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Background The efficacy and safety of thrombomodulin alfa (TM-α), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). Objective To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters. Patients/methods The 227 patients of the full analysis set population described in the original phase 3 trial in Japan were included in this analysis. Changes in parameters between before and after TM-α or heparin administration in each of the two patient groups, with underlying diseases of either hematologic malignancy or infection, were studied separately and results were compared between TM-α and heparin treatment groups in a post hoc manner. Results TM-α administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-α administration reduced consumption of endogenous anticoagulants such as antithrombin and protein C by DIC, compared with the heparin group. DIC scores were decreased in both TM-α and heparin groups during the 6-day treatment. Conclusion TM-α can alleviate intravascular coagulation and consumption of anticoagulants without extending coagulation times. This may be associated with the relatively low risk of bleeding during TM-α treatment.

To investigate treatment effects of thrombomodulin alfa (TM-α) in patients with disseminated intravascular coagulation (DIC) having infection as the underlying disease, retrospective subanalysis of a double-blind, randomized controlled phase 3 trial was conducted. In the phase 3 trial, 227 DIC patients (full-analysis set) having infection and/or hematologic malignancy as the underlying disease received either TM-α (0.06 mg·kg for 30 min once daily) or heparin (8 U·kg·h for 24 h) for 6 days using the double-dummy method. Among these patients, 147 patients with noninfectious comorbidity leading to severe thrombocytopenia (e.g., hematologic malignancy, or aplastic anemia) were excluded from the present analysis, and 80 patients with infectious disease and DIC were extracted and subjected to the present retrospective subanalysis. Disseminated intravascular coagulation resolution rates were determined using the DIC diagnostic criteria for critically ill patients at 7 days, and mortality rates were evaluated at 28 days. In the TM-α and heparin groups, DIC resolution rates were 67.5% (27/40) and 55.6% (20/36), and 28-day mortality rates were 21.4% (9/42) and 31.6% (12/38), respectively. Mortality rates of patients who recovered from DIC were 3.7% (1/27) in the TM-α group and 15% (3/20) in the heparin group. These results suggest TM-α may be valuable in the treatment of DIC associated with infection.

Bone marrow toxicity is a great challenge for physicians treating patients with non-Hodgkin's lymphoma (NHL) and prescribed chemotherapy. Granulocyte colony-stimulating factor (G-CSF) prevents myelotoxicity, but the optimal timing and scheduling of G-CSF administration has not been ascertained. We investigated leukocyte count oriented G-CSF administration schedules, as related to full dose administration of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) chemotherapy, with shortened intervals. Thirty-eight Japanese patients with NHL were included in this study. The standard CHOP combination was administered in six cycles. Patients were given G-CSF in a dose of 2 micrograms/kg/day, subcutaneously starting the day when total leukocytes were3,000/microliters. When leukocyte count remained at3,000/microliters, G-CSF was started 10 days following CHOP. Treatment with G-CSF was discontinued after the leucocyte count reached10,000/microliters, and CHOP was started the next day (CHOP-G treatment; CHOP-G). Doses were not modified in any patient. Patients over 70 years of age received 2/3 of the standard dosage. In the first cycle of CHOP, the day of initiation of G-CSF was 9.6 days following CHOP in the first cycle and 7.7 to 8.5 days during 2 to 6 cycles. The mean duration of G-CSF injection was 7.4 days with a range from 6.8 to 8.0 days, in each CHOP cycle. The mean intervals of CHOP-G was 14.7 days during six consecutive courses, and there was no prolongation of the intervals, even in later cycles. In 23 patients who received all six cycles of CHOP-G, the overall response rate was 91.3% (73.9% complete remission; CR and 17.4% partial remission; PR). In 32 patients with intermediate grade NHL, the overall response rate was 84.4% (65.5% CR and 18.8% PR). Thus, the full dose CHOP with G-CSF, based on the leukocyte count oriented schedule, can be achieved with shortened intervals, an approach which will increase the quality of life (QOL) for the patients by reducing the days of treatment as well as the cost of G-CSF.

