朝倉英策，高橋芳右，内山俊正，他(日本血栓止血学会DIC診断基準作成委員会). 日本血栓止血学会 DIC診断基準2017年版. 日本血栓止血学会誌 [Internet]. 2017;28(3):369–391. Available from: http://www.jsth.org/wordpress/wp-content/uploads/2015/04/28巻3号_DIC診断基準.pdf
Satoshi Gando, Hideo Wada, Hidesaku Asakura, Toshiaki Iba, Yutaka Eguchi, Kohji Okamoto, Yasuhiro Ohtomo, Kazuo Kawasugi, Shin Koga, Kazuhide Koseki, Hajime Tsuji, Toshihiko Mayumi, Atsuo Murata, Masao Nakagawa, Shigeatu Endo
Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients.
Clin Appl Thromb Hemost. 2005 Jan;11(1):71-6.
Abstract/Text
New Japanese diagnostic criteria were prepared for disseminated intravascular coagulation (DIC) in critically ill patients and their usefulness was compared with the criteria of the International Society of Thrombosis and Haemostasis (ISTH) and those of the Japan Ministry of Health and Welfare (JMHW). In a retrospective study of patients with platelet counts of less than 150 x10(3)/mL, 52 cases (33.3%), 66 cases (42.3%), and 101 cases (64.7%) were diagnosed as DIC by the ISTH, JMHW, and new Japanese DIC criteria, respectively. The DIC state as diagnosed by the new Japanese DIC criteria included both DIC states as diagnosed by ISTH or JMHW criteria. Some DIC states diagnosed by the JMHW criteria included those diagnosed by ISHT criteria but this was not universal. The mortality of DIC as diagnosed by the ISTH or JMHW criteria was markedly high, compared to that for DIC diagnosed by the new Japanese criteria. The mortality of patients without DIC by ISTH was also high when they were diagnosed as DIC by the new Japanese criteria. The frequency of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection. The mortality of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection, and the mortality of overt-DIC by ISTH diagnostic criteria was also high in patients without infection.
Satoshi Gando, Toshiaki Iba, Yutaka Eguchi, Yasuhiro Ohtomo, Kohji Okamoto, Kazuhide Koseki, Toshihiko Mayumi, Atsuo Murata, Toshiaki Ikeda, Hiroyasu Ishikura, Masashi Ueyama, Hiroshi Ogura, Shigeki Kushimoto, Daizoh Saitoh, Shigeatsu Endo, Shuji Shimazaki, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group
A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria.
Crit Care Med. 2006 Mar;34(3):625-31.
Abstract/Text
OBJECTIVES: To validate scoring algorithm criteria established by the Japanese Association for Acute Medicine (JAAM) for disseminated intravascular coagulation (DIC) and to evaluate its diagnostic property by comparing the two leading scoring systems for DIC, from the Japanese Ministry of Health and Welfare (JMHW) and International Society on Thrombosis and Haemostasis (ISTH).
DESIGN: Prospective, multicenter study during a 3-month period.
SETTING: General critical care center in a tertiary care hospital.
PATIENTS: Two hundred seventy-three patients with platelet counts<150x109/L were enrolled.
INTERVENTION: None.
MEASUREMENTS AND MAIN RESULTS: The JAAM, JMHW, and ISTH DIC scoring algorithms were prospectively applied within 12 hrs of patients meeting the inclusion criteria (day 0) to days 1-3, by global coagulation tests. The numbers of systemic inflammatory response syndrome (SIRS) criteria and Sequential Organ Failure Assessment (SOFA) scores were determined simultaneously. Mortality associated with any cause was also assessed 28 days after the enrollment. All global coagulation tests and SIRS criteria adopted in the JAAM criteria and their cutoff points were validated with use of SOFA scores and mortality rate. DIC diagnostic rate of the JAAM DIC scoring system was significantly higher than that of the other two criteria (p<.001). The JAAM DIC algorithm was the most sensitive for early diagnosis of DIC (p<.001). PATIENTS who fulfilled the JAAM DIC criteria included almost all those whose DIC was diagnosed by the JMHW and ISTH scoring systems. The JAAM DIC scores showed significant correlation with SOFA scores ([rho]=0.499; p<.001). SOFA score and mortality rate worsened in accordance with an increase in the JAAM DIC score. Fibrinogen criteria had little effect in predicting outcome for the DIC patients, and a total score of 4 points in the JAAM scoring system without fibrinogen was closely related to poor prognosis. According to the results, we revised the JAAM criteria by excluding fibrinogen and confirmed that the DIC diagnostic properties of original criteria remained unchanged in the revised JAAM criteria.
