今日の臨床サポート

播種性血管内凝固(DIC)(血液内科)

著者: 野村昌作 関西医科大学内科学第一講座

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2019/09/26
参考ガイドライン:
日本血栓止血学会 DIC診断基準 2017年版:血栓止血誌2017;28(3);369-391.
患者向け説明資料

概要・推奨   

  1. DICは敗血症患者の12~26%にみられ、発症率は高い。また、DICに関する早期診断のための特異的な所見は少ないため、血液検査データを参考にして常に敗血症の合併症として考慮し、症状の悪化などの綿密なフォローアップにて除外をすることが勧められる(推奨度1)。
  1. アンチトロンビンは、感染症を基礎疾患としたDICに対して有効である可能性がある(推奨度1)。
  1. 低分子ヘパリンはDICの中等度以上の臓器障害を改善し、出血の危険が少ない(推奨度1)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
野村昌作 : 奨学(奨励)寄付など(中外製薬,協和キリン)[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1. 以下の4つの問題点について改定されている。
  1. 一般的止血検査に、血小板数の経時的減少、アンチトロンビン(AT)、凝固活性化関連マーカーである可溶性フィブリン(SF)やトロンビン-AT 複合体(TAT)を加えることに有用性はあるか?
  1. 旧厚生省DIC診断基準(旧基準)の特異性は十分継承されているか?
  1. 旧基準でDICと診断する前に、DICの早期診断は可能か?
  1. 生命予後を反映しているか?

病態・疫学・診察

疾患情報  
  1. 播種性血管内凝固症候群(DIC)の診断は、基礎疾患の病状を確認し、診断基準に挙げられている凝固線溶系の異常を表す各種検査項目を測定することにより可能となる。
  1. 現在広く用いられているDICの診断基準は、日本の厚生労働省のDICの診断基準、国際血栓止血学会/科学的標準化委員会のovert-DIC、日本救急医学会の急性期DIC診断基準の3つである。
  1. DIC診断基準の比較:表<図表>
  1. わが国におけるDIC患者数は7万3,000人/年である。DICの2大症状は、出血症状と臓器症状であるが、臓器症状と思われる臨床症状が出現すると、予後はきわめて不良である(死亡率56%)。
  1. 基礎疾患の種類によってDICの病態は大きく異なる。DICの病態が凝固優位か線溶優位かによって、治療方針も異なってくる。
問診・診察のポイント  
  1. DICを起こしやすい基礎疾患が存在するかどうか確認する。

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文献 

著者: M Levi, H Ten Cate
雑誌名: N Engl J Med. 1999 Aug 19;341(8):586-92. doi: 10.1056/NEJM199908193410807.
Abstract/Text
PMID 10451465  N Engl J Med. 1999 Aug 19;341(8):586-92. doi: 10.1056/N・・・
著者: 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)
雑誌名: Thromb Haemost. 2001 Nov;86(5):1327-30.
Abstract/Text
PMID 11816725  Thromb Haemost. 2001 Nov;86(5):1327-30.
著者: 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
雑誌名: 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.

PMID 16521260  Crit Care Med. 2006 Mar;34(3):625-31.
著者: 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
雑誌名: 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.

PMID 11597289  JAMA. 2001 Oct 17;286(15):1869-78.
著者: Koji Yamamoto
雑誌名: Rinsho Ketsueki. 2017;58(10):2141-2149. doi: 10.11406/rinketsu.58.2141.
Abstract/Text Restrictive transfusion is the most common and appropriate treatment for patients with bleeding disorders because it is associated with better prognosis. However, hematologists are not familiar with the indication for and effect of using fresh frozen plasma (FFP) for transfusions, which has been inappropriately used to date. FFP should not be transfused for preventing bleeding or improving coagulation test results (i.e., PT and APTT). Instead, FFP transfusion should be performed to manage hemostasis, based on the fibrinogen levels of <150 mg/dl in patients' plasmas. Severe hypofibrinogenemia can cause critical coagulopathy, which results in massive bleeding. Early and sufficient FFP transfusion can overcome this condition. In addition, in patients with severe hypofibrinogenemia and active bleeding due to hyperfibrinolytic DIC associated with acute leukemia, the administration of concentrated fibrinogen products (e.g., cryoprecipitate or fibrinogen concentrates) is effective for maintaining hemostasis.

PMID 28978859  Rinsho Ketsueki. 2017;58(10):2141-2149. doi: 10.11406/r・・・
著者: N Sakuragawa, H Hasegawa, M Maki, M Nakagawa, M Nakashima
雑誌名: 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.

PMID 8128454  Thromb Res. 1993 Dec 15;72(6):475-500.
著者: Fabián Jaimes, Gisela De La Rosa, Carlos Morales, Fernando Fortich, Clara Arango, Daniel Aguirre, Alvaro Muñoz
雑誌名: Crit Care Med. 2009 Apr;37(4):1185-96. doi: 10.1097/CCM.0b013e31819c06bc.
Abstract/Text OBJECTIVE: The primary aims of this study were to determine the effects of heparin on length of stay and change from baseline multiple organ dysfunction (MOD) score. Secondary objectives were to estimate the effects of heparin on 28-day all-cause mortality, and to determine the possible effect modification on 28-day all-cause mortality, in subgroups defined by site of infection and baseline values of Acute Physiology and Chronic Health Evaluation II score, MOD score, and d-dimer.
DESIGN: Randomized, double-masked, placebo-controlled, single-center clinical trial, testing low dose continuous infusion of unfractioned heparin (UFH) as complementary treatment for sepsis.
SETTING: Five hundred fifty bed University Hospital and referral center in Medellín, Columbia.
PATIENTS: Three hundred nineteen patients admitted at the emergency room with signs indicative of sepsis.
INTERVENTIONS: Patients were randomly assigned to receive placebo or UFH (500 units/hour for 7 days).
MEASUREMENTS AND MAIN RESULTS: The median length of stay in patients discharged alive in the placebo group was 12.5 days (interquartile range = 8-20), and 12 days (interquartile range = 8-19.5) in the heparin group (p = 0.976). The MOD score improved equally in the two treatments arms with an average decline of 0.13 and 0.11 per day for the placebo and heparin groups (p = 0.240), respectively. The overall 28-day mortality was 16% in the placebo group and 14% in the heparin group (p = 0.652). Subgroup analyses did not show any statistically significant reduction in 28-day mortality with UFH. There was only one serious adverse event on a patient who received heparin but it was fully resolved without complications.
CONCLUSIONS: Our findings suggested that UFH may be a feasible and safe intervention in sepsis. However, this study was not able to demonstrate a beneficial effect on the chosen primary outcomes or in the 28-day mortality rate.

PMID 19242322  Crit Care Med. 2009 Apr;37(4):1185-96. doi: 10.1097/CCM・・・
著者: H Saito, I Maruyama, S Shimazaki, Y Yamamoto, N Aikawa, R Ohno, A Hirayama, T Matsuda, H Asakura, M Nakashima, N Aoki
雑誌名: 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.

PMID 17059423  J Thromb Haemost. 2007 Jan;5(1):31-41. doi: 10.1111/j.1・・・

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