Coagulofibrinolytic System Research Articles

Sepsis-induced disseminated intravascular coagulation: an international estrangement of disease concept.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.

Time Course of Coagulo-Fibrinolytic Derangements During Acclimatization to High Altitude in Rabbits and a Preliminary Study on the Possible Mechanisms.

Zhong, Xin, Zhao Ye, Xiaolin Zhou, Renqing Jiang, Yijun Jia, Wenqiong Du, Haoyang Yang, Lin Zhang, Bai Lu, and Zhaowen Zong. Time course of coagulo-fibrinolytic derangements during acclimatization to high altitude in rabbits and a preliminary study on the possible mechanisms. High Alt Med Biol. 23:240-248, 2022. Background: Conflicting data exist regarding changes in the coagulation system during acclimatization to high altitude (HA), which makes the prevention of thromboembolic events difficult. The present study aimed at observing the dynamic changes in the coagulo-fibrinolysis system during acclimatization to HA and at exploring the possible mechanisms. Materials and Methods: Twenty rabbits of both sexes were randomly divided into two groups, including group A rabbits (healthy plain controls) and group B rabbits (acutely exposed to HA). A traditional coagulation test, thromboelastography analysis, and full blood cell count were used to assess the coagulo-fibrinolytic changes at different time points. Plasma was collected to examine the levels of relevant biomarkers. Results: Six hours and 1 day after acute exposure to HA, the coagulo-fibrinolytic system demonstrated a hypercoagulable state. Further, 3 days after exposure to HA, group B rabbits showed hypocoagulability, increased fibrinolysis, and lower clot firmness and 7 days after exposure to HA, delayed coagulation, decreased fibrinolysis, and increased clot firmness were observed. Subsequently, 14, 21, and 28 days after exposure to HA, we found increased clot firmness. Increased platelet counts and concentrations of fibrinogen and plasminogen activator inhibitor-1 contributed to this change. Conclusion: The coagulo-fibrinolytic derangements during acclimatization to HA in rabbits demonstrated a dynamic pattern.

Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats

The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting.

THE EFFICACY OF X-COATED CARDIOPULMONARY BYPASS CIRCUIT SYSTEMS IN PATIENTS WITH OPEN HEART SURGERY

[Background] We have reported the efficacy of a new coating material, poly-2-methoxyethyl acrylate (PMEA) for cardiopulmonary bypass (CPB) circuit in porcine PCPS models. In this study, we evaluated the efficacy of PMEA coating (X coating®) in patients with open heart surgery. [Methods and Materials] Twenty-one patients underwent valve surgeries under X-coated CPB circuits (group X, n=5), non-coated circuits (group C, n=8) or heparin (ionically bound-heparin, Hepaface®)-coated circuits (group H, n=8). We analyzed the complement system, inflammatory system, platelet system and coagulofibrinolytic system in blood samples, after anesthesia induction, 10min after heparin administration, 30min after extracorporeal circulation establishment, 60min after protamine administration. We also examined plasma proteins adsorbed onto the hollow fibers of the oxygenators after CPB in each group. [Results]Platelet system: Platelet counts decreased gradually during CPB in all groups. There were no significant differences between 3 groups. The plasma levels of platelet factor 4 and P-selectin were lower in group X than in group C. Complement system: The elevations in plasma C3a levels were less in group X than in group C. They were equal to in group H. Coagulofibrinolytic system: The plasma levels of TAT complex and D-dimer were lower in group X than in group C. Inflammatory system: The plasma levels of IL-6 and IL-8 were lower in group X than group C. Adsorbed plasma proteins, especially fibrinogen were markedly less in group X than in group C and H. [Conclusion] In this clinical study, the superior biocompatibility of X-coating was confirmed as CPB coating material, and its efficacy seemed to be compatible to heparin coating as for various chemical reactions induced by CPB. In addition, it may exceed the heparin coating as for suppression of the adsorption of plasma proteins such as fibrinogen. X coating may be suitable for the improvement of biocompatibility of CPB in the clinical settings.

Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model

Argatroban is a selective thrombin inhibitor synthesized in Japan. Argatroban, which has a high affinity for thrombin, and markedly inhibits thrombin-induced reactions, has been used in patients with artherosclerosis obliterans. The efficiency of argatroban, instead of heparin, as an anticoagulant in dog models of cardiopulmonary bypass was explored. In the first study, argatroban was administered as a bolus plus infusion for 1 h during cardiopulmonary bypass at doses of 1.0 mg+10 μg/kg per min, 2.0 mg+10 μg/kg per min and 3.0 mg+10 μg/kg per min ( n=2 per group). Activated clotting time and arterial gas analyses were performed beforehand and 10 min thereafter. In the second study, there were four groups. In the first group ( n=5), no coated extracorporeal circuit was used and heparin (2 mg/kg) was used as an anticoagulant. In the second group ( n=5), a coated extracorporeal circuit was used and heparin was used (2 mg/kg) as an anticoagulant. In the third group ( n=3), no coated extracorporeal circuit was used and argatroban (2.0 mg+10 μg/kg per min) was used as an anticoagulant. In the fourth group ( n=5), a coated extracorporeal circuit was used and argatroban was used (2.0 mg+10 μg/kg per min) as an anticoagulant. All animals were perfused for 120 min at 40 ml/kg per minute. Platelet count, activated clotting time, thrombin–antithrombin III complex, antithrombin III, fibrinogen, fibrinogen degradation products and C3a were measured to evaluate platelet, coagulofibrinolytic and the complement system. Activated clotting time values and the effect of argatroban during cardiopulmonary bypass indicated a dose-dependent response. The next highest dosing group (2.0 mg+10 μg/kg per minute) had activated clotting time values of 250–300 seconds during cardiopulmonary bypass, and fell after reaching near-normal levels within 60 minutes. No clots were noted in the extracorporeal circuit. The argatroban group showed lower levels in their coagulofibrinolytic system compared with the heparin group. The platelet count remained at a high level in the argatroban group. It is concluded that the combination of heparinized cardiopulmonary bypass circuits, and the use of argatroban as an anticoagulant, is safe and reduces the activation of coagulation and fibrinolytic systems and preserves platelet count.

Argatroban as a Potential Anticoagulant in Cardiopulmonary Bypass-Studies in a Dog Model

Argatroban is a selective thrombin inhibitor synthesized in Japan. Argatroban, which has a high affinity for thrombin, and markedly inhibits thrombin-induced reactions, has been used in patients with artherosclerosis obliterans. The efficiency of argatroban, instead of heparin, as an anticoagulant in dog models of cardiopulmonary bypass was explored. In the first study, argatroban was administered as a bolus plus infusion for 1 h during cardiopulmonary bypass at doses of 1.0 mg + 10 μg/kg per min, 2.0 mg + 10 μg/kg per min and 3.0 mg + 10 μg/kg per min ( n = 2 per group). Activated clotting time and arterial gas analyses were performed beforehand and 10 min thereafter. In the second study, there were four groups. In the first group ( n = 5) no coated extracorporeal circuit was used and heparin (2 mg/kg) was used as an anticoagulant. In the second group ( n = 5). a coated extracorporeal circuit was used and heparin was used (2 mg/kg) as an anticoagulant. In the third group ( n = 3), no coated extracorporeal circuit was used and argatroban (2.0 mg + 10μg/kg per min) was used as an anticoagulant. In the fourth group ( n = 5), a coated extracorporeal circuit was used and argatroban was used (2.0 mg + 10 μg/kg per min) as an anticoagulant. All animals were perfused for 120 min at 40 ml/kg per minute. Platelet count, activated clotting time, thrombin—antithrombin III complex, antithrombin III. fibrinogen, fibrinogen degradation products and C3a were measured to evaluate platelet, coagulofibrinolytic and the complement system. Activated clotting time values and the effect of argatroban during cardiopulmonary bypass indicated a dose-dependent response. The next highest dosing group (2.0 mg + 10 μg/kg per minute) had activated clotting time values of 250–300 seconds during cardiopulmonary bypass and fell after reaching near-normal levels within 60 minutes. No clots were noted in the extracorporeal circuit. The argatroban group showed lower levels in their coagulofibrinolytic system compared with the heparin group. The platelet count remained at a high level in the argatroban group. It is concluded that the combination of heparinized cardiopulmonary bypass circuits, and the use of argatroban as an anticoagulant, is safe and reduces the activation of coagulation and fibrinolytic systems and preserves platelet count.