CONCLUSIONS: The JAAM scoring system has an acceptable property for the diagnosis of DIC. The scoring system identified most of the patients diagnosed by the JMHW and ISTH criteria. Revised JAAM DIC criteria preserved all properties of the original criteria for DIC diagnosis. The revised scoring system can be useful for selecting DIC patients for early treatment in a critical care setting.
F B Taylor, C H Toh, W K Hoots, H Wada, M Levi, Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH)
Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.
Thromb Haemost. 2001 Nov;86(5):1327-30.
Abstract/Text
J L Vincent, A de Mendonça, F Cantraine, R Moreno, J Takala, P M Suter, C L Sprung, F Colardyn, S Blecher
Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine.
Crit Care Med. 1998 Nov;26(11):1793-800.
Abstract/Text
OBJECTIVE: To evaluate the use of the Sequential Organ Failure Assessment (SOFA) score in assessing the incidence and severity of organ dysfunction in critically ill patients.
DESIGN: Prospective, multicenter study.
SETTING: Forty intensive care units (ICUs) in 16 countries.
PATIENTS: Patients admitted to the ICU in May 1995 (n = 1,449), excluding patients who underwent uncomplicated elective surgery with an ICU length of stay <48 hrs.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: The main outcome measures included incidence of dysfunction/failure of different organs and the relationship of this dysfunction with outcome. In this cohort of patients, the median length of ICU stay was 5 days, and the ICU mortality rate was 22%. Multiple organ dysfunction and high SOFA scores for any individual organ were associated with increased mortality. The presence of infection on admission (28.7% of patients) was associated with higher SOFA scores for each organ. The evaluation of a subgroup of 544 patients who stayed in the ICU for at least 1 wk showed that survivors and nonsurvivors followed a different course. This subgroup had greater respiratory, cardiovascular, and neurologic scores than the other patients. In this subgroup, the total SOFA score increased in 44% of the nonsurvivors but in only 20% of the survivors (p < .001). Conversely, the total SOFA score decreased in 33% of the survivors compared with 21% of the nonsurvivors (p < .001).
CONCLUSIONS: The SOFA score is a simple, but effective method to describe organ dysfunction/failure in critically ill patients. Regular, repeated scoring enables patient condition and disease development to be monitored and better understood. The SOFA score may enable comparison between patients that would benefit clinical trials.
W A Knaus, E A Draper, D P Wagner, J E Zimmerman
APACHE II: a severity of disease classification system.
Crit Care Med. 1985 Oct;13(10):818-29.
Abstract/Text
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
日本血栓止血学会学術標準化委員会DIC部会ガイドライン作成委員会：科学的根拠に基づいた感染症に伴うDIC治療のエキスパートコンセンサスの追補. 日本血栓止血学会誌 25: 123-125, 2014.
B L Warren, A Eid, P Singer, S S Pillay, P Carl, I Novak, P Chalupa, A Atherstone, I Pénzes, A Kübler, S Knaub, H O Keinecke, H Heinrichs, F Schindel, M Juers, R C Bone, S M Opal, KyberSept Trial Study Group
Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.
JAMA. 2001 Oct 17;286(15):1869-78.
Abstract/Text
CONTEXT: Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.
OBJECTIVE: To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.
DESIGN AND SETTING: Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.
PATIENTS: A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).
MAIN OUTCOME MEASURE: All-cause mortality 28 days after initiation of study medication.
RESULTS: Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).
CONCLUSIONS: High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.
Johannes N Hoffmann, Dieter Mühlbayer, Marianne Jochum, Dietrich Inthorn
Effect of long-term and high-dose antithrombin supplementation on coagulation and fibrinolysis in patients with severe sepsis.
Crit Care Med. 2004 Sep;32(9):1851-9.
Abstract/Text
OBJECTIVE: Sepsis is frequently associated with coagulatory activation, which may contribute to deteriorated organ function. Antithrombin is one important endogenous coagulation inhibitor that is therapeutically applied during sepsis. This study investigates the effect of 14-day antithrombin application on coagulatory variables.
DESIGN: Prospective study.
SETTING: Surgical intensive care unit of a university hospital.
PATIENTS: Forty patients with severe sepsis.
INTERVENTIONS: Patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 20, controls) or antithrombin substitution that aimed at a plasma antithrombin activity > or =120% during a long-term (14-day) study period (n = 20, antithrombin). To allow comparative analysis of laboratory variables over time, all patients who did not survive the 14-day-period (five controls and six antithrombin patients) were prospectively excluded from the final evaluation. Their data were included in an intent-to-treat analysis.
