The thrombelastograms in whole blood were investigated in 57 patients with liver and biliary tract deseases. These patients were acute hepatitis (6 patients), inactve chronic hepatitis (11), active chronic hepatitis (5), postnecrotic and portal cirrhosis (18), hepatoma (8), metastatic cancers of the liver (4) and pancreatic cancer with jaundice (5), who were diagnosed by histological findings, operation and autopsy, clinical observation and chemical liver function tests.
The r-values in most of the patients were normal except of the several cases with liver cirrhosis or pancreatic carcinoma.
The k-values in a part of the patients with liver cirrhosis were larger, and smaller in the case with metastatic carcinoma, while most of the patients were normal.
The ma-values in the patients with liver cirrhosis decreased markedly. However, those in the other patients were normal except of the carcinomas of the liver or the pancreas increased or decreased.
In the two patients with liver cirrhosis who were died of hepatoma after 5 years, the whole-blood-thrombelastogram (TEG) revealed that the ma-values in both of them in the former state were markedly reduced and in the latter state were shown normal.
As the measurement of fibrinolysis by the whole-blood-TEG may not be established, we tried to take the values of f₁ and f₂₄ for the criteria of the measurement. The reduction rates (%) of the amplitude at one or 24 hours after the time of the ma-point were determined for the value as a f₁ or as a f₂₄.
Mean value of the % f₂₄ in the patients with liver cirrhosis markedly increased, but in the cancer of the pancreas the % f₁ as well as the % f₂₄ decreased. It may be possible that the fibrinolysis was accelerated in the liver cirrhosis but it was reduced in the cancer of the pancreas.
We emphasize that the whole-blood-TEG is very useful not only for the examination method of coagulation and fibrinolysis in blood but also for the daily clinical diagnostic examination in liver and biliary tract diseases, especially in liver cirrhosis and hepatoma.

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The diagnostic value of five differerent clotting tests were evaluated on 109 patients with acute and chronic liver disease. The tests were performed Hepaplastintest (Normotest), Thrombotest, prothrombin time, active partial thromboplastin time and fibrinogen determination. More than 90% of the patients gave abnormal values in some of the tests.
1. Most of the patients with acute hepatitis gave slightly abnormal values and their changes were well correlated to clinical condition. The prognosis of a few patients with markedly decreased levels of hepaplastin test was always poor.
2. Most of the patients with chronic hepatitis showed abnormal values. No significant discrepancy was observed between active type and inactive type of the disease.
3. The majority of the patients of liver cirrhosis showed marked abnormality. Among the tests, the hepaplastin test seemed to the useful to differentiate the compensative phase from incompensative phase, giving moderately decrease in the former, markedly decrease in the latter.
4. The results of hepaplastin test and BSP tolerance test were usually parallel with each other.

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In order to clarify diagnostic significance of blood coagulation tests in various hepatobiliary diseases, the activities of coagulation factors measured by Hepaplastintest, Thrombotest and prothrombin time, and the inhibition index (P IVKA) as well as the lipid contents in blood, which may influence on coagulation system, were analysed.
Results: An average value of Hepaplastintest in patients with acute hepatitis was 90±31%. In the course of acute hepatitis, the value of Hepaplastintest dropped under 60% at the stage of climax, and recovered rapidly to the normal range in two or three weeks preceding the normalization of other liver function tests. While the activities of coagulation factors were fluctuated markedly in the course of acute hepatitis, they used to fix in a lower range with lesser fluctuation when it is developed to chronic hepatitis.
In chronic liver diseases, an average value of Hepaplastintest was 79±18% in chronic hepatitis and 56±16% in cirrhosis of the liver.
Hypercoagulable state was observed in the hepatobiliary diseases with hyperlipemia such as obstructive jaundice, intrahepatic cholestasis and primary biliary cirrhosis. Hypercoagulation state was also seen in hyperlipemic patients without liver damage and in nephrotic syndrome without azotemia. These findings suggest that serum lipids may accelerate the activity of coagulation systems.
The presence of endogenous inhibition on coagulation systems, expressed by Inhibition Index (value of Hepaplastintest-value of Thrombotest/value of Hepaplastintest), was observed at the climax of acute hepatitis, in the course of chronic active hepatitis and in obstructive jaundice. In the course of acute hepatitis, Inhibition Index rose at the stage of climax and dropped to the normal range in accordance with the normalization of the values of coagulation tests. While hypocoagulation state, seen in the severe obstructive jaundice, was normalized by the administration of vitamin K with normalization of coagulation activity and Inhibition Index.
Conclusion: In the various liver function test, Hepaplastintest is the most sensitive and suitable to evaluate an ability of protein synthesis of the hepatocytes in various hepatobiliary diseases, and if the clinical course of the diseases is followed by Hepaplastintest and Thrombotest as well as Inhibition Index, the significant informations may be derived for the understanding of the pathophysiological phases and the evaluation of their prognosis.

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I. Pathological study of autopsy cases with liver diseases.
Thirty-four cases out of 56 cases with liver or biliary tract disease were complicated with gastrointestinal hemorrhage as autopsy findings. Eighty-four per cent of patients with liver cirrhosis were complicated with gastrointestinal hemorrhage (Table 1), however the site of bleeding could not be identified in almost all cases, except one case with bleeding from esophageal varices and another case with bleeding from gastric and duodenal ulcers. The bleedings from gastric ulcers were recognized in 8 cases and 2 cases with bleedings from esophageal varices were observed in 13 cases of hepatoma associated with liver cirrhosis (Table 2).
From these observations, it seems that the identification of the bleeding site is very difficult in many cases with liver cirrhosis, and also difficult to find out the confirmation of bleeding from esophageal varices, even if the presence of varices have been identified in cases (Table 2). Therefore, it is important many to recognize the abnormality of blood coagulation in patients with liver diseases.
II. Interrelation between coagulation factors and proteases.
In chronic liver diseases including 17 cases with chronic hepatitis, 4 cases with pre-cirrhosis and 23 cases with liver cirrhosis, good correlation between Hepaplastintest and ICGK (r=0. 466, p<0.01), Cholinesterase (r=0.463, p<0.001), Albumin (r=0.366, p<0.02) and Total Bilirubin (r=-0.450, p<0.01) were observed (Table 3). There was no significant correlation between Hepaplastintest and Albumin content, however slight correlation between Hepaplastintest and GOT was observed in cases with chronic hepatitis. The different mechanism of reduction of coagulation factors might be considered between chronic hepatitis and liver cirrhosis.
In cases with liver cirrhosis, no alternation of fibrinogen contents were observed and Streptokinase activated Plasmin activity were decreased and also contents of C₃ and C₄ were diminished. There was significant correlation between Hepaplastintest and contents of C₃ in chronic liver diseases (Table 4).