Urinary gamma-carboxyglutamic acid (gamma-Gla) levels were determined in healthy subjects of all ages. The urinary gamma-Gla levels were highest in infants (0-1 years), then fell in an age-dependent manner, again in subjects reaching a minimum value in adults, then gradually increased over 60 years of age. Urinary gamma-Gla levels therefore change markedly with aging. The relationships between the urinary gamma-Gla excretion and plasma levels of prothrombin and protein C in patients with various hepatic diseases or diabetes mellitus were examined and compared with those in healthy adults. Both plasma prothrombin and protein C levels were decreased in all patients with liver disease compared with healthy adults. In patients with hepatitis and liver cirrhosis, the decrease did not, however, affect the gamma-Gla excretion. In addition, in patients with hepatoma or carcinoma with liver metastases, the urinary gamma-Gla levels were increased. In patients with diabetes mellitus, the urinary gamma-Gla levels and plasma levels of prothrombin and protein C tended to increase, but this was not significant. The present results indicate that simultaneous measurement of the levels of urinary gamma-Gla and plasma prothrombin and protein C is a useful tool for the diagnosis of liver diseases and diabetes mellitus.

Background: Thrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation. Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular domain of thrombomodulin. ART-123 has been shown to have a wider safety margin than other anticoagulants and to have a favorable antithrombotic profile with less bleeding in animal and in vitro experiments. ART-123 is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. Objective: We conducted a multicenter, double-blind, randomized parallel-group trial to compare the efficacy and safety of ART-123 to those of heparin for the treatment of disseminated intravascular coagulation (DIC) associated with infection or hematologic malignancy. Methods: DIC was diagnosed according to the diagnostic criteria established by the Japanese Ministry of Health and Welfare. DIC patients were assigned to receive ART-123 (0.06 mg/kg for 30 min, once a day) or heparin sodium (8 units/kg/h for 24 h) for six days using a double dummy method. The primary efficacy endpoint was DIC resolution rate (rate of recovery from DIC). The secondary endpoints included clinical course of bleeding symptoms, and mortality at 28 days. Results: 234 DIC patients were randomized (117 in each arm). DIC resolution rate was 66.1% for the ART-123 group and 49.9% for the heparin group (difference 16.2%; 95% CI 3.3–29.1), thus demonstrating that ART-123 is significantly superior to heparin for the improvement of DIC. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (p=0.0271) and the disappearance rate of bleeding symptoms in the ART-123 group was higher than that in the heparin group (35.2% vs 20.9%; difference 14.3%). The incidence of bleeding-related adverse events up to 7 days after the start of administration was lower in the ART-123 group than in the heparin group (43.1% vs 56.5%; difference; −13.4%; p=0.0487). The mortality rate at 28 days in the ART-123 group was 22.0% vs 25.5% in the heparin group (difference −3.4%; p=0.5396). Although no significant differences were seen, 28-day mortality for the ART-123 group was slightly lower. The mortality rate of patients with DIC secondary to infection in the ART-123 and heparin groups was 28.0% (14/50) and 34.6% (18/52), respectively, indicating a 6.6% lower mortality in the ART-123 group. Conclusion: When compared with low-dose heparin, ART-123 more significantly improves DIC and alleviates bleeding symptoms in DIC patients. The incidence of bleeding-related adverse events is significantly lower with ART-123 than with heparin. Because of its safety and efficacy, ART-123 appears to be a first-line agent in the management of DIC.

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.

Coagulation-fibrinolitic system and platelet in hepatitis, liver cirrhosis, and liver cirrhosis with hepatoma were investigated.Results:1) The shortening of 131I-fibrinogen turnover rate were recognized.2) In hepatitis, plasminogen and antithrombin III showed the decrease.3) As regards to the platelet function, the decrease in platelet count and the increase in platelet volume were recognized, but platelet factor 3 availability showed the elevation in several cases.4) The appearance of endotoxin were recognized.5) In comparison between Reptilase Time (R. T.) and Thrombin Time (T. T.), the discrepancy of both value, and the prolongation of RT were recognized.6) Fibrin polymerisation were prolonged in hepatitis, but in several cases of liver cirrhosis and liver cirrhosis with hepatoma fibrin polymerisation were shortened.Conclusion: From the above results, it was suggested that in hepatitis, thrombotic tendency under hypo-coagulable state were shown, and we considered the possibility of progress to DIC in hepatitis with fibrinogen abnormality due to hepatocelluler damage.

