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Background We compared the prognostic value of plasma high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases. Methods We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system. Results Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, plasma HMGB1 level of 8 ng/mL, and plasma histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, plasma HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: − 0.05 to 0.78, p = 0.08). Conclusions Plasma HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.

INTRODUCTION A criterion for disseminated intravascular coagulation (DIC) that reflects the status of controlled coagulopathy would be useful for determining when to stop treatment. Use of the DIC criteria of the Japanese Society on Thrombosis and Hemostasis (JSTH) for predicting the outcome during recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) treatment was evaluated. METHODS A retrospective, multicenter survey was conducted in 798 medical facilities in Japan. Of the 4342 patients who underwent TM-α treatment, 193 with infection-associated DIC were investigated. RESULTS The 28-day mortality rate increased with the increase in JSTH DIC scores at the end of TM-α treatment, with a Cramer's coefficient of association of 0.431. A reduced platelet count (odds ratio [OR]: 0.847, P

Background In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the fibrinogen value. The relationship between hypofibrinogenemia and outcomes of DIC in infectious diseases has thus remained unclear. Methods We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for DIC and suspected DIC. Hypofibrinogenemia was defined by a fibrinogen level Results Hypofibrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were significantly higher in infectious disease patients with hypofibrinogenemia, suggesting that in patients with infectious diseases, hypofibrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both significantly lower for infectious disease patients with DIC with hypofibrinogenemia than for those without hypofibrinogenemia, this difference was not observed in DIC patients with hematological diseases. Conclusions Hypofibrinogenemia among infectious disease patients with DIC may reflect increased consumption of fibrinogen due to accelerated coagulation reactions, while hypofibrinogenemia among hematological disease patients with DIC may be caused by fibrinogenolysis due to hyperfibrinolysis, and frequently results in bleeding and multiple-organ failure.

Introduction In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the fibrinogen value and the relationship between hypofibrinogenemia and the outcomes of infectious DIC has remained unclear.Materials and Methods We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for with DIC and suspected DIC. Hypofibrinogenemia was defined by a fibrinogen level of Results Hypofibrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were significantly high in infectious disease patients with hypofibrinogenemia, suggesting that in patients with infectious diseases, hypofibrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both significantly lower in infectious disease patients with DIC with hypofibrinogenemia than in those without hypofibrinogenemia, this difference was not observed in DIC patients with hematological diseases.Conclusion In infectious disease patients with DIC, hypofibrinogenemia may reflect from the increased consumption of fibrinogen due to an accelerated coagulating reaction, while that in hematological disease patients DIC may be caused by fibrinogenolysis due to hyperfibrinolysis, and frequently results in bleeding and multiple-organ failure.

The frequency of severe antithrombin deficiency (SAD) was examined in the hematopoietic disorder-, infectious-, and basic-types of the disseminated intravascular coagulation (DIC). A posthoc analysis of 3008 DIC patients (infectious-type, 1794; hematological disorder-type, 813; and basic-type, 401) from post-marketing surveillance data of thrombomodulin alfa was performed. The clinical features of patients and outcomes were compared between patients with and without SAD, using an antithrombin cutoff value of 50%. Patients with SAD accounted for 40.4% of infectious-type DIC, 8.0% of hematopoietic disorder-type DIC, and 26.7% of basic-type DIC. There was no significant difference in thrombin–antithrombin complex levels between patients with and without SAD. The decreased fibrinogen level and differences in clinical features were significantly greater but the increases in fibrinolytic markers were significantly lower in patients with SAD than in those without. The 28-day survival rate was significantly lower in patients with SAD than in those without. Severe antithrombin deficiency was observed in all types of DIC, including hematopoietic disorders. Both hypofibrinolysis and hypercoagulability in patients with SAD may cause multiple organ failure and poor outcomes.