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It has been well known that levels of blood coagulation factors decrease in various liver diseases and this decrease relates to the development of disseminate intravascular coagualtion (DIC). In the present study, serial dilution protamin sulfate (SDPS) test and hepaplastin (Hp) test were performed to evaluate the clinical role of the changes in blood coagulation factors in various liver diseases.
Out of 65 cases of various liver disease, 5 cases including 3 of subacute hepatitis, 1 of hepatic cirrhosis and hepatic cancer, were positive for SDPS test. These five cases died shortly after the development of positive SDPS test, suggesting that development of DIC is the terminal event of severe liver diseases. PIVKA index, which is an index of circulating anticoagulant level, was not rel ated to the development of DIC in this study.
Hp test, which represnts the total activity of factor II, VII and X, were decreased markedly in subacute hepatitis, moderately in liver cirrhosis, and slightly in classical acute hepatitis and chronic hepatitis, respectively. In intrahepatic cholestasis, values of Hp test were normal, despite of marked jaundice and elevation of serum transaminase activity. In acute hepatitis, values of Hp test were clossely related to the extent of hepatic cell necrosis. The levels of serum prealbumin, which is mainly produced in the liver and has rapidly turnover rate, showed similar change to that of Hp test and correlation between Hp test and serum prealbumin levels was significant statistically. In the hepatectomized rats, values of Hp test and the residual liver weigt were significantly correlated. These results suggested that Hp test or serum prealbumin level is an excellent index to evaluate the total functioning hepatic cell mass.
At present time, there is no specific test to evaluate the total functioning hepatic cell mass, which is one of the most important factors to decide prognosis of liver disease. Determination of Hp test values and serum prealbumin level are essential for the treatment various liver diseases.

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In four groups of liver diseases, Hepaplastin test and other coagulation tests were studied and compared with various liver function tests.
The value of Hepaplastin test in liver cirrhosis revealed 49.1%±16.8 S. D., in acute hepatitis 69.7%±17.5 and in chronic hepatitis 71.5%±16.8.
In 5 cases of 7 cholestasis, in which the value of Hepaplastin test remained normal, obstructive Lipoprotein (Lp-X) were positive. But in all cases of 6 cholestasis, in which the value of Hepaplastin test were reduced, Lp-X were negative.
The value of Hepaplastin test revealed good correlation with Choline esterase, α-Lipoprotein and Lecithin-cholesterol acyl transferase activity which reflect the reduction of synthesis in liver cells, and also revealed good correlation with ICG-R₁₅.
It is already known that the osmotic fragility of RBC decreases in liver diseases. We found that the value of Hepaplastin test correlated with the end osmotic pressure of hemolysis of RBC measured by Coil planet centrifuge system.
We judged the prognosis of hepatitis by considering the combination of Hepaplestintest and α-Lipoprotein value. The patients that the value of Hepaplastin test and α-Lipoprotein remained normal in spite of the remarkable elevation of S-GOT, made rapid recovery. In the value of Hepaplastintest and α-Lipoprotein recovered after normalization of S-GOT, the elevation of S-GOT recurred after a few monthes.
Hepaplastintest, test for extrinsic clotting system which measures factors II, VII and X is said to reflect the liver function. In our study, Hepaplastin test seems to be usefull for the judgement of prognosis of liver diseases except cholestasis.

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Blood coagulation activities were measured with Hepaplastintest in patients with various chronic liver diseases: 21 cirrhosis of the liver, 33 chronic hepatitis and 24 miscellaneous liver diseases. In chronic liver diseases, HPT values decreased following the degree of hepatic injury. The mean value of HPT were 69. 38±12. 12% in chronic inactive hepatitis, 54.38±9.60% in chronic active hepatitis and 54.02±11.77% in liver cirrhosis.
We were compared the value of HPT in each group of liver diseases classified laparoscopically, and the mean value of HPT were 71.5% in smooth liver group and 60.73% in coarsely irregular liver group, but tended to low in nodular liver group (50% or below).
Then, the value of HPT was compared with other liver function tests and blood coagulation and clotting tests. And there was a negative correlation between HPT and retention rate of ICG (15′) (r=-0.6117, p<0.001), and also a correlation was recognized between HPT and blood platelets (r=0.5417, p<0.001).
But no correlation could be demonstrated between HPT and serum transaminase activity.
In conclution, HPT is a sensitive diagnostic test for mild hepatic impairement.