Changes in Coagulofibrinolysis followed by Surgery under the Use of Tourniquet on a lower Extremity

44 patients underwent surgery on a lower extremity under the use of tourniquet. Blood samples were obtained from the radial artery and the femoral vein on the involved leg, at the time of the inflation of tourniquet and one hour after its release. Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fbg), antithrombin III (AT III), solubule fibrin monomer complex (SFMC), thrombin-antithrombin III complex (TAT), D-dimer, plasminogen (Plg), α2-plasmin-inhibiter (PI) and plasmin-plasmin inhibitor complex (PIC) were measured as analyses of coagulofibrinolysis. Total CK activity (CK), CK isoform ratio (IR) and myoglobin (Mb) were measured as a indicator of tissue injury.TAT denoted always a significantly higher value in venous sample. After the release of tourniquet, APTT shortened and PT ratio decreased both significantly. Fbg and AT III showed significant decreases and TAT significantly increased. Plg and PI showed significant decreases and PIC significantly increased. CK, IR and Mb showed significant increases. TAT showed positive correlations with CK, IR and Mb. PIC showed positive correlation with CK, IR and Mb. Only IR in venous sample was correlated with the duration of tourniquet.The values of APTT, PT, Fbg, AT III, TAT, Plg, PI and PIC suggest changes caused by a local hypercoagulofibrinolytic state. We should follow serial changes of these values to estimate the coagulofibrinolytic system in the patient with a local hypercoagulofibrinolytic state.

Effects of Nafamostat Mesilate on Platelets and Coagulofibrinolysis During Cardiopulmonary Bypass Surgery

The effect of nafamostat mesilate (FUT-175) on platelet membrane glycoproteins and the coagulofibrinolytic system were analyzed. Twenty-five patients undergoing aorto-coronary bypass surgery were randomly distributed into an FUT treated group and a control group. In the control group, anticoagulation was achieved with sodium heparin (3 mg/kg) immediately before cardiopulmonary bypass (CPB). In the FUT treated group, in addition to the usual treatment with heparin, FUT-175 was infused continuously at a rate of 2 mg/kg/hr. In the control group, alpha 2 plasmin inhibitor/plasmin complex (PIC) and fibrinogen/fibrin degradation products (FDP) D-dimer increased significantly during CPB, reaching 6.1 +/- 5.1 micrograms/ml and 576 +/- 200 ng/ml, respectively, at 60 min of CPB. PIC and FDP D-dimer remained significantly lower in the FUT treated group than in the control group. GPIb on platelets decreased significantly in both groups, but remained higher in the FUT treated group (81 +/- 5% vs. 56 +/- 21% at 60 min of CPB, P < 0.01). There were no significant changes in GPIIb/IIIa on platelets throughout the procedure in either group. Blood loss after CPB was significantly lower in the FUT treated group than in the control group (778 +/- 277 ml vs. 1,342 +/- 426 ml, P < 0.01). The authors conclude that FUT-175 improves hemostasis after CPB, not only by inhibiting fibrinolysis, but also by preserving platelet GPIb during CPB.

P-72 - Effects of KC-764, an anti-plate-let agent, on the coagulo-fibrinolytic system.

P-72 - Effects of KC-764, an anti-plate-let agent, on the coagulo-fibrinolytic system.