Background Although disseminated intravascular coagulation (DIC) is life-threatening, any organ failure associated with DIC resolution and outcomes have been unclear. Patients and methods A total of 2795 DIC patients (infection: 1990, hematological malignancy: 805) were analyzed in the post-marketing surveillance of thrombomodulin alpha (TM-α). The background factors of sequential organ failure assessment (SOFA) and antithrombin (AT) were investigated in DIC with infectious disease for their association with DIC resolution and outcome using κ statistics, indicating DIC resolution and survival or DIC non-resolution and non-survival. The same analyses were performed for total bilirubin, creatinine, lactate dehydrogenase, and underlying disease in DIC with hematological malignancy. Results In DIC with infectious disease, higher SOFA score severity was closely correlated with lower overall survival in both the DIC resolution and non-resolution groups, but AT activity was not. κ coefficients were 0.234, 0.295, and 0.311 for the SOFA score 0–6, 7–12, and 13–24 groups, respectively. In DIC with hematological malignancy, κ coefficients of total bilirubin were 0.251 and 0.434, and those of creatinine were 0.283 and 0.437 in the normal and abnormal groups, respectively, showing better concordance in the abnormal group than in the normal. Other factors had poor concordance. Conclusion In DIC with infectious disease, DIC resolution is an important therapeutic target in patients who have higher SOFA score severity. In DIC with hematological malignancy, DIC resolution is similarly important in patients with abnormality of bilirubin and/or creatinine. Trial registration The clinical characteristics and treatment outcomes of patients with DIC treated with TM-α between May 2008 and April 2010 were retrospectively analyzed by subgroup analysis of the post-marketing surveillance data.

We evaluated the diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 232 patients with suspected DIC without hematopoietic injury or infection. The diagnoses of the patients were as follows: DIC (n = 116), pre-DIC (n = 54), and non-DIC (n = 63). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic analysis. The area under the curve and odds ratio for the global coagulation test (GCT) scores in the diagnosis of “DIC” were high, whereas those for the diagnosis of “DIC and pre-DIC” were low, suggesting that the addition of a reduced platelet count (RPC), antithrombin (AT), and soluble fibrin (SF)/thrombin AT (TAT) complex was required to diagnose DIC and pre-DIC. When the GCT score with the RPC, AT, and TAT/SF values was used, the cutoff DIC score for the diagnosis of DIC or DIC and pre-DIC was 6 points. For predicting the outcome, a scoring system that used the GCT result was useful, but the addition of RPC, AT, or SF/TAT was not. The modified diagnostic criteria of JSTH, which included the GCT score and the RPC, AT, and TAT/SF values, were useful for diagnosing both DIC and pre-DIC.

Disseminated intravascular coagulation (DIC) is a serious disease that, in the presence of underlying disease, causes persistent, generalized, marked coagulation activation. Early treatment based on an appropriate diagnosis is very important for improving patients’ prognosis, to which end diagnostic criteria play a key role. Several criteria have been proposed, but each has its strengths and weaknesses, and improved criteria are needed. Widespread use of coagulofibrinolytic markers has elucidated that the pathology of DIC differs greatly as a function of the underlying disease. Thus, discriminating use of DIC diagnostic criteria that take underlying diseases into account is important. DIC diagnostic criteria that are well known in Japan include the Japanese Ministry of Health and Welfare’s old DIC diagnostic criteria (JMHW criteria), the International Society on Thrombosis and Haemostasis’s DIC diagnostic criteria (ISTH criteria), and the Japanese Association for Acute Medicine’s acute-stage DIC diagnostic criteria (JAAM criteria). Those criteria have their respective drawbacks: the sensitivity of the ISTH criteria is poor, the JAAM criteria cannot be applied to all underlying diseases, and the JMHW criteria have poor sensitivity in the case of infections, do not use molecular markers, and result in misdiagnosis. The Japanese Society on Thrombosis and Hemostasis’s newly proposed provisional draft DIC diagnostic criteria (new criteria) use diagnostic criteria classifications of “hematopoietic disorder type”, “infectious type”, and “basic type” based on the underlying pathology. For the hematopoietic disorder type the platelet count is omitted from the score, while for the infectious type, fibrinogen is omitted from the score. Also, points are added if the platelet count decreases with time. In the new criteria, molecular markers and antithrombin activity have been newly included, and as a countermeasure for misdiagnosis, 3 points are deducted if there is liver failure. In this paper, we discuss various problems encountered with DIC diagnosis, and we describe the new criteria together with the events that led to their creation. These new diagnostic criteria take into account the underlying diseases of wide area, and we expect that they will serve clinicians well due to the above adaptations and improvements.