Plasma vasoactive intestinal peptide (VIP) concentrations of normal individuals and patients with pancreatitis were studied using a VIP RIA kit. The inter-assay and intra-assay variation of this kit were between 2.1 and 9.4%. The VIP levels increased in the acute phase of acute pancreatitis and patients with chronic pancreatitis. The VIP concentration increased during the first 30 min of glucose tolerance test, but this increase was much smaller than that in insulin. These results suggest that this kit is useful for physiologic and pathologic changes in the VIP level.

We have investigated the effect of the injection of secretin and glucagon in pancreatitis on the coagulation and fibrinolysis.After the injection of secretin, we noticed the decrease of platelet aggregation and of the intrinsic coagulation factors (especially aggregation) and the increase of FDP, while as to the plasma fibrinogen no marked change. But by the injection of glucagon after secretin, we found normalization of decreased platelet aggregation due to the secretin and increased FDP, and as above mentioned, the decreased factor showed a slight elevation.From the results of this investigation we draw the following conclusion: In pancreatitis the consumption of intrinsic coagulation factors and the elevation of fibrinolysis were found under the stimulus of secretin, and at the same time, both the consumption and the hyperfibrinolysis were normalized by the use of glucagon.

We have investigated the platelet volume of normal adults and a few cases of several diseases. Coulter Counter ZBI was used in measuring the platelet volume. The results are as follows:1) About the investigation of normal adults, the platelet volume in females and old persons showed a slight increase.2) In the advanced stage of ITP, both the mode and the mean platelet volume showed the decrease, while in the recovered stage of ITP, normalization was shown.3) In chronic active hepatitis and liver cirrhosis, the platelet volume was generally large, and showed the decrease after bleeding.4) In DM and IHD, the platelet volume showed a slight increase. From the above results we are of the opinion that the measurement of the platelet volume gives a great help in understanding the platelet function. On the other hand the change of the platelet volume is closely related to haemorrhagic diathesis.

We investigated the platelet volume in perinatal period using Coulter Counter ZB.1) When EDTA was used as an anticoagulant, we found the platelet volume was larger than that in cases using citrate, oxalate, heparin, ACD, and CPD.2) Platelet volumes in cord blood and newborn's blood were smaller than those in adult male's and their mother's blood just after delivery.3) Adult female's platelet volume was larger than adult male's platelet volume.4) The platelet volume in the early and late stage of pregnancy were smaller than adult female's platelet volume.Just before the delivery, the platelet volume became larger, became smaller again just after the delivery, and got to as large as adult female at one month after the delivery.

N-benzoyl-L-tyrosyl-p-aminobenzoic acid (Bz-ty-PABA) was orally administered to 11 controls, 10 patients with chronic pancreatitis, 7 patients with diabetes mellitus and 6 patients with liver cirrhosis. The cumulative 6 h recovery rate of PABA in the urine was significantly lower (P less than 0.005) in patients with chronic pancreatitis (49.1 + or - 10.1 percent), diabetes mellitus (50.4 + or - 20.4 percent) and liver cirrhosis (52.5 + or - 13.0 percent) than in the control group (79.5 + or - 12.0 percent) (mean + or -S.D.). This test is considered to be useful in the diagnosis of pancreatic exocrine insufficiency, especially in chronic pancreatitis. Patients with diabetes mellitus frequently has demonstrable abnormality of pancreatic exocrine function. Liver cirrhosis causing severe impairment of liver functions seemed to interfer with the elimination of PABA.

Fibronectin (Fn.) is widely distributed in human tissue and plasma. The ability of the Reticulo-endothelial system (RES) to retain normal phagocytic activity has been directly correlated with plasma levels of Fn.It is the purpose of this study to determine the levels of Plasma Fn., platelet associated (PA) Fn. and IgG in malignancy and sepsis.PA-IgG and PA-Fn. were measured by immunoperoxidase technique.Plasma levels of Fn. were significantly decreased in malignancy and sepsis. PA-IgG and PA-Fn. levels were significantly elevated in the advanced stage of these diseases. Thus, PA-IgG and PA-Fn. levels showed increases in parallel with the decrease in plasma Fn., both of which were normalized in conjunction with the remission of these diseases.It was concluded from these findings that plasma Fn. is depleted in patients with advanced malignancy and sepsis. These diseases are almost accompanied by DIC. This may be due to the removal of fibrin aggregates from blood by the RES. These state of thrombin stimulation are suggested by the levels of increased PA-IgG and PA-Fn.

