Protein C and'the Development of Skin Necrosis During Anticoagulant Therapy Dear Sir, Coumarin skin necrosis is thought to be the consequence of diffuse thrombosis of the small venules in the lesions with secondary bleeding due to the coumarin-induced hypocoagulability (1, 2). The report by one of us (V. H.) of a patient who developed skin necrosis not only during the initial phase of oral anticoagulant therapy, but also at the onset of cholestatic vitamin K deficiency (3), questions the proposed pathogenic mechanisms such as toxic influences of oral anticoagulants and hypersensitivity vasculitis due to the coumarin drug. In the report it was suggested that PIVKAs might play a role in the development of skin necrosis. Recently it has been recognized that during the initial phase of oral anticoagulant therapy-there is a rapid drop not-only of factor VII but also of protein C, their biological half-lives being very similar. Protein C is a vitamin K dependent protein (4) Thrombotest (sec) 36 35.5 S 3 9

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SummaryDuring long-term treatment with the long-acting coumarin derivative phenprocoumarol (marcoumar) no statistically significant difference in the depression of the activity of coagulation factors II, VII, IX, and X was found. The shorter-acting anticoagulants acenocoumarol (sintrom), warfarin sodium (coumadin), and dicoumarol, possibly lower factor IX somewhat less and factor X somewhat more than they do factors II and VII.A 2.5-fold prolongation of the “prothrombin” time (using Owren 5 s human brain thromboplastin) and the same prolongation of the thrombotest time appear to correspond with a depression of all four factors from 100% down to approximately 20’%, the normal standard being a mixed population with a mean age of 29 years.Separate determination of one of the four coagulation factors concerned is pointless; “prothrombin” time estimation, and more specifically thrombotest, still remain the most reliable methods for controlling the anti-vitamin K action of anticoagulants during long-term treatment.

SummaryFor 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 per cent 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.