Previous studies showed an early increase in concentrations of thrombin-antithrombin III complex (TAT) and fibinopeptide A (FPA) during thrombolytic therapy; but the mechanism of activation of coagulation with fibrinolysis is not known. The aim of this study is to clarify the mechanism of activation of coagulation with tissue-type plasminogen activator (t-PA) in vitro. Prothrombin fragment 1+2 (F1+2), TAT and FPA levels significantly increased in anticoagulated normal plasma after incubation with t-PA (1×10³U/ml and 1×10⁴U/ml) compared without t-PA and the increas of these marker levels was dose dependent. By incubation of normal plasma and coagulation factor deficient plasma (factor V, VII, IX, X deficient plasma) with t-PA (1×10³U/ml), generations of F1+2 and FPA significantly decreased in factor V, VII and X deficient plasma compared to standard plasma, however the amount of F1+2 and FPA generated in factor IX deficient plasma was comparable with normal. F1+2 immunoreactivity also increased in normal plasma after incubation with plasmin. By incubation of purified prothrombin (physiological concentration) with t-PA and plasmin, no generations of F1+2 were observed with t-PA, but one tenth levels of generations of F1+2 observed with plasmin compared to addition of plasmin to normal plasma.
These results demonstrated not only an activation of prothrombin but also an activation of extrinsic pathway (in part via factor VII) associated with stimulation of fibrinolysis.

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Aiming at eclucidating the status of blood coagulation and fibrinolysis in twin pregnancy, we measured molecular markers representative of blood coagulation and fibrinolysis in the peripheral and the cord blood obtained from 20 mothers and their babies, respectively, at the time of delivery.
Molecular markers determined were antithrombin III (AT-III), thrombin-AT-III complex (TAT), plasmin-α₂-plasmin inhibitor complex (PIC), D-dimer, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), t-PA-PAI-1 complex and active PAI-1, Decreased levels of AT-III and increased levels of TAT in blood samples derived from the mothers indicated that the mothers were most likely in the hypercoagurable state. On the contrary, PAI-1 and active PAI-1 in the mothers were found to be increased significantly as compared with those in control, suggesting that fibrinolysis was suppressed in the mothers. The plasma levels of t-PA-PAI-1 complex in the mothers and their babies were found to be decreased significantly as compared with those in control. No significant changes were observed in the levels of PIC, D-dimer and t-PA, however. Similarly, the levels of AT-III in the cord blood was significantly reduced but that of TAT was increased, though in the second baby alone. On the other hand, PAI-1 was significantly elevated. Thus in twin babies, there was also an inclination to the hypercoagulable and hypofibrinolysic state. The observed hypercoagulability and hypofibrinolysis may underlie impared proliferation of placenta leading to growth retardation of the fetus.

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The concentration of vitamin K in the hepatic tissues and plasma, and that of the sex steroid hormones in plasma of Wistar-lmamichi rats fed with a commercial diet were measured at 2, 4, 6 and 10 weeks of age in the male rats and at 2, 4, 6 and 9 weeks of age in the female rats.
At 6 week-old, the level of PK and MK-4 in the hepatic tissues were 23.37±3.51ng/g, and 10.89±2.24ng/g, respectively, in the female rats, which were significantly higher than those in the age-matched male rats. The plasma levels of PK and MK-4 in female rats were also higher than those in the male rats.
The plasma estradiol level at 6 week-old (42.35±18.17pg/ml) in female rats were higher than those at 4 week-old. The plasma progesterone level at 6 week-old (29.00±19.96ng/ml) in female rats were higher than those at 4 week-old. In male rats, the plasma testosterone level were 0.18±0.12ng/ml at 6 week-old, and 2.16±0.65ng/ml at 10 weekold. The plasma estradiol level also icreased in accordance with sexual maturation.
In both male and female rats, the liver PK and MK-4 level increased in accordance with sexual maturation (Fig. 7, 8). These findings suggest that estradiol and testosterone are engaged in increasing the vitamin K level in the hepatic tissues.

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In the Jichi Medical School Cohort Study, a multi-center study aiming at the elucidation of factors underlying cerebral vascular diseases and myocardial infarction, we have attempted to see whether plasma fibrinogen, known among Caucasians as a risk factor for stroke and myocardial infarction, contributed also to the incidence of such diseases among Japanese. The blood samples were obtained from 3815 inhabitants, 1563 men and 2252 women, ranging from 40 to 79 years of age, in nine districts selected from Kanto to Kyushu during the periods of July-November, 1992 and May-November, 1993. The plasma fibrinogen level was found to be higher in women (the mean±SD: 244.9±52.1mg/dl) than in men (242.7±56.3mg/dl), although these values were apparently reduced as compared with those reported in previous studies on Caucasians. Furthermore, there was a significant increase in plasma fibrinogen after the menopause in women as reported elsewhere, suggesting possible participation of sexual hormones in the regulation of fibrinogen level in plasma. The plasma fibrinogen was significantly increased in current smokers, alcohol non-drinkers and subjects with a history of cerebral vascular disease.
The cross-sectional data showed that plasma fiblinogen levels were associated with some cardiovascular risk factors. Prospective studies are needed to elucidate the causality between the higher plasma fibrinogen level and the cardiovascular diseases in Japan.

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