体外循環下開心術におけるＧａｂｅｘａｔｅ Ｍｅｓｉｌａｔｅ（ＦＯＹ）の応用

The purpose of this study was to evaluate the effects of gabexate mesilate (FOY®) on coagulofibrinolytic system during cardiopulmonary bypass (CPB) in open heart surgery. Twenty-four patients were diveded into two groups: group A consisted of 13 patients administered only heparin (3mg/kg), and group B consisted of 11 patients administered FOY (40mg/kg/hr) in addition to heparin (3mg/kg). The following parameters were examined; fibrinopetide A (FPA), fibrinopeptide B β15-42 (FPB β15-42), tissue plasminogen activator antigen (t-PA; Ag), and contact factors (FXII, high molecular weight kininogen, prekallikrein). Fibrinolytic activity was also determined by the fibrin plate method. FPA increased significantly during CPB in group A, but it did not in group B. FPB β15-42 and t-PA; Ag increased druing CPB in both groups to the same degree. Cl-INA resistant fibrinolytic activity was similar in both groups, but fibrinolytic activity determined by kaolin activated euglobulin showed less change in group B. Factor XII decreased in group A, but they did not in group B. It's concluded that FOY suppresses the coagulation system and intrinsic fibrinolytic system probably by the effect on the contact factors.

398 Coagulofibrinolytic system and its inhibitors in the patients undergoing cardiopulmonary bypass

398 Coagulofibrinolytic system and its inhibitors in the patients undergoing cardiopulmonary bypass

Development of Diabetic Microangiopathy and Plasma Proteins Related to the Coagulofibrinolytic System

Development of Diabetic Microangiopathy and Plasma Proteins Related to the Coagulofibrinolytic System

Comparative study of the alterations on coagulo-fibrinolytic system in the plasma exchange with two diffevent substitution solutions

Comparative study of the alterations on coagulo-fibrinolytic system in the plasma exchange with two diffevent substitution solutions

SIII-3 - Studies on the anticoagulant and fibrinolytic drugs on thechange of Coagulo-fibrinolytic system in renal disease.

SIII-3 - Studies on the anticoagulant and fibrinolytic drugs on thechange of Coagulo-fibrinolytic system in renal disease.

Influence of coagulant and antifibrinolytic agents on coagulation and fibrinolysis after pulmonary cancer operation

Coagulation and fibrinolysis system is important on the release and stickness of criculating cancer cells after the cancer operation. We showed that pulmonary metastasis was protected by decrease of platelets, inhibition of platelet function and inducement of fibrinolytic activity in rat.According to those experimental studies, Influence of coagulant and antifibrinolytic agents on coagulo-fibrinolytic system after operation were investigated in pulmonary cancer cases. Inspite of un-used coagulant agents, we observed that fibrinolytic activity was decreased, antiplasmin activity was increased and adhesitveness of platelets was enhanced.The difference of coagulant agents used groupes and un-used groupes was not recognized. It is suported that the anti-coagulant and Fibrinolytic agents is better than the coagulant and antifibrinolytic agents for cacer operation.