The generation of thrombin–antithromin (AT) complex (TAT) or soluble fibrin (SF) was prospectively compared with prothrombin fragment 1 + 2 (F1 + 2) generation in patients with disseminated intravascular coagulation (DIC). The plasma levels of TAT, SF, and F1 + 2 were significantly higher in the DIC group than in the non-DIC group. The differences in these levels between the DIC group and non-DIC group were significantly related to infections and hematopoietic tumors. There were no significant differences in the TAT/F1 + 2 ratio between DIC and non-DIC patients, but the SF/F1 + 2 ratio was significantly higher in the DIC group than the non-DIC group. The plasma AT activity was significantly higher in patients with DIC with resolution than in those without resolution, and in survivors than in nonsurvivors. These findings suggest that the ratio of TAT/thrombin is constant between the patients with and without DIC but that the ratio of fibrin formation/thrombin might increase in DIC.

Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), d-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, d-dimer, and SFMC were recommended to be 8.3 and 42.0 μg/mL, 2.4 and 22.0 μg/mL, and 3.4 and 138.0 μg/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin-related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders.

Disseminated intravascular coagulation (DIC) sometimes has a poor outcome, and therefore early diagnosis and treatment are required. This study prospectively evaluated the hemostatic abnormalities and the onset of DIC in 613 patients with underlying diseases to identify a useful marker for diagnosing Pre-DIC. Pre-DIC was defined as the condition of patients within a week before the onset of DIC. Initially, 34.4% of patients were diagnosed with DIC, and about 8.5% of the patients without DIC were diagnosed as DIC within a week after registration (pre-DIC). The mortality of DIC, Pre-DIC and "without DIC" was 35.3%, 32.4% and 17.2%, respectively. All hemostatic parameters were significantly worse in "DIC" than "without DIC" and the values of the prothrombin time ratio, platelet count and fibrin monomer complex could classify the three groups; "DIC", "pre-DIC" and "without DIC". No useful marker was identified that provided an adequate cutoff value to differentiate "pre-DIC" from "without DIC". A multivariate analysis identified clinical symptoms that were related to poor outcome. DIC must be treated immediately; there is no specific marker to identify pre-DIC.

The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS.

症例は, 80歳女性. 既往疾患として, 28年前 (52歳時) より再生不良性貧血のため, 蛋白同化ステロイド (プリモボラン®) の投与を受けていた. 2008年10月上旬, 労作時息切れ, 心窩部痛を主訴に, 再生不良性貧血で治療を受けていた当院内科を受診, 小球性貧血の増悪を指摘された. 消化管の精査で, 多発ポリープを併存した, 前庭部から体下部の進行胃癌と診断された. 腫瘍部の生検では, 中分化腺癌の所見であった. 同年11月上旬, 幽門側胃切除, D2郭清術を施行した. 病理所見は, 腺扁平上皮癌で, pT3 (SE), pN0, H0, P0, CY0, M0, fStage IIであった. 胃内の多発ポリープの病理所見は, 腺腫であった. 再生不良性貧血による汎血球減少のため, 術後補助化学療法は施行できなかったが, 術後1年3ヶ月を経過した現在, 無再発で生存している. また, 汎血球減少の改善も認められた. 胃原発の腺扁平上皮癌は比較的まれで, その頻度は1 ％未満とされている. 今回, 再生不良性貧血の治療経過中に発症した1例を経験したので報告する.

Marginal zone B-cell lymphoma (MZBL) is occasionally associated with prominent plasma cell differentiation. However, MZBL rarely exhibits histological features that resemble plasmacytoma arising from a localized plasma cell variant of Castleman's disease (PCCD). We here report a histologically similar case that was associated with primary cutaneous tumor. The patient was a 57-year-old woman with a 5-year history of cutaneous nodules. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the cutaneous tumor, whereas various numbers of CD5+ centrocyte-like (CCL) cells, which were arranged in a marginal zone distribution pattern, occupied the peripheral region of the tumor. The majority of the lymphoid follicles had atrophic or regressive germinal centers resembling hyaline-vascular Castleman's disease. CCL cells were observed to have colonized a few of the lymphoid follicles. Immunohistochemistry revealed that these cells had a monotypic intracytoplasmic kappa chain. Without treatment, the patient was quiescent, but 2 years later, there was a transformation to the large cell type. These observations suggest that MZBL needs to be distinguished from PCCD, and that untreated cutaneous MZBL may undergo a high-grade blastic transformation similar to other indolent lymphoproliferative disorders.