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In order to clarify coagulation and fibrinolysis in hepatic cirrhosis following items were examined.
1) Counts of megakaryocyte and its classification. 2) Lifespan of ⁵Cr-labeled platelet. 3) Platelet volume and its distribution (Coulter Counter ZB). 4) Platelet spreading test (Breddin's method). 5) Platelet aggregation (Evans Aggregometer). 6) Platelet Factor-3 (Kaolin). 7) Serum phospholipids and its fractionation. 8) Hepaplastin test (Eisai pharmaceutical Co, test for II, Vll, X factors) 9) Plasma fibrinogen (Tyrosine). 10) FDP (HIT). 11) Protamine sulfate test (Lipinski's). 12) Total plasmin (fibrin plate). 13) Plasminogen and antiplasmin (lysine sepharose affinity chromatography) 14) Factor XIII (Urayama's). from these examinations following facts were clarified.
1) Reduction of platelet counts is due to disturbance of platelet formation and enhanced breakdown of platelets and may either due to pooling in the spleen.
The remarkable reduction and its characteristic asthenic pattern of platelet aggregation may suggest hypofunction of the platelet cell. It may be supported with the facts of the large spreading tendency of the platelet and reduction of PF-3 availability.
2) Hepaplastin test clearly shows reduction of extrinsic factor in cirrhosis of the liver.
3) In regard to f ibrinolysis, in case of the hepatic cirrhosis, plasma fibrinogen tends to decrease, on the other hand protamind sulfate test tend to show higher value.
Total plasma plasmin increased remarkably, on the other hand, plasminogen and antiplasmin slightly decreased. Factor XIII decreased either in case of cirrhosis.
Whether the enhanced fibrinolysis may occur primary or secondary must be examined more in detail.

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It was well known that a bleeding tendency frequently occurred as a troublesome complication in liver cirrhosis. In this paper, abnormalities of coagulation were studied in 30 cases with liver cirrhosis admitted in St. Luke's Int'l Hospital of Tokyo. Fifteen patients were active cases showing jaundice, ascites or esophageal varices.
Thrombocytopenia(lower than 10×10⁴/mm³) were found in nineteen cases(65.5%), and the drop in platelet count lower than 5×10⁴/mm³ in six patients (20.7%). Since the degree of thrombocytopenia paralled with the weight of spleen, and the megakaryocytes were normal or rather increased in the bone marrow, the chief cause of thrombocytopenia in liver cirrhosis was concluded as hypersplenism.
Factor II, V, VII and X decreased respectively in the frequency of 39.3%, 32.1%, 39.3% and 47.4% of cases. In general, the drop in factor II, V and VII were more striking in the active stage than in other stage. The extent in deficiency of these factors paralled with the decrease of serum albumin. Howerver, factor XIII was normal in all cases. Plasma fibrinolytic activity increased in twenty-two cases(78.6%), and this phenomenon was more strking in active stage than in inactive stage of liver cirrhosis. Furthermore, the degree of increase in fibrinolysis correlated to the elevatin of serum γ-globulin. As platelet functions, clot retraction decreased in seven cases (35%), and adhesiveness reduced in four cases (20%).
Platelet aggregation impaired in fourteen patients (63.6%), and this finding was more prominent in the cases with increased fibrinolytic activities. These results may indicate that the elevated fibrinogen-fibrin degradation product impaired the aggregation of platelet.
But the activity of platelet-3 decreased in only four cases (20%).
From the results presented here, we can conclude that the hemorrhagic tendency occur due to the complex of decreases in platelet number, platelet functions and clotting factors, and increased fibrinolytic activities. However, these results had no relation with the histological type of liver cirrhosis.

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Blood coagulation activities of Hepaplastintest, Thrombotest and fibrinogen were studied and compared to the results of liver function tests. Subjects were 46 cases of liver cirrhosis, 7 of chronic hepatitis, 3 of acute hepatitis and 1 of liver cancer not accompanying liver cirrhosis. Using the same subjects, factor XIII was examined on activation by the addition of cysteine and on presence of inhibitor. The results obtained are as follows.
1) Hepaplastintest showed highly significant positive correlation with cholinesterase, significant negative correlation with total bilirubin and tendency toward positive correlation with the A/G ratio. These facts show that the reagent may become a potent indicator in recognizing the stage and state of liver cirrhosis.
2) Thrombotest tended to correlate negatively both with total bilirubin and with γ-globulin. As compared to the case of Hepaplastintest, its correlation with liver function was generally low.
3) Fibrinogen tended to correlate only with cholinesterase.
4) Among the group of liver diseases mainly composed of liver cirrhosis, about a half of cases that were low in the level of factor XIII had disorder of activation of various degree. Presence of inhibitor of factor XIII was denied in all but one of liver cancer.

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Nowadays There is no donbt that coagulation studies of hepatic damages give information for the severity, but the clear relationship in this diagnostic value is not established yet.
Present studies indicated that hemostatic tests have some pathophysiogical significance for disturbed liver functions.
Coagulation and fibrinolytic tests, such as bleeding time (BT), clotting time (CT), recalcification time (RT), prothrombin time (PT), thrombotest (TT) hepaplastintest (HPT), activated partial thromboplastin time (APTT), T E G, concentration of factor V, VIII, IX and fibrinogen (Fbg.), platelet counts (Plt. C), F D P, plasminogen (Plg.), antithrombin III (A T III), α₂-macroglobulin (α₂-Mac.), and α₁-antitrypsin (α₁-A T) were made on 6 cases with acute hepatitis (A H), 14 with inactive chronic hepatitis (inact. C H), 4 with active chronic hepatitis (act. C H), 12 with liver cirrhosis without ascites (L C ascites(-)), 3 with liver cirrhosiswith ascites (L C ascites(+)), and 7 other liver disorders such as Banti's syndrome, acute cholestasis and hypercitrullinemia.
BT, RT and CT were almost in normal range. Prolonged PT and decreased TT and HPT value were shown in CH and L C groups, but in A H, PT TT and HPT were all in normal range. APTT was prolonged in many cases of each group. In L C with or without ascites, T E G ma was shortened and Plt. C decreased. Low concentration of F V and IX was revealed in many cases with C H and L C. Fbg. level elevated in some cases with A H and other liver disoders, but in most cases with C H and L C showed its decrease. In each group. F D P was almost in normal and Plg. was not elevated.
Fibrinolytic inhibitors showed variable changes in same group. In A H, three inhibitors were all in normal range. In C H, A T III was in normal range and α₂-Mac. and α₁-A T were slightly increased. In L C ascites(-), A T III decreased and α₂-Mac. and α₁-A T increased. In L C ascites(+), A T III decreased, α₂-Mac. increased and α₁-A T was in normal.
There were 19 cases out of 46, with normal values in screening liver function tests in the present study. They had abnormal values with high frequency in TT, APTT, TEGma, α₂-Mac., Plt. C, PT and so on. Thirty-three percent of them showed decreased HPT value. So that these coagulation and fibrinolytic tests may be utilized in the diagnostic procedure for liver functions.
Abnormal hemostatic results were reffered with TTT, ZTT, Ch-E and serum albumin level in the presnt studies which were performed mainly on chronic liver diseases, and thues these Suggested disturbed protein metabolism, especially in live cells.

