Thromboplastin Related Differences in the Determination of International Normalised Ratio: A Cause for Concern?

Summary

When the International Normalised Ratio (INR) is used for control of oral anticoagulant therapy the same result should be obtained irrespective of the laboratory reagent used. However, in the UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation INRs determined using different reagents have been significantly different.

For 18 NEQAS samples Manchester Reagent (MR) was associated with significantly lower INRs than those obtained using Diagen Activated (DA, p = 0.0004) or Instrumentation Laboratory PT-Fib HS (IL, p = 0.0001). Mean INRs for this group were 3.15, 3.61, and 3.65 for MR, DA, and IL respectively. For 61 fresh samples from warfarin-ised patients with INRs of greater than 3.0 the relationship between thromboplastins in respect of INR was similar to that observed for NEQAS data. Thus INRs obtained with MR were significantly lower than with DA or IL (p <0.0001). Mean INRs for this group were 4.01, 4.40, and 4.59 for MR, DA, and IL respectively.

We conclude that the differences between INRs measured with the thromboplastins studied here are sufficiently great to influence patient management through warfarin dosage schedules, particularly in the upper therapeutic range of INR. There is clearly a need to address the issues responsible for the observed discrepancies.

• References

• 1 Loeliger LA. Van den Besselaar AMHP, Broekmans AW. Intensity of oral anticoagulation in patients monitored with various thromboplastins. N E J Med 1983; 308: 1228-9
• 2 Jennings N, Kennedy DA, Skinner RK. An evaluation of 5 commercial rabbit brain thromboplastins. Supplies Technology Division, NHS Procure-ment Directorate 1987; UK DHSS STD 87-12
• 3 Denson KWE. Thromboplastin - sensitivity, precision and other character-istics. Clin Lab Haem 1988; 10: 315-28
• 4 WHO Expert Committee on Biological Standardisation. Thirty third report WHO Technical Report Series 1983; 687: 81-105
• 5 Hermans J, Van den Besselaar AMHP, Loeliger EA, Van der Velde EA. A collaborative study of reference materials for thromboplastins. Thromb Haemost 1983; 50: 712-717
• 6 Kirkwood TBL. Calibration of reference thromboplastins and standardisa-tion of the prothrombin time ratio. Thromb Haemost 1983; 49: 238-214
• 7 Hirsh J, Levine M. Confusion over the therapeutic range for monitoring oral anticoagulant therapy in North America. Thromb Haemost 1988; 59: 129-132
• 8 Bussey HI, Force FW, Bianco TM, Leonard AD. Reliance on prothrombin time ratio causes significant error in anticoagulant therapy. Arch Intern Med 1992; 152: 278-282
• 9 Ansell JD. Imprecision of prothrombin time monitoring of oral anticoag-ulation: A survey of hospital laboratories. A J Clin Path 1992; 98: 237-239
• 10 Hirshe J. Substandard monitoring of warfarin in North America: Time for change. Arch Int Med 1992; 152: 257-258
• 11 Loeliger EA, Van den Besselaar AMHP, Lewis SM. Reliability and clinical impact of the normalisation of the prothrombin times on oral anticoagulant control. Thromb Haemost 1985; 53: 148-154
• 12 Poller L, Tabener DA, Thompson JM, Morris J, Mibasham RS, Shinton NK. Effect of the choice of WHO International Reference Preparation for thromboplastin on INR. J Clin Path 1993; 46: 64-66
• 13 van den Besselaar AMHP, Lewis SM, Mannucci PM, Poller L. on behalf of the Subcommittee. Status of present and candidate International Reference Preparations (IRP) of thromboplastin for the prothrombin time. Thromb Haemost 1993; 69-85
• 14 van den Besselaar AMHP. Multi-center study of replacement of the Inter-national Reference Preparation for thromboplastin, Rabbit, Plain. Thromb Haemost 1993; 70: 794-799
• 15 van den Besselaar AMHP, Bertina RM. Multi-center calibration of the sec-ondary reference material for thromboplastin, Rabbit, Plain, Coded CRM 149R. Thromb Haemost 1991; 65: 263-267
• 16 Thompson JM, Tabener DA, Poller L. Automation and prothrombin time: a United Kingdom field study of two widely used coagulometers. J Clin Path 1990; 43: 679-84
• 17 Poggio M, van den Besselaar AMHP, van der Velde EA, Bertina RM. The effects of some instruments for prothrombin time testing on the Internation-al Sensitivity Index (ISI) of two rabbit tissue thromboplastin reagents. Thromb Haemost 1988; 62: 868-874
• 18 D’Angelo A, Seveso MP, D’Angelo SV, Gilardoni F, Macagni A, Manotti C. Comparison of two automated coagulometers and the manual tilt tube method for the determination of prothrombin time. Amer J Clin Path 1989; 92: 321-328
• 19 Poller L, Thompson JM, Tabener DA. Effect of automation on the pro-thrombin time test in NEQAS surveys. J Clin Path 1989; 42: 097-100
• 20 van Rijn JLML, Schmidt NicoA, Rutten W. Correction of instrument and reagent based differences in determination of the International Normalised Ratio for monitoring anticoagulant therapy. Clin Chem 1989; 355: 840-843
• 21 Ray MJ, Smith IR. The dependence of the International Sensitivity Index on the coagulometer used to perform the prothrombin time. Thromb Haemost 1990; 63: 424-429