Objective Disseminated intravascular coagulation (DIC) is often associated with infection and a poor outcome. In this study, useful markers for predicting poor outcomes were examined. Methods The frequency of DIC and organ failure, outcomes and hemostatic markers were prospectively evaluated in 242 patients with infections. Results Seventy-seven patients were diagnosed with DIC, 36 of whom recovered from the condition. The rate of DIC or resolution of DIC was highest in the patients with sepsis and lowest in the patients with respiratory infections. Mortality tended to be high in the patients with respiratory infections. The DIC score, sepsis-related organ failure assessment (SOFA) score, prothrombin time (PT) ratio and thrombin-antithrombin complex level were significantly high in the patients who did not recover from DIC. The age, DIC score, SOFA score, PT ratio and levels of thrombomodulin and plasminogen activator inhibitor (PAI)-I were significantly high in the non-survivors. Factors related to a poor outcome included resolution of DIC, the SOFA score, age and the PT ratio. Factors related to resolution of DIC included the SOFA score and age, while factors related to the SOFA score included the levels of PAI-I, leukocytes, fibrinogen, D-dimer and platelets. Conclusion The outcomes of septic patients primarily depend on the SOFA score and the resolution of DIC, which are related to organ failure.

Patients with suspected disseminated intravascular coagulation (DIC) were prospectively evaluated for various types of underlying diseases, and the usefulness of hemostatic markers were examined for each patient with DIC due to various underlying diseases. The main underlying disease of DIC was infectious diseases, hematologic malignancies, and solid tumors, and a high resolution rate from DIC was observed in obstetric diseases and hematologic malignancies. The diagnosis of DIC was related to a poor outcome in trauma/burn victims and those with infectious disease. In the main underlying disease, it is suggested that DIC would be excluded in patients with hematologic malignancies or solid tumors with a platelet count of more than 100,000/μl and in the patients with an FDP of less than 10 μg/ml, and fibrinogen of less than 100mg/dl, suggesting the presence of DIC. The prothrombin time was a sensitive marker, but fibrinogen levels were not sensitive for DIC due to infectious diseases. The plasmin plasmin inhibitor complex in hematologic malignancy, and soluble fibrin monomer complex, antithrombin and thrombomodulin in patients with infectious disease, were sensitive markers for the diagnosis of DIC. Although hemostatic markers were useful for the diagnosis of DIC, the usefulness varied depending on the different underlying diseases.

Diagnostic criteria for non-overt disseminated intravascular coagulation (DIC) have been proposed by the International Society of Thrombosis and Hemostasis, but are not useful for the diagnosis of early phase of overt-DIC (pre-DIC). Therefore, in the current study the non-overt DIC diagnostic criteria were modified using the global coagulation tests, the change rate in the global coagulation tests and molecular hemostatic markers to detect the pre-DIC state and were prospectively evaluated in 613 patients with underlying DIC disease. The frequencies of patients with DIC (DIC positive), late onset DIC, and without DIC (DIC absent) were 29.5%, 7.2%, and 63.3%, respectively. The modified non-overt-DIC criteria can correctly predict 43/44 patients (97.7%) who were DIC absent at admission and became DIC positive, within a week (late onset DIC state). The mortality rate was higher in DIC positive compared with pre-DIC (37.6% vs. 22.7%, P < 0.05) or DIC negative (37.6 vs. 13.7%, P < 0.01). It was also significantly higher in pre-DIC compared with DIC negative (P < 0.05). Thus, these modified non-overt DIC diagnostic criteria might therefore be useful for the diagnosis of early-phase DIC.