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The procoagulant activity of antihemophilic factor (AHF-Ac) and AHF-like antigen (AHF-Ag) level in liver diseases have not been well studied, although it has already been shown that the level of vitamin K dependent clotting factors such as prothrombin, factors VII, IX and X is a very sensitive parameter of liver function.
We studied AHF-Ac and AHF-Ag in 13 patients with acute hepatitis (AH), 15 with chronic active hepatitis (CAH), 20 with compensated liver cirrhosis (CLC) and 16 with decompen-sated liver cirrhosis (DCL). Also were performed coagulation studies in the same patients, such as hepaplastintest, prothrombin time, kaolin-activated PTT and assays of fibrinogen, prothrombin, factors V and IX.
Hepaplastintest was normal in the majority of patients with AH, whilst many cirrhotic patients showed abnormal value. Prothrombin time and APTT were also within normal limits in the majority of cases of AH, CAH and CLC. Level of prothrombin and factor IX was proved to be a good parameter of liver function, although that of fibrinogen and factor V was insensitive to liver damage.
AHF-Ac and AHF-Ag were both increased in almost all patients with the hepatic disorders mentioned above. The mean values of the AHF-Ac were 257±139% in AH, 124±53% in CAH, 104±30% in CLC and 189±74% in DLC, whilst those of AHF-Ag were 190±89%, 189±50%, 207±56% and 344±191% respectively.
AHF-Ac in cirrhotic patients correlated well with serum γ-globulin level (p<0.01) and also was there close correlation between AHF-Ac and serum bilirubin level in patients with AH, but not statistically significant.
The AHF-Ac/AHF-Ag ratio in patients with AH was 1.53±0.94, in contrast to 0.70±0.31 in CAH, 0.54±0. 24 in CLC and 0.63±0.27 in DLC, which showed higher level of AHF-Ac than that of AHF-Ag in AH.
The cause of increased level of AHF in hepatic disorders still remains unknown, although increased extrahepatic production of AHF due to stress states and delayed inactivation and clearance of this factor in the liver may be playing a main role.

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The phenomenon that serum comlement level in some patient is reduced in its early component C1, C4 and C2, while normal i n plasma (Glovsky, M. M. & Alenty, A.: J. Immunol., 111; 305, 1973. Gewurz, H.: J. Immunol., 111, 305, 1973.) is further investgated in patients with liver diseases.
Eight out of 120 patients with liver diseases, who showed high colloidal reaction as well as transaminase, revealed 20 per cent less CH 50 in serum than in plasma; 3 cirrhosis of the liver, 2 chronic active and 3 chronic inactive hepatitis. This dissociation of complement in serum and plasma did not correspond to the severity of diseases, nor the presense of HBAg or cryoglobulin. The decrease of serum complement, in another words activation of classical pathway of complement in vitro, is observed when serum is separated in cold, or serum separated at 37°C is transferred to 0° to 11°C for 4 hours, indicatig that this is “cold activation” of complement.
Cold activation of complement is prevented by the addition of EDTA, heparin or citrate to blood, probably due to preventing clot formation, or to removing Ca⁺⁺. Increase of ionic strength by the addition of NaCl also prevented the cold activation, suggesting Cl could not be activated in the high ionic strength condition. It is interesting that vitamin E had an effect to inhibit the cold activation, while trans-AMCHA, Trasylol, or soy bean trypsin inhibitor failed.
Thrombotest (TT) and Hepaplastintest (Normotest; HP) described by Owren, which are able to detect clotting factors II, VII and X, are investigated in patients with liver diseases before and after incubating the citrated plasma at 4°C for 20 hours, and compared with the changes of CH50. Most of the cases showed the activation of HP, while no specific tendency in TT. Eight out of 24 cases revealed the decrease of CH50, and it was confirmed that thease 8 cases showed activation of TT and HP as well, indicating the activation of complement is closely related to that of coagulation factors.
A case K. N., 45-year-old man with chronic inactive hepatitis and angioedema, was furhter investigated, and his citrated plasma showed activation of TT and CH50 in 4 hours at 4°C, and HP over 10 hours. These activation of TT, HP and complement is also prevented in the presense of vitamin E.
At the present knowledge, there is no evidence that what is the factor producing cold activation of complement, and how vitamin E works. However, since clinical informations have been obtained in serum complement, and not in plasma, this dissociation of complement in serum and plasma must be clarified.

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With regard to mechanism of development of bleeding tendency in hepatic deseases, coagulopathy mainly or cirrhosis of the liver (especially about correlation of Hepaplastintest and Thrombotest with every coagulation factor, and relationship of hepatic deseases with DIC) was studied.
Methods: Every coagulation factor, HPT, TT, whole plasmin, Eug+SK, Eug+UK, ELT, α₁-antitrypsn, α₂-Macroglobulin, Antithrombin III, plasminogen, FDP and number of platelets were measured respectively.
Results anb Conclusions: The decrease of TT, PT, V, VII, and plasminogen was detected in accordance of the degree of liver damage which is indicated by value of HPT. Among inhibitory factors on coagulation and fibinolysis, the value of ATIII correlated fairly well with that of HPT, but the value of α₁AT and α₂M does not correlated with.
In many cases, the count of platelets decreases and FDP shows higher level than normal. The above results seem having close resemblance to the bata of DIC. It seems difficult to detect whether liver disease is attended with DIC or not, but α₂M and α₁AT were found not to decrease in liver damage and the value of α₂M and α₁AT seems an index of DIC when these factors decrease.