MEASUREMENTS AND MAIN RESULTS: Antithrombin supplementation normalized global coagulation tests and increased prothrombin activity as well as fibrinogen concentration, reflecting less coagulation factor consumption (percent change from baseline in prothrombin activity, p <.01 vs. controls at days 9, 11-14 of antithrombin vs. controls [unpaired Student's t-test]; fibrinogen concentration, p <.01 vs. controls at days 10, 11, 13, and 14 of antithrombin). Simultaneously, antithrombin reduced contact system activation as indicated by increasing prekallikrein activities over time (% change, p <.01 vs. controls at days 6, 9-14) and increased protein C activities when compared with controls (% change, p <.01 vs. controls at days 10-14). Most changes occurred from day 7 to day 14 of antithrombin supplementation. Antithrombin did not influence C1 esterase inhibitor, plasminogen, alpha2 antiplasmin, or platelet counts (p >.01).
CONCLUSION: In this first study on long-term antithrombin therapy, antithrombin significantly reduced septic coagulatory response in patients with severe sepsis when given over 14 days.
J Kienast, M Juers, C J Wiedermann, J N Hoffmann, H Ostermann, R Strauss, H-O Keinecke, B L Warren, S M Opal, KyberSept investigators
Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.
J Thromb Haemost. 2006 Jan;4(1):90-7. doi: 10.1111/j.1538-7836.2005.01697.x.
Abstract/Text
BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality.
OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC.
PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination.
RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02).
CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.
Christian J Wiedermann, Nicole C Kaneider
A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.
Blood Coagul Fibrinolysis. 2006 Oct;17(7):521-6. doi: 10.1097/01.mbc.0000245302.18010.40.
Abstract/Text
The objective was to estimate the effect of antithrombin therapy on mortality in disseminated intravascular coagulation (DIC) of severe sepsis and septic shock. Randomized clinical trials (RCT) on patients with DIC and severe sepsis or septic shock assigned to intravenous antithrombin or placebo were searched. Eligible studies reported death as the outcome measure. Of 35 RCT, 32 trials were excluded because patients were not randomized to antithrombin versus placebo, or no separate data on patients with DIC were given. In three RCT, 364 patients with severe sepsis or septic shock and DIC were randomized. The disease severity, definition of DIC, dose and duration of treatment varied among the trials. In two of the three RCT, data were from subgroup analyses (patients not stratified by DIC). The combined odds ratio for short-term all-cause mortality in those who received antithrombin was 0.649 (95% confidence interval, 0.422-0.998). Data on bleeding complications in patients treated with antithrombin were reported only in one of the RCT and were not considered suitable for systematic safety estimation. In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival. Current available evidence, however, is not suited to sufficiently inform clinical practice.
江木盛時，小倉裕司，他. 日本版敗血症診療ガイドライン 2020. 日集中医誌. 2021;28 Suppl:S 291-S 305.
H Saito, I Maruyama, S Shimazaki, Y Yamamoto, N Aikawa, R Ohno, A Hirayama, T Matsuda, H Asakura, M Nakashima, N Aoki
Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial.
J Thromb Haemost. 2007 Jan;5(1):31-41. doi: 10.1111/j.1538-7836.2006.02267.x. Epub 2006 Oct 13.
Abstract/Text
BACKGROUND: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C.
OBJECTIVES: We conducted a multicenter, double-blind, randomized, parallel-group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART-123) to those of low-dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection.
METHODS: DIC patients (n = 234) were assigned to receive ART-123 (0.06 mg kg(-1) for 30 min, once daily) or heparin sodium (8 U kg(-1) h(-1) for 24 h) for 6 days, using a double-dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days.
RESULTS: DIC was resolved in 66.1% of the ART-123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3-29.1]. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding-related adverse events up to 7 days after the start of infusion was lower in the ART-123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487).
CONCLUSIONS: When compared with heparin therapy, ART-123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.
T Nishiyama, T Matsukawa, K Hanaoka
Is protease inhibitor a choice for the treatment of pre- or mild disseminated intravascular coagulation?
Crit Care Med. 2000 May;28(5):1419-22.
Abstract/Text
OBJECTIVE: To investigate the effect of a protease inhibitor, gabexate mesylate, on patients with pre- or mild disseminated intravascular coagulation (DIC) in comparison with a control group receiving no anticoagulation therapy.
DESIGN: Prospective, randomized, controlled study.
SETTING: General intensive care unit at a general hospital.
PATIENTS: Adult patients (40) with a DIC score between 6 and 8 (pre- or mild DIC).
INTERVENTIONS: In 20 patients, gabexate mesylate (2 mg/kg/hr) was administered as 2 mL/hr in saline (treated group) and in another 20 patients, saline (2 mL/hr; control group) was administered during the study (7 days).