Thrombin-antithrombin III complex (TAT) is a good marker of intravascular thrombin generation. Oral anticoagulant therapy can be expected to be effective when intravascular thrombin generation is suppressed to an adequate range. TAT levels in the blood plasma from 61 patients receiving warfarin therapy and 12 patients prior to the initiation of warfarin therapy were determined. The degree of anticoagulation was monitored by the one-stage prothrombin time method (PT). Although PT levels were higher than the control range (more than 35%) in 14 of the patients receiving warfarin therapy, there was no significant difference in mean plasma TAT levels between these 14 patients and the 46 patients whose PT levels were within the control range. The mean TAT level in all patients receiving warfarin therapy (1.76±0.46ng/ml) was significantly lower than that in the patients before anticoagulation (5.19±1.97ng/ml) and was nearly the same as the normal control (2.00±0.58ng/ml). No significant relationship was observed between the levels of TAT and PT (%, INR). In several patients receiving warfarin therapy, serial changes in plasma levels of TAT and PT were followed. It was noted that plasma TAT levels always remained within the normal range even if PT (%) deviated from control range, while both PT (%) and TAT levels shifted in a similar direction. These results suggest that conventional PT may not always be an appropriate index to monitor oral anticoagulant therapy, and that the optimal range of anticoagulation for hypercoagulable states should be set according to the plasma levels of TAT.

SummaryEarly treatment of disseminated intravascular coagulation (DIC) is recommended but global coagulation tests used in authorized DIC criteria are not sensitive for diagnosis of early-phase DIC. We examined the plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC) and D-dimer in patients with suspected DIC to determine the cutoff values for diagnosis of DIC. Plasma levels of D-dimer, TAT and PPIC were significantly elevated in patients with DIC and correlated with DIC score. The cutoff values were determined using the receiver operative curve analysis. The cutoff value represented the point at which the sensitivity curve crossed the specificity curve. The cutoff values of D-dimer, TAT and PPIC for DIC were 12. 0 µg/ml, 11.0 ng/ml and 1.8 µg/ml, respectively. These values were moderately to highly sensitive for the diagnosis of DIC but not for poor outcome. The combination of D-dimer, TAT and PPIC showed high sensitivity and low specificity when one or more tests were positive, but showed low sensitivity and high specificity when all three tests were positive. We conclude that hemostatic molecular markers might be useful for the diagnosis of DIC and should be confirmed by several trials.

Although thrombomodulin (TM) in circulating blood is regarded as an indicator of vascular endothelial disorders, blood TM levels are also known to be affected by renal dysfunction. We measured plasma TM levels in primary glomerular disease (PGD) and lupus glomerulonephritis (GN) with the EIA method, and assessed the extent to which renal dysfunction and endothelial disorders contribute to plasma TM levels in these diseases. The plasma TM/serum creatinine (TM/Cr) ratio was significantly higher in lupus GN patients than in PGD patients or normal controls. A significant positive correlation was found between plasma TM and serum Cr levels in both PGD and lupus GN patients, but the slope (A) of the regression line (TM = A • Cr + B) in lupus GN patients was significantly steeper than in PGD patients. We conclude that plasma TM levels are greatly influenced by renal dysfunction, but that not only renal dysfunction but endothelial disorders may be an important determinant of increased plasma TM levels in diseases such as lupus GN.

We report a very rare case of primary Hodgkin's disease of the bone in a 56-year-old male. It presented with sudden onset of paraparesis which suggested an extradural tumor. Early appropriate therapy for similar patients with Hodgkin's disease can improve their prognosis.