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Twenty parameters for coagulation, fibrinolysis and their inhibitors were studied in 79 patients with liver diseases, including 15 cases of acute hepatitis, 1 of fulminant hepatitis, 13 of chronic hepatitis, 41 of liver cirrhosis and 9 of primary liver cancer.
In acute hepatitis; plasminogen, factor V, factor VII, antithrombin III (AT III) and α₁ antitrypsin (α₁AT) tended to be decreased. Serial thrombin time 30′(STT 30′) was prolonged in 60% of cases. Fibrinogen-fibrin degradation product (FDP) was within the normal range. In only one case paracoagulation test was positive.
In fulminant hepatitis; platelet count, plasminogen, thrombotest, hepaplastintest, fibrinogen, AT III and α₁AT were decreased. Prothrombin time (PT) and STT 30′ were prolonged. FDP was increased (40üg/ml). These results were highly suggestive of not only severe synthetic failure but also of disseminated intravascular coagulation (DIC).
In liver cirrhosis; platelet count, thrombotest, hepaplastintest, plasminogen, fibrinogen, factor V, factor VII, AT III and α₁AT tended to be decreased. Increase in FDP and in α₂ macroglobulin was found in 31% and 37% respectively. STT 30′ was prolonged in 87%. Paracoagulation test was positive in 15%.
In chronic hepatitis; almost all parameters showed a similar pattern as liver cirrhosis, however PT, thrombotest and hepaplastintest tended to give normal results.
In primary liver cancer; plasminogen and AT III were decreased while α₁AT was increased. STT 30′ was prolonged in 67% and FDP was increased in 33%.
Partial thromboplastin time was almost normal in liver diseases.
In severe cases, the coagulation analysis revealed the increase of FDP, prolongation of STT 30′ and decrease of platelet count, AT III, plasminogen and coagulation factors except factor VIII (F. VIII) activity. As these findings were consistent with DIC, diagnosis of DIC in patients with liver diseases, especially liver cirrhosis should be made more carefully.
Increase of F. VIII activity and F. VIII-related antigen, and decrease of F. VIII activity/F. VIII-related antigen ratio were obsereved in liver diseases, suggesting production-consumption imbalance of F. VIII. Measurement of F. VIII activity and F. VIII-related antigen might be helpful in diagnosis of DIC in patients with liver diseases.

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Activity and antigenicity of the factors of blood coagulation and fibrinolysis were examined in various kinds of liver diseases, including acute or chronic hepatitis, liver cirrhosis (LC), hepatoma and obstructive jaundice.
The most frequent abnormality of blood coagulation in these cases were the combination of decrease of platelet count, disturbance of its aggregation and increase of fibrin degradation product (FDP) in plasma.
The secondary abnormality was the prolongation of PT and PTT in addition to above findings.
The activity of Factor XIII (FXIII), its antigenicity of subunit A and subunit S were in normal level in chronic hepatitis group.
But these titers were high in LC and low in hepatoma.
The activity and antigenicity of plasminogen decreased in chronic hepatitis and obstructive jaundice, and especially in the cases of LC and hepatoma. The activity of plasmin inhibitors decreased in LC and hepatoma but antigenicity of α₂-Macroglobulin (α₂-M) was in normal limit.
The clinical courses of two cases of LC were presented which developed disseminated intravascular coagulopathy (DIC) during the intensive clinical observation.
The first case, 71 years old male, was LC and complicated with gastrointestinal tract bleeding. In this case, prolonged PT and PTT, decreased fibrinogen increased FDP were observed.
The second case, 66 years old male, had been suffering from LC and developed DIC after the injection of Factor IX concentrate.
In these cases, dissociation between activity and antigenicity of FXIII, plasmin, plasminogen, plasmin inhibitors and antithrombin III (AT-III) were observed.
Such dissociation between activity and antigenicity of those factors were reproducible in vitro experimentally by means of adding small by means of adding small amount of thrombin or streptokinase to normal plasma.
It was expected that the analysis of the relationship between activity and antigenicity of coagulation and fibrinolysis factors provides a new concept in elucidating the mechanism of multifarious bleeding tendency in the liver diseases.

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Coagulation and fibrinolytic system in cirrhosis, hepatoma with cirrhosis and hepatoma without cirrhosis was studied.
The cases of liver cirrhosis showed the decrease of coagulant factors and anti-coagulant factors, hyperactivity of plasminogen and plasmin system and the decrease of protease inhibitors. Those results suggested strongly the degree of the liver damage.
In the cases of hepatoma with cirrhosis, abnormalities were observed more strongly than the hepatoma without other changes on the coagulation and fibrinolytic findings but hepatoma with cirrhosis had less abnormalities than liver cirrhosis alone.
And the values of the complement-III in the hepatoma with cirrhosis were showed the normal upper range. Those results demonstrated that no abnormal activations of the complement III were acted on those states. From the reason of those results in the hepatoma with cirrhosis, the progressions of the cirrhosis and the refusal reaction to hepatoma were thoght to be not so remarkable.

