Biomedical subjects
Publications and source records attributed to E A Loeliger.
The modified (and thereby simplified) thromboplastin calibration procedure using pooled lyophilized normal and patient plasmas is shown to equal, for batch-to-batch control of Thrombotest, the calibration procedure described by Biggs and Denson, which makes use of individual freshly prepared patient plasmas.
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Long-term stability of the WHO International Reference Preparation (IRP) of thromboplastin 67/40 and of two secondary preparations, WHO IRP 68/434 and the Dutch RP 73/528 was assessed by two criteria on the basis of the basis of data obtained in the period 1969-79. The clotting times of normal plasmas determined with these preparations over this 10 year period did not show changes which were of practical importance. Moreover, the slopes of the lines relating clotting-time ratios of 67/40 to ratios obtained with 68/434 or 73/528 did not give any firm reasons to assume a systematic change of these slopes with time. These lines were determined by linear regression analysis of individual patient ratios. Corrections were applied to the original data for modifications of the assay technique made during the past 10 years.
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We investigated two cases of recurrent jaundice, both involving repeated exposure to phenprocoumon and suggestive of coumarin-induced hepatitis. The first patient showed the histologic picture of cholestasis during the second bout of jaundice, the other that of chronic aggressive hepatitis. In both patients, the hepatitis appearance disappeared after termination of the first exposure to the coumarin drug, in the first case without additional drug therapy. In the second case, prednisone therapy was instituted when phenprocoumon administration was withdrawn. In both cases, hepatopathy recurred after reexposure to the drug. In one of these patients, and with his consent, a third bout of jaundice was provoked with phenprocoumon.
For patients on oral anticoagulation controlled with Quick's prothrombin time test using rabbit brain thromboplastin American clinicians proposed in the early 1940s that the lower limit of prolongation be taken at 1.5 and the upper limit at 3, corresponding to 10-30% prothrombin activity on a saline dilution curve. Thromboplastins derived from other tissues and species were later introduced, methods were modified, and adsorbed plasma was used instead of saline in the construction of the dilution curve to obtain percentage prothrombin activity; ratios and percentages lost their initial significance, but too often without the clinicians' awareness. With the detection of PIVKAs, finally, it became clear that transformation of prothrombin times into percentage activity, as obtained from dilution curves, could never be a valid means of standardization. It also became evident that only direct comparison of thromboplastins with (fresh) plasma from patients on stabilized oral anticoagulants could be used to determine equivalent therapeutic ranges for different types of thromboplastins. Reference thromboplastins were established and calibration procedures developed. A series of well-controlled clinical trials has provided sufficient information to define, in terms of these reference thromboplastins, therapeutic ranges for the prophylaxis and treatment of venous as well as arterial thrombosis. Definition of the ranges in terms of the biochemical defect induced by coumarin congeners remains, however, to be established.
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Results obtained with the original calibration procedure of Biggs and Denson obtained by one expert laboratory compare well with those obtained from the ICTH/ICSH collaborative study. The simplified calibration procedure described in 1975 should only be used for the assessment of inter-batch variability of a given brand of thromboplastin; for the calibration of unlike thromboplastins, the simplified procedure should be revised by using more than two abnormal plasmas, e.g. different plasmas representing seven levels of anticoagulation between international calibrated ratios (ICRs) from 1.5 to 4.5. The formula for the calculation for the proposed ICRs based on the calibration constant should be modified to allow for instances where the calibration line for dissimilar thromboplastins, fitted in the therapeutic range, does not pass through the origin of ratio 1,1.
Two spectrophotometric assays for prothrombin have been developed and compared with a one stage coagulant and an immunological assay. One of these assays (called the XAPC assay) uses a combination of factor Xa, phospholipid, Ca2+ and factor V as activator of prothrombin, and measures only normal prothrombin. The second (the ECAR assay) uses Echis carinatus venom as activator. This assay measures both normal prothrombin and PIVKA II (protein induced by vitamin K antagonists/absence). Combination of the results obtained by the XAPC and ECAR assays provides rapid and reliable information on the degree of "subcarboxylation" of prothrombin (oral anticoagulation, vitamin K deficiency). For patients on long term anticoagulant treatment the prothrombin time (Thrombotest) shows better correlation with the ratio prothrombin/prothrombin plus PIVKA II (XAPC/ECAR) than with the factor II concentration. For patients starting the anticoagulant treatment there is no correlation between the Thrombotest time and the XAPC/ECAR ratio. It seems doubtful that (a) spectrophotometric factor II assay(s) will be as useful as the prothrombin time in the control of oral anticoagulation.
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Standardization of the thromboplastin most commonly used for anticoagulant control in The Netherlands has been achieved by the Dutch Reference Laboratory for Anticoagulant Control. The system established for control indicates the performance characteristics of each batch of thromboplastin in patients relative to a national calibration batch. Calibration constants were assessed according to an ICTH/ICSH proposal and with a reproducibility of approximately 2% (CV). With the use of a given calibration constant of the International Reference Preparation of Thromboplastin (1.0) and after assessment of the calibration constant of the National Reference Preparation in international terms (0.93), the accuracy of calibration with the various modifications of the calibration procedure is of the order of magnitude of 3% (CV). On the basis of the calibration protocol, physicians will be provided with correlation tables containing, for their convenience, prothrombin (thromboplastin) times in terms of the reference thromboplastin (uniform, i.e., batch-independent, prothrombin times), conventional prothrombin activity (percentages), and in due course with International Calibrated Ratios. With this approach current practice in the prescription of oral anticoagulants will be maintained. Opportunity is given, however, to aim at internationally proposed therapeutically optimal target values.
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Successful prevention of the progression of incipient hemorrhagic skin necrosis by timely administration of vitamin K1 in a woman treated with phenprocoumon is presented. From a critical review of the literature strong evidence emerges that coumarin necrosis does only occur in cases with severe initial drug induced hypocoagulability. Non- recognition thusfar of its importance is due to insufficient knowledge of the biological activities of thromboplastin preparations presently used in the laboratory control of oral anticoagulation. All well documented cases with apparently adequate Quick values were monitored with Faktor VIII insensitive thromboplastin. Therefore, such preparations should no longer be used in anticoagulant control.
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