Abstract 1297 Poster Board I-319 Introduction Several diagnostic criteria for disseminated intravascular coagulation (DIC) have been proposed by Colman RW et al, Japanese Ministry Health and Welfare (JMHW) and International Society of Thrombosis and Haemostasis (ISTH) etc. The efficacy of treatment in relation to the DIC score when the treatment was begun showed that greater efficacy was achieved in pre-DIC than in DIC patients, suggesting that early diagnosis and early treatment are important. Then, the diagnostic criteria for non-overt DIC was proposed by ISTH/SSC subcommittee in order to diagnose of early phase DIC but it was still not established. In this study, modified non-overt DIC diagnostic criteria using molecular hemostatic markers and antithrombin (AT) has been prospectively evaluated. Total 613 patients suspected to be associated with DIC in nine institutes were registered in this prospective study for DIC diagnostic criteria from January 1, 2005 to December 31, 2008. There were 219 patients with infectious disease, 142 with solid cancer, 115 with hematopoietic tumor, 29 with aneurysm, 10 with obstetrics disease, 23 with trauma, 5 with liver disease, 70 with other disease. Materials and Methods Overt-DIC or non-overt DIC was diagnosed by modified overt-DIC diagnostic criteria or modified non-overt DIC diagnostic criteria using abnormalities or changes of platelet count, prothrombin time (PT), fibrinogen, fibrin and fibrinogen degradation products (FDP), AT, soluble fibrin monomer complex (SFMC), D-dimer and thrombin-AT complex (TAT). Pre-DIC was considered the state within a week before onset of DIC. Measurement of PT, fibrinogen, platelet count, FDP were carried out in each institutes based on numerous previous reports. TAT, SFMC, D-dimer and AT activity were measured in SRL Inc. TAT was measured by enzyme immunoassay (EIA) using. SFMC and D-dimer were measured by latex immune agglutination test using T-test, respectively. AT activity was measured by heparin cofactor activity. Results Frequency of overt-DIC was 29.5 % in 613 patients suspected to be associated with DIC, and the highest frequency of overt-DIC was observed in the patients with obstetrics disease or liver disease. Pre-DIC state was detected in 44 of 613 patients (7.2 %) and the highest frequency of pre-DIC was observed in the patients with hematopoetic tumor (12.2 %). Frequency of non-overt DIC in the patients with overt-DIC, with pre-DIC or without overt-DIC was 97.8 %, 97.7 % or 17.0%, respectively. The mortality of 28 days was the highest in the patients with overt DIC (37.6%), and it was also high in those with non-overt DIC (32.9%) and with pre-DIC (27.3%) in comparison to the patients without overt DIC (15.2%) and those without non-overt DIC (13.8%). Discussion Modified non-overt DIC diagnostic criteria is more sensitive for DIC than overt DIC diagnostic criteria and is related to the outcome. Non overt DIC diagnostic criteria might be able not only to diagnose DIC but also to predict early phase of DIC. Disclosures No relevant conflicts of interest to declare.

Plasma levels of thrombin-antithrombin III complex(TAT), plasmin- α 2 -plasmin inhibitor complex(PAP), von Willebrand factor antigen (vWF:Ag) plasminogen activator antigen(PA) and plasminogen activator inhibitor-1 antigen(PAI-1), were determined in 110 patients with arterial thromboembolic diseases within 4 weeks after attack (Th; 41 cases with myocardial infarction and 69 with cerebral infarction), 67 patients with various types of carcinoma(Ca; 31 cases without metastasis and 36 with metastasis)and 50 age-matched healthy individuals(Co). The following results were obtained: 1) Mean plasma levels of TAT, PAP, vWF:Ag, PA and PAI-1 were significantly higher in Th than Co. 2) Mean plasma levels of TAT, PA and PAI-1 were significantly higher in Ca than Co regardless of metastasis but those of PAP and vWF:Ag were significantly higher only in Ca with metastasis than Co. 3) Significant relationship was observed between plasma levels of TAT and PAP both in Th and Ca. 4) Significant relationship was also observed between plasma levels of TAT and vWF:Ag, PA or PAI-1 in Th, but not in Ca. It is suggested from these results that the coagulopathies observed in these patients result from the activation of intravascular blood coagulation and fibrinolysis, and that vascular endothelial cell damage may play an important role in the activation in Th.