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In order to know the causative factors of abnormal bleeding tendency following surgery on the patients with obstructive jaundice, fibrin/fibrinogen degradation products (FDP) including fibriolytic activity, platelet counts, platelet retention and aggregation, and the blood coagulation systems were investigated.
Total 20 patients with obstructive jaundice were studied. 16 of them had malignant tumor and the rest four had choledocholithiasis.
The serum FDP level was elevated significantly in most of these patients and showed a some correlationship with the increase of the serum total bilirubin and alkalinephosphatase values. However, the elevation of FDP could not be explained only by the degree of obstructive jaundice.
The serum FDP level did not show any intimate correlation with the serum γ-globulin and BUN values. This might suggest that the serum FDP level is under the influence of some other agents rather than the liver or kidney disfunction.
The serum FDP elevation is often appreciated as one of the reliable diagnostic indicator for the syndrome of DIC. In general, the syndrome of DIC usually accompanies abnormal decrease of plasma fibrinogen level, platelet counts and prolongation of the prothrombin time. On the contrary, in these 20 cases these lab. results were within normal limits.
In studying the relationship between the elevation of serum FDP or serum bilirubin and platelet retention or platelet aggregation, platelet aggregation was suppressed in these patients with either the marked increase of FDP level or the elevation of serum total bilirubin value.
But or on the other hand, fibrinolytic activity, which was measured by the fibrin plate method and euglobulin clot lysis time was found not to be increased.
In spite of the presence of high serum FDP, the syndrome of DIC was not apparent. It is not clear that the elevation of serum FDP was due to malignant tumor, chronic DIC or obstructive jaundice. However, these data suggest that the elevation of serum FDP have some influence on the postoperative bleeding tendency in the patients with obstrutive jaundice.

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Hemostatic studies were performed in 64 patients with obstructive jaundice. Elevated fibrinogen level, shortened “r” and “r+k” and increased “ma” in thrombelastogram, prolonged serial tbrombin time, elevated fibrin degradation products, positive ethanol gelation test, decreased plasminogen activator activity, increased antiplasmin activity and increased α₁-antitrypsin level were observed. All of these changes were statistically significant when compared with normal controls. In addition, levels of antithrombin-III and plasminogen decreased, but no significance was observed statistically. These hemostatic data revealed the presence of hypercoagulable state with decreased fibrinolytic activity and several evidences of intravascular coagulation.
In order to elucidate the cause of these characteristic patterns in hemostatic studies, the correlation between these hemostatic parameters and liver function tests was studied. Changes in prothrombin time, plasminogen and antithrombin-III were well correlated with albumin, γ-globulin and TTT which mainly reflect liver cellular damage. Accordingly, low levels of plasminogen and antithrombin-III in some cases of this series may be attributable not only to enhanced consumption, but also to decreased synthesis in liver. In addition, serum fibrinogen level which is the most important factor in this hypercoagulable state showed positive correlation with alkaline phosphatase and cholesterol which reflect the degree of biliary obstruction.
Six out of 64 cases were diagnosed as disseminated intravascular coagulation (DIC). Five of 6 cases were complicated with biliary infection. In this series, bacteriological examination of bile was performed in 43 cases and gram negative bacilli were found in 32 cases. In addition, 22 cases eventually suffered from cholangitis.
Recently we experienced a very interesting patient with massive bleeding tendency complicated with biliary infection. High antiactivator activity in a low molecular weight fraction was detected in the gel filtration pattern of Lysine Sepharose treated serum through G-200 Sephadex. From these observations it is suggested that this low molecular fraction may have an important role in the decreased fibrinolytic activity in obstructive jaundice.
The present study revealed the presence of hyper-coagulable state in obstructive jaundice which may be easely leading to DIC.

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We have often experienced the haemorrhagic diathesis in liver diseases.
We have now investigated the haemostasis in hepatitis and liver cirrhosis, especially about the fibrinogen and the platelet.
Then results are as follows.
1) In active stage of acute hapatitis and in liver cirrhosis, PT prolonged, but PTT showed little change.
2) The plasma fibrinogen increased in active stage of acute hepatitis, but decreased in chronic hepatitis and liver cirrhosis.
3) Fibrinolytic activity increased, while AT-III decreased.
4) In chronic hepatitis platelet count and platelet aggregation decreased, and negative correlation was recognized between platelet aggregation and γ-globulin.
5) The enargement of platelet volume measured by Coulter counter was found in liver diseases, and it related to the change of haemorrhagic diathesis in some cases.
6) ¹³¹ I-labelled fibrinogen half life shortened in hepatitis, especially in liver cirrhosis. And in several cases we recognized the prolongation of fibrinogen half after the injection of heparin.
From the results of our investigation in liver diseases, our conclusion is that the thrombotic tendency and the intravascular coagulation are closely related to the progress of hepatitis.

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The clinical and experimental findings related to the mechanism of hepatic cell necrosis in associated with intravascular coagulation were studied.
The results and conclusion of our work are summarized as follows.
1) Endotoxemia as detected by the Limulus Test, was often found in the patients with fulminant hepatitis and the close correlation found between the development of endotoxemia and the occurence of both renal impairment and intravascular coagulation.
2) Experimental endotoxin D. I. C. and liver cell necrosis.
E. coli endotoxin was injected into the rabbit portal vein and 24 hours later a ten-fold dose of endotoxin was injected in an ear vein.
Extensive liver necrosis was found which was complicated by fibrin microthrombi in the Sinusoid or necrotic area.
Similar changes were found in the kidneys and intestinal tract.
In fluminant hepatitis complicated by D. I. C., the pathogenesis and haemorrhagic diathesis ressemble that was found in our experimental study.

