoagulants, and aspirin after the year 2010.  Semin Thromb Hemost. 2008;  34 58-73
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Lippi G, Franchini M, Montagnana M, Guidi G C. Genomics and proteomics in venous thromboembolism: building a bridge toward a rational personalized medicine framework.  Semin Thromb Hemost. 2007;  33 759-770
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Kelton J G, Hirsh J. Bleeding associated with antithrombotic therapy.  Semin Hematol. 1980;  17 259-291
    PubMedGoogle Scholar
  • 18 Hirsh J. Is the dose of warfarin prescribed by American physicians unnecessarily high?.  Arch Intern Med. 1987;  147 769-771
    CrossrefPubMedGoogle Scholar
  • 19 Poller L. International normalized ratio (INR): the first 20 years.  J Thromb Haemost. 2004;  2 849-860
    CrossrefPubMedGoogle Scholar
  • 20 Favaloro E J, Lippi G, Adcock D. Preanalytical and postanalytical variables: the leading causes of diagnostic error in hemostasis?.  Semin Thromb Hemost. 2008;  34 612-634
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Favaloro E J, Hamdam S, McDonald J, McVicker W, Ule V. Time to think outside the box? Prothrombin time (PT), international normalised ratio (INR), international sensitivity index (ISI), mean normal prothrombin time (MNPT) and measurement of uncertainty (MU): a novel approach to standardisation.  Pathology. 2008;  40 277-287
    CrossrefPubMedGoogle Scholar
  • 22 Poller L, Thompson J M, Taberner D A, Clarke D K. The correction of coagulometer effects on the international normalized ratio.  Br J Haematol. 1994;  86 112-117
    CrossrefPubMedGoogle Scholar
  • 23 Ray M J, Smith I R. The dependence of the international sensitivity index on the coagulometer used to perform the prothrombin time.  Thromb Haemost. 1990;  63 424-429
    PubMedGoogle Scholar
  • 24 Poller L, Triplett D A, Hirsh J, Carroll J, Clarke K. A comparison of lyophilized artificially depleted plasmas and lyophilized plasmas from patients receiving warfarin in correcting for coagulometer effects on international normalized ratios.  Am J Clin Pathol. 1995;  103 366-371
    PubMedGoogle Scholar
  • 25 van Rijn J L, Schmidt N A, Rutten W P. Correction of instrument and reagent based differences in determination of the international normalized ratio (INR) for monitoring anticoagulant therapy.  Clin Chem. 1989;  35 840-843
    CrossrefPubMedGoogle Scholar
  • 26 Ebert R F. PTs, ISIs and INRs: a primer on prothrombin time reporting.  Clin Hemost Rev. 1994;  7 1-20
    PubMedGoogle Scholar
  • 27 World Health Organization .Annex 3 – Guidelines for Thromboplastins and Plasma Used to Control Anticoagulant Therapy. WHO Technical Report Series No. 889. Geneva, Switzerland; World Health Organization 1999: 64-93
    Google Scholar
  • 28 Loeliger E A, van den Besselar A MPH, Lewis S M. Reliability and clinical impact of the normalization of the prothrombin times in oral anticoagulant control.  Thromb Haemost. 1985;  53 148-154
    PubMedGoogle Scholar
  • 29 Cunningham M T, Johnson G F, Pennel B J, Olsen J D. The reliability of manufacturer-determined instrument-specific international sensitivity values for calculating the international normalized ratio.  Am J Clin Pathol. 1994;  102 128-133
    PubMedGoogle Scholar
  • 30 Ng V L, Levin J, Corash L, Gottfried E L. Failure of the international normalized ratio to generate consistent results within a local medical community.  Am J Clin Pathol. 1993;  99 689-694
    PubMedGoogle Scholar