Tissue factor activity (TFA) of leukemic cells (1 x 10(8) cells/mL) was measured in 44 patients with acute nonlymphoid leukemia (ANLL) by the one-stage assay using factor-IX deficient plasma (OSA-dIX) and two-stage assay (TSA). According to the preventative heparin dose schedule based on the TFA measured by the TSA, all disseminated intravascular coagulation (DIC) was controlled successfully. The procedure of the TSA was too complicated for clinical use, and its minimal measurable value was 125 units (U)/L of TFA. The OSA-dIX was simpler in its procedure and sensitive enough to measure accurately a TFA quantity as small as 30 U/L with high reproducibility. In 20 ANLL patients with 125 U/L or more of TFA measured by both assays, there was a significant relationship between their logarithms of TFA (r = 0.93, P less than 0.01). These results suggested that DIC complication in ANLL patients would be controlled successfully by the administration of heparin dosage based on the TFA measured by the OSA-dIX.

Apoprotein part of tissue factor of human placenta was purified 871 fold from the starting material with 4.2% yield by concanavalin A-Sepharose affinity chromatography and SDS-PAGE. The molecular weight of purified apoprotein was 45,000 in non-reduced condition and 49,000 in reduced condition. Tissue factor of human leukemia cells ( FAB classification:M2 and M3 ) and cultured leukemia cell lines (HL-60 and Molt-4) was analyzed using specific rabbit anti-tissue factor IgG raised against purified material. Endotoxin stimulated HL-60 and Molt-4 also expressed procoagulant activity which was inhibited by tissue factor immune IgG. By immunostaining of the purified material, the lysate of leukemia cells ( M2 and M3 ) and cultured leukemia cells (HL-60 and MOLT-4 ) revealed a major band of the same apparent molecular weight. Immuno-electron microscopic study on tissue factor of HL-60 cells produced the following findings: stimulation by endotoxin resulted in the formation of pseudopods of the cell membrane, and immunogold particles accumulated mainly on these pseudopods and cisternal spaces of rough endoplasmic reticulum, indicating exposure of the tissue factor to the surface of perturbed cell membrane with concurrent increase in tissue factor synthesis.

Levels of VIIIR; AG and PA in the venous blood before and after 5 minutes tourniquet and fbg metabolism were determined in 19 patients with arterial thromboembolic disease and 4 age-matched healthy volunteers and the following results were obtained;patient group control group p valuemean±SD mean±SDVIIIR; AG before tourniquet (%) 206.1±60.7 117.5±14.4 p

To investigate the process of activation mechanism of blood coagulation by leukocytes, binding of radiolabelled Factor X and the activation of Factor X on the cell surface of leukocytes were studied by using cultured leukemia cell line, Molt-4 cells. Cells were cultured in RPMI 1640 medium with 10% inactivated fetal, calf serum at a concentration of 1x106cells/ml. After 6 hours' stimulation with 1 ug/ml of endotoxin(LPS: Escherichia coli 026:B6), cells were separated by centrifugation, washed three times with Tris containing NaCl buffer(pH 7.5, TBS), and then suspended in TBS containing 0.5% bovine serum albumin(TBS-BSA) to the concentration of 5x106 cells/ml. Factors X, VII and IX were purified from fresh-frozen human plasma by the method of Bajaj in a modified version. Factor VIII was purified from cryoprecipitate as starting material. Factor X labelled with 1-125 by the method of McFarlane showed a single band on autoradiography. Specific radioactivity was 0.3 mCi/mg. For the study on binding of Factor X, TBS-BSA solution containing 4 mM of CaClp, various amounts of radiolabelled Factor X with/without purified Factors VII, VIII and IX were added to the LPS-stimulated washed cell suspension and mixed well. N-butyl-phtalate was layered over the reaction mixture after incubation at room temperature for various minutes. Total amount of bound Factor X was calculated from the radioactivity of the cell pellet separated by centrifugation of the reaction mixture. The Xa activity generated in the supernatants was assayed using S2222.Results: Factor X bound specifically to the LPS-stimulated Molt-4 cells. Amount of bound Factor X and the dissociation constant was 1.0 ng/5x10bcells (5.2x103sites/cell) and 5x106M, respectively. More amounts of Factor X bound when Factors VIII and IX were present in the reaction mixture than their absence. Five times more Factor Xa was generated when Factors VII, VIII and IX were present in the reaction mixture as compared with presence of Factor VII, alone. These results suggest that blood coagulation cascade proceeds on the LPS-stimulated leukocyte surface.