Abstract
The effects of Warfarin on the generation of thrombin and fibrin have been examined with the following results:
1. The normal 48 hour serum and its fractions (each fraction of 0-30, 30-40, 40-50% and their mixtures) which were fractionated with the saturated solution of ammonium sulfate significantly reduced the recalcification time, the thromboplastin time (plasma tested+tissue thromboplastin) and the prothrombin time of the Warfarin plasma, and the prothrombin time of the Warfarin serum. It was found that such reductions of time were caused by the stable factor contained in the normal 48 hour serum. The coagulation times of the normal and the Warfarin plasma were less than the prothrombin time when the thromboplastin complex (plasma treated Ca3(PO4)2+CaCl2+thromboplastin +48 hour serum or CaCl2+thromboplastin+48 hour serum) was added.
2. The quantity of prothrombin decreased by about 50% 24 hours after the first administration of Warfarin (0.25mg) and it decreased progressively according to the number of administration. Even though the prothrombin time of the Warfarin plasma was prolonged over 300 sec., 8 to 15% of the prothrombin still remained in the Warfarin plasma.
3. The quantity of prothrombin conversion in the Warfarin blood increased slightly when the normal 48 hour serum was added.
4. The quantity of the stable factcr decreased by 80 to 90% 24 hours after the first administrationof Warfarin (0.25mg) and it disappeared almost completely 24 hours after the second or third administration of Warfarin. The stable factor primarily decreased more significantly than prothrombin.
5. The quantities of the labile factor and prothrombin in the normal plasma showing the minimum value of the prothrombin time were in the ratio of 1:1, but in the Warfarin plasma the rate of prothrombin to the labile factor increased according to the prolongation of the prothrombin time (2:3∼1:4). The ratio between the stable factor and the Warfarin plasma changed to a higher rate of the stable factor quantity according as the increases of the prothrombin time value (1:9∼3:7).
6. In the initial stage of coagulation the consumption of prothrombin in the Warfarin blood was considerably abnormal, but when the normal 48 hour serum was added to the Warfarin blood the consumption became normal.
7. The time that thrombin activity reached the maximum after collecting the Warfarin blood was prolonged according to the increase in the prothrombin time. After the coagulation of blood, the thrombin activity decreased rapidly.
8. The conversion times of prothrombin and fibrinogen and the time of fibrin generation in the Warfarin plasma were prolonged according to the prolongation of the prothrombin time, the prolongation of the prothrombin conversion time being remarkable. However, each time mentioned above was significantly shortened by adding the normal 48 hour serum.
9. The quantity of fibrin in the Warfarin plasma decreased according to the prolongation of the prothrombin time, and even though the normal 48 hour serum was added its quantity did not increase.
10. The time necessary for the disappearance of fibrinogen in the Warfarin serum was prolonged according to the increase in the prothrombin time.
11. The retractility of clot in the Warfarin blood decreased according to the prolongation of the prothrombin time. It did not increase with the addition of the normal 48 hour serum.
12. From the results of the studies up to date, the mechanism of the prolongation of the prothrombin time in the Warfarin plasma can be explained as follows. The prolongation of theprothrombin time in the Warfarin plasma can be attributed to the decrease in the production of thrombin, and to the prolongation of the conversion times of prothrombin and fibrinogen, and of the generation time of fibrin, which is caused by the decrease in prothrombin
