INHIBITION RATHER THAN ENHANCEMENT OF HEMOSTATIC SYSTEM ACTIVATION DURING INITIATION OF ORAL ANTICOAGULANT TREATMENT

Coumarin-induced skin necrosis is believed to be due to a transient hy percoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X d uring initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a tec h technique that investigates coagulation activation in the microcircu lation. We determined in 10 healthy volunteers the concentrations of p rothrombin fragment F1+2 (f1.2) and thrombin-antithrombin complex (TAT ) in blood emerging from an injury of the microvasculature (bleeding t ime incision) before and after initiation of both high-intensity and l ow-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F VIIa) and the activities of F II, F VII, F X and protein C were me asured in venous blood. A rapid decline of F VII and protein C was obs erved in venous blood with activities at 24 h of 7 +/- 1% and 43 +/- 2 %, respectively, during the high-intensity regimen. A 20 to 30% reduct ion of f1.2 and TAT was seen in venous blood at 72 h with no major dif ference between the high- and the low-intensity regimen. F VIIa levels were substantially affected by anticoagulation with a >90% reduction at 48 h during the high-intensity regimen. Following high-intensity co umarin, a >50% decrease in the f1.2 and TAT levels was found in shed b lood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT lev els was seen neither in shed blood nor in venous blood. Our data do no t support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-in duced skin nekrosis.