The optimal level of anticoagulation for decreasing experimental metastases

Anticoagulation with warfarin is effective in decreasing experimental metastases, presumably by preventing the fibrin coagulum demonstrated to be necessary for the lodging of tumor cells. To determine the optimal level of anticoagulation for maximal antimetastatic effect, two similar experiments were completed with a methylcholanthrene-induced sarcoma in C57Bl mice. Footpad tumors were produced by tumor cell injection and the mice were divided into four equal groups: control, and groups on 1, 2, and 3 mg. per liter of warfarin, respectively. Control and anticoagulated mice were amputated at the same interval. Three weeks after amputation, all were killed and their metastases were quantitated. Prothrombin times ranged from 10 seconds in the control to 30 seconds in the 3 mg. per liter group. In Experiment 1, there was a significant reduction of pulmonary metastases at all levels of anticoagulation. The controls showed a mean number of 7.7 metastases per mouse, as compared to 2.9 (p less than 0.002) at 1 mg. per liter, 2.1 (p less than 0.0035) at 2 mg. per liter, and 0.7 (p less than 0.002) at 3 mg. per liter. In Experiment 2, the significant effect was found only at the 3 mg. per liter dose, with those mice having 2.3 metastases per mouse as compared with 5.5 in the controls (p less than 0.0001). We conclude that full anticoagulation in the range of 2.5 to 3 times normal is required for a maximal antimetastatic effect.