Optimal therapeutic range for oral anticoagulants.
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Biomedical subjects
Publications and source records attributed to L Poller.
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The WHO international scale of reporting prothrombin time results is based on the calibration of local and commercial thromboplastin reagents used in the test against an international reference preparation to derive an International Sensitivity Index (ISI) for each batch of local reagent. This quantifies an individual reagent's responsiveness to the coumarin induced defect. Once the ISI has been assigned, the derivation of International Normalised Ratios (INR) for reporting results depends on the use of a scientific calculator by which the local ratio is raised to the power of the ISI of the local reagent or use of an alternative formula and logarithms. A system for interpretation of INR, without the need for calculations, is presented for the known range of thromboplastins between 1.0 and 3.0 ISI in nomogram form. This chart may facilitate the general application of the INR system.
The reliability of the international normalized ratios (INR) system in the induction phase of coumarin administration has been studied in 15 serial patients over the first 7-40 days of treatment (mean 13.1). The INR results obtained with a variety of thromboplastin reagents have been compared with those obtained with the WHO second primary IRP, BCT/253. A wide divergence of INR values was observed with the various thromboplastins on each day of testing. INR values cannot therefore be relied upon with some of these reagents in the early days of anticoagulant treatment. This probably arises from the difference in responses of the thromboplastins to depression of vitamin K-dependent clotting factors. Consistent deviations from the IRP suggested that additional error may be due to inaccurate calibration of their products by the manufacturers. When the slopes of the sensitivity of the individual reagents to clotting factors II, VII and X were compared, however, results overall more closely approximated to those of the IRP when the INR were substituted for simple prothrombin ratios.
National External Quality Assessment Scheme surveys on the prothrombin time test carried out in hospitals in the United Kingdom have been performed at regular intervals since 1972. Performance has been assessed by comparing observed variability between hospitals with that predicted by a statistical model. The model was based on results from 53 survey plasmas issued between 1980 and 1987. These showed a linear correlation between logarithms of mean and standard deviation of reported ratios. Precision improved until the human brain thromboplastin, Manchester Comparative Reagent, was withdrawn in January 1986. There then followed a pronounced overall deterioration which, by October 1987, had not corrected to the levels achieved by 1985. When the recent results from 1986-87 were analysed according to Quick test reagent only one reagent (ISI 1.1) showed an improvement in precision. Performance of the other Quick test reagents, all with higher ISI values, had not regained the standards of precision previously achieved by the human brain reagent.
A prospective study was carried out to see whether a small fixed dose of warfarin (1 mg daily) given before operation (mean 20 days) would prevent deep vein thrombosis in patients having major gynaecological surgery. One hundred and four patients were randomised into three groups: fixed minidose warfarin; full dose oral anticoagulation; and no treatment (controls). There was a significantly lower incidence of deep vein thrombosis in the minidose warfarin and full dose anticoagulant treatment groups (9% (3/32) and 3% (1/35) respectively) than in the controls (30%; 11/37) but no significant difference between the two anticoagulant treatment groups. Prothrombin time and the activated partial thromboplastin time were normal on the day of surgery in the warfarin treatment group, whereas times were prolonged in the group given full dose anticoagulation. Mean haemoglobin concentrations fell in all three groups after operation but the fall was significantly less in the minidose warfarin treatment group than after full dose anticoagulation. The benefit from full dose oral anticoagulant prophylaxis, based on a preoperative international normalised ratio of 1.5-2.5 with rabbit brain Manchester reagent, was similar to the protection achieved in an oral anticoagulant treatment group controlled with human brain Manchester comparative reagent at a similar level of anticoagulation. The lack of disturbance of normal haemostasis at the time of operation together with a significant reduction in deep vein thrombosis may encourage surgeons to introduce minidose prophylaxis with warfarin.