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The hemorrhagic diathesis in liver diseases are very complicated because of the disorders of vessel-, platelet- and coagulofibrinolytic system. Severe bleeding is known to be caused in the patients with fulminant hepatitis with DIC. We have reported these facts several years. In this study, the hemorrhagic diathesis of liver diseases (especially with DIC) was studied with special references to the activities of anticoagulation and antifibrinolysis, and the diagnosis of hepatitis associated with DIC was also discussed.
Quantative determination of antithrombin III, and α₂-macroglobulin was carried out by single radial immunodiffusion. The mesurement of antiactivator and antiplasmin was carriedd out by means of the plasminogen free fibrin plate.
The results obtained were as follows: (1) In liver cirrhosis (12 cases), the mean values of antithrombin III, α₂ macroglobulin, antiplasmin and antiactivator were respectively 14.0±4.8, 344.4±135.0, 71.7±19.3(mg/dl). and 37.3±18.4(%).
(2) In acute hepatitis (8 cases), the mean values of antithrombin III, α₂ macroglobulin, antiplasmin and antiactivator were respectively 17.5±2.6, 220±24.9, 70.0±9.9(mg/dl) and 28.0±19.4(%).
(3) The usual approach to detect the liver disease accompanied by DIC is to consider the low value of α₂ macroglobulin and the markedly increased value of antiactivator. The dynamic change of antithrombin III, which plays an important role for the diagnosis of DIC, was not so helpful for the diagnosis of the liver diseases accompanied by DIC.
(4) There noted the discrepancy between the value of Eug+SK and that of Eug+UK in the 2 patients with fulminant hepatitis accompanied by DIC.
Therefore, this finding may be very useful for the diagnosis of DIC in liver diseases.

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A case of liver cirrhosis: S. S., 52 years old male. He complained hematemesis from the varix of esophagus, and he was operated on esophagean transection.
But bleeding continued severely from the operation site.
He was injected by fresh blood, Factor IX concentrate and fibrinogen as replacement therapy, and Trasylol for stoppage of bleeding.
Unfortunately he complained bleedineg continually, and became anuria finally resulting in expiration, by coagulation disorders.
By autopsy, many microthrombi were found at lung, kidneys, intestines etc.
He was diagnosed disseminated intravascular coagulation syndrome by laboratory coagulation studies and autopsy findings.
Factor IX concentrate contains factor II, VII, IX X and Xa.
When AcG (factor V) was added in the reaction mixture of Factor IX concentrate (Prothrombin-complex by Seegers), thromboplastin and Ca⁺⁺, much thrombin was yielded. And when Factor IX concentrate was dissolved in 2.5Mol of glycine solution (pH 7.2), and stayed at 4°C for 2.5 months, there was observed much thrombin from factor II activated by factor Xa.
When factor IX concentrate was infused into rabbit, the rabbit was died of DIC with the complication of many microthrombi in the target organs.
Facor IX concentrate (Prothrombin-complex) would be a DIC-inducer when it was infused much amount into the patient, especially with with antiplasmin.

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The fibrinolytic activity and its effect on the degradation of fibrinogen in liver diseases were studied.
The plasminogen activity was markedly decreased in nine out of 18 patients with acute hepatitis and 24 out of 37 with cirrhosis with statiscally significant difference as compared to the decrease in 8 out of 22 patients with chronic hepatitis.
The rate of positiveness of fibrin and/or fibrinogen degradation products (FDP) was 42% (n=45) in cirrhosis, 31% (n=29) in acute hepatitis and 24% (n=29) in chronic hepatitis.
On the other hand, plasminogen activity correlated negatively with serum transaminase level in acute hepatitis. Plasminogen activity also had an inverse correlation zink sulufate turbidity test in chronic hepatitis. Similar tendency was observed in cirrhosis, and in acute hepatitis.
The ma value of thrombelastogram was decreased in cirrhosis and chronic hepatitis while these were within normal limits in acute hepatitis, intrahepatic cholestasis and cholecystoli thiasis. The r+k values were prolonged in acute hepatitis, chronic hepatitis and cholecystolithiasis while those were within normal ranges in cirrhosis and intrahepatic cholestasis.
In hepatitis or cirrhosis, , tissue activator activity of necropsy livers was elevated whereas these were profoundly decreased in cancer of the stomach, hepatoma, cancer of the lung and nephritis.
Not infrequently, we have cases of hepatitis in which activations, of fibrinolytic system are absent despite positive FDP in serum. In these cases cathepsin activity is found to be elevated. It therefore appears that cathepsin is related to the degradation of fibrinogen.
From those results, it was considered cathepsin to play as local fibrinolysis in liver tissue.
A case of toxic hepatitis with symptoms simulating intravascular coagulation syndrome was presented and its, pathogenesis diagnosis and treatment were discussed.

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Fibrinolytic activity and serum lipids were determined in 44 patients with liver cirrhosis. Euglobulin clot lysis time (ELT) was shorter in patients with liver cirrhosis than in normal. And ELT was significantly shorter in cases with ascites compared with that of the compensated stage. ELT in the hemorrhage group having a ruptured esophagial varices was significantly longer than in the ascites group, and the average of hemorrhage group was the same as that of normal.
There was a significant decrease in plasma fibrinogen in both groups with ascites and hemorrhage compared with the compensated group. The ascites group showed the lowest value of plasma fibrinogen. But there were no differences in FDP among three groups with compensation, ascites and hemorrhage.
There was a positive correlation between plasma fibrinogen and serum triglycerides, so that plasma fibrinogen was decreasing in parallel with serum triglycerides concentration. It is suggested that both decreases of plasma fibrinogen and serum triglycerides were caused by result of reduced production as a liver dysfunction.

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Recently it has been paid attention whether the liver diseases might induce the disseminated intravascular coagulation (DIC) or not, although it has well known that the liver diseases contribute to the hemorrhagic diathesis.
In this paper, we studied on the incidence and severity of thrombus formation and DIC in 183 autopsy cases of liver diseases which were consisted of 64 cases of liver cirrhosis, 68 cases of liver cirrhosis complicated with liver cancer, 36 cases of liver cancer and 15 cases of acute or subacute hepatitis. A few thrombi were found, usually in the lung, in more than 50% of these cases with liver diseases, but the cases with disseminated thrombi in various organs were present in one out of 64 cases of liver cirrhosis and in 3 out of 68 cases of liver cirrhosis complicated with liver cancer.
These results revealed that the liver diseases might not so frequently induce the DIC as speculated by clinicians. In the liver cirrhosis and liver cancer, the elevated FDP level could be considered as the result of either the thrombus formation in the portal vein and the esophageal varix, or the hemorrhage in the upper alimentary tract. In the liver cirrhosis, hemorrhagic diathesis was observed in 49 cases (76.6%), and varix, erosion and ulceration were in 32 cases (50.0%). And in the liver cirrhosis complicated with liver cancer, hemorrhagic diathesis was observed in 41 cases (60.3%), and varix, erosion and ulceration were in 30 cases (44.1%).
Primary hyperfibrinolysis and elevated local fibrinolytic activities in the esophageal varices and upper alimentary tract might contribute to the hemorrhage in the upper alimentary tract.