Studies on the antihemophilic factor in patients with the artificial valve

The thromboembolism following the artificial valve replacement in patients with acquired heart valve diseases is one of the most important complications. The studies have been aimed to clarify the specific abnormalities of the platelet function and the coagulofibrinolytic system after the valve replacement.Methods and MaterialsTwenty-six patients with heart valve diseases were divided into 2 groups as follows, in 11 of them the valve repair has been performed (group I), and 15 the valve replacement has been done (group II). Laboratory data have been chronologically checked 2 months after the operation. All patients of group II and some of group I had anticoagulant therapy postoperatively. Platelet aggregation was studied with an aggregometer of Bryston's Co., with the modified method of O'Brien's technique. ADP and collagen were used as aggregating agents. Fibrinogen and plasmin activity in plasma were measured by ordinary methods. FDP in plasma was estimated by the HIT method. Factor VIII procoagulant activity (VIII-AHF) was determined by a one-stage method, and the factor VIII related antigen (VIII-AGN) and antithrombin III in plasma were quantitatively determined by electrophoresis in agarose gel containing antibodies (Laurell's method).ResultsThe value of T1/2 of the platelet aggregation induced by both of ADP and collagen were shorter in group II than group I, and the value of R was smaller in group II than group I. The small R means that the aggregability of platelet was enhanced by the activated factor XII. High values of FDP were noticed more frequentry in group II than in group I but plasmin activity of plasma was not detected by standard fibrin plate method. VIII-AHF ranged from 50 to 3000, and significant difference was not found between the two groups. VIII-AGN also ranged from 50 to 400%, but the mean of group II and group I were 197±28%, and 151±17% respectively. The amount of VIII-AGN in group II was slightly increased and it is interesting to find that the high value of VIII-AGN was shown in patients with Starr-Edwards ball valves, but not in patients with Hancock Xenograft valve.The mean ratio of VIII-AHF to VIII-AGN for both groups were almost same value but about half of the examined samples in group II showed significantly less value than the normal range but only 1/3 in group II.In these studies in patient with heart valve disease, there was no consistent correlation between ratio of VIII-AHF to VIII-AGN and FDP or LDH.Antithrombin III was all normal in group I patients but in group II patients some samples showed reduced value out of the normal range and the mean value of group II was smaller than that of group I.The reduced value of ratio of VIII-AHF to VIII-AGN and AT-III were found in patients with artificial heart valve and this indicates that VIII-AHF and AT-III may be consumed by the formation of microthrombus and VIII-AGN may be produced reactively. In addition we reported previously that hyperaggregability of platelet and FDP production were found more frequentry in patients with artificial heart valve. It would be also important to be pointed out that such a hypercoagulable state was induced even in these patients in good controlled state given by clofibrate and warfarin.

Influence of Operation on Blood Coagulation and Fibrinolysis in Cancer Patiens

Patients with malignant disease are often complicated by bleeding or thrombosis. In recent years, altered blood coagulation and fibrinolytic system in malignancy has been reported by many investigators. In this study, the changes of coagulation and fibrinolytic system in patient with malignant tumors were followed up during and after operation.Material and method: The series consisted of twenty-three patients in the following diagnostic categories: malignant lymphoma (1); carcinoma of the stomach (10), breast (5), large intestine (3) and pancreas (1); and cholelithiasis (3). Plasma fibrinogen, plasminogen, α1-antitrypsin, α2-macroglobulin and antithrombin III were determined by single radial immunodiffusion method. Fibrin and fibrinogen degradation product in serum was determined by hemaggultination inhibition titer. Platelets were counted by automatic counter.Result and Discussion: The patients were divided in three groups; the first group (15 cases) was malignant disease with laparotomy, the second group (5 cases) was malignant desease without laparotomy and the third group (3 cases) was non-malignant disease. In many cases with tumors, plasma fibrinogen levels were elevated pre-operatively. It was observed that the concentration of fibrinogen was decreased during the first post-operative day and greatly increased until one or two weeks after operation. In most cases, the number of platelets was decreased for a few days and thereafter it was increased over the pre-operative value in two weeks after operation. The elevated concentration of FDP in serum was found in three of the twenty patients with tumors pre-operatively. After operation, serum FDP was elevated for two or three weeks in most cases of malignancy and especially in the cases of inoperable tumors, the elevated concentrations of FDP and fibrinogen were found at third week after operation.The concentrations of plasminogen, α2-macroglobulin and antithrombin III were decreased during operation and returned to pre-operative value until to seven days after operation. Although individual variations were observed pre-operatively, α1-antitrypsin concentrations in patients with tumors were increased during and after operation and returned to pre-operative value in about third week post-operatively.From these data, it is suggested that cancer patients have a delicately balanced coagulofibrinolytic system and its disorder may be induced by surgical treatment.