MEASUREMENTS AND MAIN RESULTS: The following variables were determined at the time of admission to the intensive care unit before treatment and 1, 3, 5, and 7 days thereafter: platelet count, antithrombin III activity, serum or plasma concentrations of fibrinogen, fibrin degradation product, D-dimer, fibrin monomer, thrombin-antithrombin III complex, and plasmin-plasmin inhibitor complex, prothrombin time ratio, and DIC score. Two patients in the treated group and four in the control group were excluded from the study because they died during the study; therefore, 34 patients were analyzed. The measured variables of coagulation and fibrinolysis were not significantly different between the two groups, except for the D-dimer on day 3 (the treated group showed a higher concentration). D-dimer concentration and DIC score went down more quickly in the control group than the treated group, but not significantly. The mortality rate at 1 month was 40% (8 of 20) in the treated group and 35% (7 of 20) in the control group, without any differences between the two groups.
CONCLUSIONS: In a limited number of patients (n = 34), gabexate mesylate (2 mg/kg/hr) could not inhibit coagulation or fibrinolysis and gabexate mesylate could not improve the DIC score or mortality rate in pre- or mild DIC.
Jun-Te Hsu, Han-Ming Chen, De-Fa Chiu, Jih-Chang Chen, Chip-Jin Huang, Tsann-Long Hwang, Yi-Yin Jan, Miin-Fu Chen
Efficacy of gabexate mesilate on disseminated intravascular coagulation as a complication of infection developing after abdominal surgery.
J Formos Med Assoc. 2004 Sep;103(9):678-84.
Abstract/Text
BACKGROUND AND PURPOSE: Gabexate mesilate (GM) is a promising anticoagulation treatment for disseminated intravascular coagulation (DIC). This study was designed to examine the effect of GM on DIC associated with the development of infection after abdominal surgery in the intensive care unit (ICU).
METHODS: From January 1999 to March 2002, 50 consecutive ICU patients suffering DIC associated with the development of infection after abdominal surgery were enrolled in this study. Twenty five of the patients were randomized to receive treatment with GM by central intravenous infusion at 1 mg/kg/hour for 5 days or longer, while the remaining 25 were not treated. Blood clotting tests were performed and cytokine levels including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were examined on days 1, 3, and 7 after admission. General blood tests and D-dimer tests were conducted before and after GM administration. The gender, age, mortality, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores and severity of DIC were compared between the 2 groups.
RESULTS: No significant difference was found between the 2 groups in TNF-alpha and IL-6 concentration on days 1, 3, and 7. The mortality rate was similar between the 2 groups. However, DIC and APACHE-II scores were significantly lower in the GM-treated patients than in controls.
CONCLUSION: In this study, GM (1 mg/kg/hour) did not reduce the concentration of TNF-alpha and IL-6, or alter the mortality rate in patients with DIC resulting from infectious complications after surgery. Nevertheless, APACHE-II scores indicated that GM reduced the DIC severity and improved the clinical condition of patients.
柴田昭，高橋芳右，服部晃，他：播種性血管内凝固症候群（DIC）に対する FUT-175（メシル酸ナファモスタット）の臨床効果－多施設後期臨床第二相試験－ . 臨床と研究 64：1887-1990（治療レベル 3b）, 1987.
N Sakuragawa, H Hasegawa, M Maki, M Nakagawa, M Nakashima
Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)--a multicenter co-operative double-blind trial in comparison with heparin.
Thromb Res. 1993 Dec 15;72(6):475-500.
Abstract/Text
This study was evaluated the effectiveness, safety and utility of FR-860 and to compare those with heparin in patients with Disseminated intravascular coagulation (DIC). A diagnosis of DIC was made based on the criteria proposed by the Research Committee on DIC in the Ministry of Health and Welfare of Japan. FR-860 (FR group, 75 anti-factor Xa international units/kg/day) and Heparin (HP group, 240 units/kg/day) were administered for 5 days by continuous intravenous infusion. The total number of enrolled patients was 126 cases, and after excluding 1 case a total of 125 cases. Moderate or higher improvement of bleeding symptoms was 33.3% in the FR group and 18.5% in the HP group. On the organic symptoms, FR group showed a significantly higher improvement rate than the HP group, 20.5% and 8.2% respectively. On the overall efficacy of cases with pretreatment plasma AT III levels of less than 21 mg/dl or less than 70%. FR group showed a significantly higher improvement rate than the HP group. The safety rate of FR-860 (93.4%) was a significantly higher than that of the HP group (79.7%). Our report demonstrates that FR-860, as a therapeutic agent for the treatment of patients with DIC, is significantly higher safety and clinical utility as compared with heparin.
