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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.

This paper reviews current methods of standardizing laboratory investigations in blood clotting, points out their shortcomings, and suggests ways of improving them. Procedures requiring standardization include the diagnosis of haemorrhagic diathesis and thrombotic tendency; the quantification of liver function; and monitoring of the effect of haemostatic replacement therapy and therapeutic anticoagulation. Care in collecting, storing, and handling blood for investigation is of primary importance. Achievements in the standardization of reagents are reviewed and examples of standardized methods are given. Although knowledge of the haemostatic process and experimental methods for its investigation have reached an advanced stage, their clinical application is still unsatisfactory owing to the inadequacy of national and international regulations. To improve the situation, one or more internationally approved laboratories for standardization and quality control, operating according to rules elaborated by experts in the field, should be designated in each country. The need for international reference laboratories is urgent.