Studies on the platelet function and coagulofibrinolytic system in patients with artificial heart valve

The thromboembolism following the artificial valve replacement in patients with acquired heart valve diseases is one of the most important complications. This study has been aimed to clarify the specific abnormalities of platelet function and coagulofibrinolytic system after the operation for valve replacement.Methods:Thirteen patients with heart valve diseases were divided into 2 groups as follows. In 7 of them the valve repair has been performed (group I), and in 6 the valve replacement has been done (group II).Laboratory data have been chronologically checked just before the operation, and for 6 months after the operation.Platelet aggregation was studied with an aggregometer (Bryston Co.), with the modified method of O'Brien's technique. ADP and collagen were used as aggregating agents.Platelet aggregation was estimated by indices of maximum aggregation rate (%), T1/2 (sec) and “R”. “R” is a new index postulated by us which means the changing rate of T1/2 (Y) obtained by change of platelet concentration (X) in collagen aggregation, that is R=d log(Y)/d log(X), We believe by clinical and experimental data that when “R” is small, the platelet aggregability is large and when “R” is large, the platelet aggregability is small.Fibrinogen and plasmin activity in plasma were measured by ordinary methods. FDP in plasma was estimated by the HIT method.Results:The mean values of T1/2 induced by both ADP and collagen were shorter in group II than group I during the course observed. However, the mean value maximum aggregation rate induced by ADP was smaller in group II than in group I. This might be resulted from the effect of clofibrate which was given in group II.Though “R”s remained in normal range in the majority of group I, they were out of normal range in about half of group II; sometimes smaller, and sometimes larger within a observation period of postoperative days. This variation of “R”s means that in patients of group II the platelet function is in a very unstable state, sometmes in hyperaggregability state by the stimulation with artificial valve, and occasionaly in hypoaggregability state by the secondary damages due to microthrombi.Specific changes were not seen in fibrinogen amount and plasmin activity but high values of FDP were noticed more frequently in group II than in group I.These results indicate that in patients with artificial heart valve, microthrombi may be made and thereafter FDP may be produced as a result of hyperaggregability of platelets.It is also important problems that such a hyperaggregability state was induced even in these patients given clofibrate and warfarin.Further studies will be needed to establish the pathogenesis and prophylactic methods for thrombosis in the patients with artificial heart valve.

Changes of anti-thrombin III, anti-thrombin and anti-thrombin in liver diseases

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.

Experimental studies on the production of pulmonary infarction, especially from coagulative and fibrinolytic studies.

In this experiment, attempts were made to clarify the mechanism with which the pulmonary infarction occurs, from coagulofibrinolytic point of view. The following results were obtained.1) Injection of the human serum (2ml./Kg.) into the rabbits provoked a hypercoagulative state within 2min. after the injection, followed by a decrease afterward with accelerated fibrinolytic activity. The control level was resumed about 1 hour after the injection.2) Changes in the coagulofibrinolytic system induced by lycopodium spores infusion progressed slowly toward a marked hypercoagulative state with reduced fibrinolytic activity seen 2 to 3 days later. Injection of the blood clots at this time yielded a high mortality among the animals.However the pulmonary infarction tended to occur in the survived.3) Although natural liquefaction of the blood clots, when injected at the 5th day after the lycopodium spores infusion, was seen in the majority of the cases, intravenous injection of t-AMCHA in combination with the procedure produced the pulmonary infarction in 62.5% of the animals, and further addition of intravenous injection of the human serum yielded the highest rate (88.9%) in producing the infarct.The tissue activator was a high activity in the infarcted area for 6 hours after the blood clot injection, but showed a decrease below control level after 3 to 5 days.4) The same procedure performed I month or later after the lycopodium infusion failed to produce the infarct.5) It is concluded from these observations that the following 3 factors, cessation of the blood flow in the collateral vessels brought by repeated microembolization as can be obtained experimentally by the lycopodium infusion, hypercoagulative state in the blood, and reduction of fibrinolytic activity, are sine qua non in producing the pulmonary infarction. Embolization of the pulmonary artery with large embolus or emboli, and injury in the capillary beds as might be brought about by a heterologous serum injection are additional factors in the occurrence of the infarcts.