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Protein C activity and antigen levels have been related to clotting activities of factors VII and X during the induction and withdrawal periods of oral anticoagulant treatment. Both factor VII and protein C activities fell rapidly during induction but factor VII showed a more rapid and much more marked depression than protein C. In contrast, reductions in factor X were much slower. Protein C antigen, although depressed rapidly at the initiation of treatment, did not subsequently fall to the same degree as protein C activity. The ratio of activity to antigen became progressively smaller. On discontinuation there was a reversal of the pattern but with two important differences. Firstly, there was evidence of an excessive rise ('rebound') of factor VII compared with the steady state levels in these patients; and secondly there was a surprisingly slow return of protein C to normal levels after the oral anticoagulant was withdrawn (levels were still below normal on day 4). These observations lend support to gradual withdrawal of oral anticoagulants after a period of long-term administration. The results suggest that after discontinuation of long-term anticoagulants patients may have increased coagulability up to four days.
An international collaborative exercise has been undertaken to calibrate a secondary international reference preparation (IRP) of thromboplastin on behalf of the International Committee for Standardization in Haematology (ICSH). This preparation of British Comparative Thromboplastin (BCT/441) is required because supplies of the WHO primary IRP (BCT/253) are necessarily limited. The calibration was performed at seven centres with only a small degree of interlaboratory variation. As a result of this study an ISI value of 1.04 has been assigned to the preparation. Opportunity was also taken to assess the reliability of a simplified calibration based on lyophilised plasmas. The results of the latter appeared reliable. BCT/441 will be available to officially designated National Control Laboratories for calibration of local thromboplastins to promote prothrombin time standardization in oral anticoagulant control.
Wide variations in procoagulant properties, lipid composition and ultrastructure of five commonly used APTT methods have been demonstrated. Performance of the methods with a range of coagulation abnormalities has been ranked. Most of the reagents obtained a high score with one or more defects, but a low score with others. A consistent good ranking throughout was only observed with one reagent. The number of significant correlations between the reagents' procoagulant activities and lipid content confirms the view that the performance of an APTT method is largely dependent upon its lipid composition. Marked differences in concentration and distribution of phospholipids, fatty acids and neutral lipids were evident. The importance of the concentration of phosphatidyl serine in regulating the procoagulant activity of an APTT method has been demonstrated. Electron microscopy provides evidence of the contrasting composition of the reagents from the more discrete uniform liposomes present in the more reliable reagents, to more ill-defined components present in those reagents which performed less well. The study highlights the need for standardisation of the APTT.
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One of the reasons why oral anticoagulants fell into disrepute is the absence of internationally accepted standardised procedures for controlling the level of anticoagulation. This deplorable situation resulted in over- and under-coagulation and uncertainty in the therapeutic range. International conformity can now be obtained by using an International Normalised Ratio (INR) which is derived from the individual result obtained in a given plasma sample and the International Sensitivity Index (ISI) of the tissue thromboplastin reagent used. Any thromboplastin reagent can be calibrated against an international primary or secondary W. H. O. reference preparation, so as to obtain its International Sensitivity Index. The new system of reporting the level of anticoagulation was designed and can only safely be applied in patients taking oral anticoagulants.
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An international collaborative exercise has been undertaken to calibrate a replacement for the first WHO primary international reference preparation (IRP) for thromboplastin. The replacement preparation is a lyophilised batch of British Comparative Thromboplastin (BCT/253, human plain) for use in the Quick prothrombin time test. Seventeen centres participated. The experimental design, calibration model and statistical analysis were based on the recommended WHO procedure. As a result of this calibration exercise an International Sensitivity Index (ISI) of 1.1 has been assigned to the preparation by WHO and it has been officially recognised as the second primary IRP for thromboplastin. The calibration of BCT/253 is an essential link in a new hierarchical structure for the standardisation of the prothrombin time. The aim is to provide a uniform international system of reporting prothrombin time results using International Normalised Ratios (INR) derived from the ISI of individual thromboplastins.