Platelet glycoprotein Ib (Glb) is the receptor for von Willebrand factor (vWF) in ristocetin-induced platelet agglutination.The levels of platelet Glb was studied by immunoperoxidase method using monoclonal anti-human platelet Glb antibody (Mouse) and peroxidase conjugated anti-mouse IgM antibody in diabetes mellitus. Platelet Glb levels were 100.8±6.7% in 10 normal subjects, 131.4±61.3% in 41 patients with diabetes mellitus, and 158.7±87.4% in 12 patients with diabetic microangiopathy.There was good correlation between Glb levels and ratio of ristocetin-induced platelet agglutination in patients with diabetes mellitus.Furthermore, a good correlation existed between levels of Glb and VIIIR: Ag measured by electroimmunoassay.These results suggested that increased levels of platelet Glb may be reflect platelet hyperfunction in diabetes mellitus.

A comparative study was conducted of the urinary level of gamma-carboxyglutamic acid (gamma-Gla) in patients with infectious diseases to investigate the mechanism of hemorrhagic diathesis occurrence resulting in post-administrative side effects of cephem-group antibiotics. The results showed that the group of administered antibiotics with N-methyl thiotetrazole (NMTT) side chains exhibited decreases in the urinary level of gamma-Gla. Especially, in the aged group of patients (over 65) with non-carcinoma infectious diseases, significant decreases in the urinary level of gamma-Gla were observed. From the above, it is considered that the administration of antibiotics with NMTT side chains has an effect of prohibiting the vitamin K function.

The clinical efficacy and safety of Cefodizime (CDZM), a new cephem antibiotic, was objectively compared with that of Cefotaxime (CTX) in patients with respiratory infections under a well-controlled comparative study. Patients were administered CDZM or CTX by drip infusion b.i.d. for 14 days in principle at a daily dose of two grams. The parameters assessed were clinical efficacy, safety and clinical usefulness. The following results were obtained: 1. On the basis of committee judgement the clinical efficacy rate was 78.1% (125/160) for the CDZM group, 82.7% (124/150) for the CTX group, and no significant difference was observed between the two drug groups. On the other hand, on the basis of judgement by physicians in charge, the clinical efficacy rate was 83.1% (133/160) for the CDZM group, 83.9% (125/149) for the CTX group, and no significant difference was observed between the two groups. 2. The corresponding figures for patients with pneumonia and pulmonary suppuration were 82.4% (70/85) for the CDZM group, 79.7% (59/74) for the CTX group and no significant difference was observed according to the committee judgement. The judgement by physicians in charge also revealed 83.5% (71/85) for the CDZM group and 82.2% (60/73) for the CTX group. No significant difference was noted between the two groups. While, the committee judgement for the clinical efficacy in patients with chronic respiratory tract infections showed 73.3% (55/75) for the CDZM group, 85.5% (65/76) for the CTX group, and no significant difference was observed between the two drug groups. The corresponding figures were 82.7% (62/75) for the CDZM group, 85.5% (65/76) for the CTX group, and no significant difference was observed between the two drug groups on the judgement by physicians in charge. Furthermore, the clinical efficacy of both drugs on chronic respiratory tract infections was assessed according to "Criteria for Evaluation of Clinical Efficacy of Chemotherapeutics on Chronic Respiratory Tract Infection". It was 76.8% (53/69) for the CDZM group, 76.3% (58/76) for the CTX group, and no significant difference was observed between the two groups. 3. The bacteriological eradication rate of causative pathogens was 92.4% out of 66 patients treated with CDZM and 95.5% out of 67 patients treated with CTX in whom judgement was possible. No significant difference was observed between the two drug groups. 4. The adverse reactions occurred in 4 (2.2%) patients for the CDZM group and 8 (4.5%) patients for the CTX group respectively, with no significant inter-group difference in frequency of these reactions for all cases.(ABSTRACT TRUNCATED AT 400 WORDS)