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Fulminant hepatic failure is usually accompanied by serious bleeding tendency and abnormal laboratory tests for coagulation-fibrinolysis. Since bleeding tendency is due to intravascular coagulation mechanism in addition to impaired synthesis of clotting factors in liver, heparin therapy has been tested by several workers for this condition.
Five cases of fulminant hepatic failure associated with coma of 3 to 4 grade were admitted in our hospital for the past 2 years and were treated with heparin and fresh frozen plasma. Before administration of heparin, coagulation study demonstrated thrombocytopenia, prolongation in prothrombin time, thrombotest and thrombin time, decrease in plasma fibrinogen, plasminogen and antithrombin III as well as slight elevation in FDP all cases. Three cases with moderate degree of coagulation disturbance began to become conscious on 4th day of heparin therapy and came completely to their senses on 7th to 10th day. In parallel with becoming conscious abnormal coagulation tests were improved and serum bilirubin tended to lower. In all of 3 cases the normalization in prothrombin time, thrombotest, fibrinogen as well as improvement of plasminogen and antithromin III were observed while no recovery in platelet counts occurred except for one case without infection.
After discontinuation of heparin therapy, however, they died of sudden massive retroperitoneal hemorrhage of unknown origin (on 61st day), mucormycosis (on 72nd day) and pulmonary comlication (on 21st day), respectively. On the other hand, the other 2 cases with a most severe coagulation disturbances could not be brought to themselves by heparin therapy and died on 5th and 7th day, respectively. Abnormal coagulation tests were also hardly improved in those cases. Postmortem examination srevealed no fibrin thrombi within sinusoid or central vein of the liver in all of 5 cases except for one who showed multiple microthrombi of the lung.
Although our laboratory data could not necessarily indicate the occurrence of intravascular coagulation, it is reasonable to say that heparin therapy is effective on the recovery from coma due to fulminant hepatic failure before serious bleeding tendency and/or coagulation abnormalities develop. In parallel with becoming conscious, in fact, coagulation-fibrinolysis being abnormal before treatment had been improved in the present cases.

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Three consecutive patients, two with fulminant hepatitis due to Hepatitis B virus infection and one with probable acute fatty liver of pregnancy, were treated with heparin and fresh-frozen plasma. All three showed hepatic coma of grade III to IV at the initial stage of the diseases and all recovered from-the coma completely after the heparin and fresh-frozen plasma treatment for 4 to 5 days. Dose of the heparin was from 12000 to 24000 units per day. No serious complications were noted during the treatment.
Case 1. 24 year-old female developed hepatic coma of grade III about two days after the appearance of jaundice. Remarkable elevation of serum bilirubin and transaminase was noted with positive HBs antigen. Prothrombin time was remarkably prolonged and platelets counts was 108000 and serum fibrinogen was 66mg/dl. Biopsy specimen obtained at the onset revealed severe hepatocyte necrosis and bleeding especially around the centrolobular area with prominent periportal cell infiltration.
The patient was treated with heparin and fresh-frozen plasma for 4 days until complete recovery of the coma. Biopsy specimen obtained about one month after the onset showed minimal changes.
Case 2. 27 year-old female of 7th month pregnancy developed jaundice, and next day, had a stillbirth. Five hours after that, she became comatose. Serum bilirubin and transaminase were markedly elevated with positive HBs antigen. Serum fibrinogen and platelets counts were within normal limits. Prothrombin time, however, was remarkably prolonged. She was recovered from coma after five days heparin and fresh-frozen plasm treatment. Biopsy specimen obtained about one month after the onset revealed only minimal cholestasis at the centrolobular area.
Case 3. 27 year-old female of about 9th month pregnancy developed jaundice. Four days later, she was delivered of a healthy baby. However, after the delivery she developed coma. Serum bilirubin was remarkably elevated with slight increase of serum transaminase. Prothrombin time was markedly prolonged and platelets counts was 51000 and serum fibrinogen was 113mg/dl. Diagnosis was made as probable acute fatty liver of pregnancy.
The patient was treated with heparin and fresh-frozen plasma and four days later the patient recovered completely from the coma. Biopsy specimen obtained about two weeks after the onset revealed minimal changes.
Recently, an evidence of intravascular coagulation has been noted in acute hepatic failure, and early and intensive therapy of heparin and fresh-frozen plasma has been reported to be effective (1, 2, 3). Our experiences also suggests that this therapy is worthy trial for acute hepatic failure.

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The effects of hepatic lobectomy on some blood clotting factors, blood biochemical examinations and fibrinolytic activity were studied on seven patients, and also on dogs under-going seventy per cent hepatic lobectomy.
Experimental data showed that prothrombin time, the amounts of fibrinogen and transaminase unit returned to normal range within two weeks after operation.
Alkaline phosphatase unit rose later than transaminase unit but former took longer time to return preoprative value than later.
Clinical data showed that when the resected liver remaind below fifty per cent, fibrinolytic activity and clotting disorders returned to normal range within three weeks after hepatectomy.
In all but two patients, liver echinococcosis with liver fibrosis and total right hepatic lobectomy, continued the prolongation of prothrombin time and fibrinolytic activity of the euglobulin fraction till three or more weeks.
we considerd that prolongation of prothrombin time and shortening of euglobulin clot lysis time caused not only because the synthetic disturbance of factors and consumption of clotting factors but also because the results of spontaneous liver circulating insufficiency causing of hyper portal pressure.

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