  • 31 Clarke K, Taberner D A, Thomsom J M, Morris J A, Poller L. Assessment of the value of calibrated lyophilized plasmas to determine international sensitivity index for coagulometers.  J Clin Pathol. 1992;  45 58-60
    CrossrefPubMedGoogle Scholar
  • 32 Fairweather R B, Ansell J, van den Besselaar A MHP et al.. College of American Pathologists Conference XXXI on laboratory monitoring of oral anticoagulant therapy.  Arch Pathol Lab Med. 1998;  122 768-781
    PubMedGoogle Scholar
  • 33 Barowcliffe T W, ven den Besselaar A MHP et al. Guidelines for Preparation, Calibration and Use of Calibrated Plasmas for ISI and INR Determination. ISTH Subcommittee on Control of Anticoagulation Maastricht, The Netherlands; International Society of Thrombosis and Hemostasis 2000
    Google Scholar
  • 34 Johnston M, Brigden M. A cross–Canada survey of prothrombin time testing. Does the establishment of local ISI values improve the accuracy of international normalized ratio reporting?.  Am J Clin Pathol. 1998;  110 683-690
    PubMedGoogle Scholar
  • 35 Brien W F, Baskerville J C, Taberner D A, Crawford L. Calculation vs. calibration curve for INR determination. Results of an interlaboratory proficiency scheme.  Am J Clin Pathol. 1999;  111 193-201
    CrossrefPubMedGoogle Scholar
  • 36 Chantarangkul V, Tripodi A, Cesana B M, Manucci P M. Calibration of local systems with lyophilized calibrant plasmas improves interlaboratory variability of the INR in the Italian external quality assessment scheme.  Thromb Haemost. 1999;  82 1621-1626
    PubMedGoogle Scholar
  • 37 van den Besselaar A M. Comparison of lyophilized plasmas with fresh plasmas for calibration of thromboplastin reagents in oral anticoagulant control.  Br J Haematol. 1996;  93 437-444
    CrossrefPubMedGoogle Scholar
  • 38 Dufty J MK, Craig S, Stevenson K J, Taberner D A. Calculation of system international sensitivity index: how many calibrant plasmas are required?.  J Clin Pathol. 1997;  50 40-44
    CrossrefPubMedGoogle Scholar
  • 39 Hubbard A R, Margetts S MA, Barrowcliffe T W. International normalized ratio determination using calibrated reference plasmas.  Br J Haematol. 1997;  98 74-78
    CrossrefPubMedGoogle Scholar
  • 40 Duncan E M, Casey C R, Duncan B M, Lloyd J V. Effect of concentration trisodium citrate on calculation of the international normalized ratio and the international sensitivity index.  Thromb Haemost. 1994;  72 84-88
    PubMedGoogle Scholar
  • 41 Arkin C F. Do we need the geometric mean as the mean normal value in INR determination?.  J Thromb Hemost. 2005;  3(Suppl 1) , abstract 1903
    PubMedGoogle Scholar
  • 42 Marlar R A. Determining the model for end-stage liver disease with better accuracy: neutralizing the international normalized ratio pitfalls.  Hepatology. 2007;  46 295-296
    CrossrefPubMedGoogle Scholar
  • 43 Tripodi A, Chantarangkul V, Primignani M et al.. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation.  Hepatology. 2007;  46 520-527
    CrossrefPubMedGoogle Scholar
  • 44 Bellest L, Eschwège V, Poupon R, Chazouillères O, Robert A. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology.  Hepatology. 2007;  46 528-534
    CrossrefPubMedGoogle Scholar
  • 45 Tripodi A. How to implement the modified international normalized ratio for cirrhosis (INR(liver)) for model for end-stage liver disease calculation.  Hepatology. 2008;  47 1423-1424
    CrossrefPubMedGoogle Scholar

Emmanuel J FavaloroPh.D. M.A.I.M.S. 

Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR)

Westmead Hospital, SWAHS, Westmead, NSW 2145, Australia

Email: emmanuel.favaloro@swahs.health.nsw.gov.au