Toshiaki Iba

Expert consensus for the treatment of disseminated intravascular coagulation in Japan

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.

Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey.

Objective:To survey the natural history of disseminated intravascular coagulation (DIC) in patients diagnosed according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system in a critical care setting. Design:Prospective, multicenter study during a 4-month period. Setting:General critical care center in a tertiary care hospital. Patients:All patients were enrolled when they were diagnosed as DIC by the JAAM DIC scoring system. Interventions:None. Measurements and Main Results:Platelet counts, prothrombin time ratio, fibrinogen, and fibrin/fibrinogen degradation products were measured, and the systemic inflammatory response syndrome criteria met by the patients were determined following admission. Of 3,864 patients, 329 (8.5%) were diagnosed with DIC and the 28-day mortality rate was 21.9%, which was significantly different from that of the non-DIC patients (11.2%) (p < .0001). The progression of systemic inflammation, deterioration of organ function, and stepwise increase in incidence of the International Society on Thrombosis and Haemostasis (ISTH) DIC and its scores all correlated with an increase in the JAAM DIC score as demonstrated by the patients on day 0. There were significant differences in the JAAM DIC score and the variables adopted in the scoring system between survivors and nonsurvivors. The logistic regression analyses showed the JAAM DIC score and prothrombin time ratio on the day of DIC diagnosis to be predictors of patient outcome. The patients who simultaneously met the ISTH DIC criteria demonstrated twice the incidence of multiple organ dysfunction (61.1 vs. 30.5%, p < .0001) and mortality rate (34.4 vs. 17.2%, p = .0015) compared with those without the ISTH DIC diagnosis. Conclusions:This prospective survey demonstrated the natural history of DIC patients diagnosed by the JAAM DIC diagnostic criteria in a critical care setting. The study provides further evidence of a progression from the JAAM DIC to the ISTH overt DIC.

Alterations in coagulation and fibrinolysis during sepsis.

Circulating levels of thrombin-antithrombin III complex (TAT) and plasmin-α2 plasmin inhibitor complex (PIC) in 49 septic patients (23 patients with organ dysfunction (OD), 26 without OD) and 11 postgastrectomy patients were measured to determine the significance of the coagulation-fibrinolytic systems in the development of OD. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin were also measured. The mean level of TAT on the day when OD occurred was significantly higher compared with the maximum level of TAT in septic patients without OD (P < .01) or postoperative patients (P < .01). There was no difference in PIC levels between the three groups. The TAT/PIC ratio was significantly higher in septic patients with OD compared with the other groups (P < .001). Septic patients with OD showed higher levels of PAI-1 (P < .001) but not of t-PA. Thrombomodulin levels were significantly higher in the septic patients with OD compared with the others (P < .001). We conclude that suppression of the fibrinolytic system contributes to the imbalance between coagulation and fibrinolysis, and that this hypercoagulabe millieu on the endothelial surface leads to the onset of OD.

Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model

Objective:Abnormalities in the vascular endothelial function play an important role in the development of septic organ dysfunction. The aim of the study was to examine the effect of recombinant human activated protein C on leukocyte-endothelial interaction in endotoxemia. Design:Experimental animal model of sepsis. Setting:University research laboratory. Subjects:Normal Wistar rats. Each animal was infused with 4.5 mg/kg lipopolysaccharide to simulate severe sepsis. Interventions:Rats were injected with endotoxin simultaneously with either a low or a high dose of recombinant human activated protein C (n = 7). One, 2, and 3 hrs after injection, mesenteric microcirculation was observed under intravital microscopy. In another series, tumor necrosis factor, interleukin-6, alanine transaminase, and blood urea nitrogen levels were evaluated (n = 5). Measurements and Main Results:The adhesive leukocyte count on the endothelium was significantly suppressed in both high-dose and low-dose groups (p < .01 and .05, respectively). The bleeding events decreased in the low-dose treatment group compared with both the control (p < .05) and high-dose group (p < .05). Microcirculatory flow as expressed by red blood cell velocity was maintained better in the low-dose group. Comparison of cytokine levels showed a significant decrease in the treatment groups. Organ damage markers were also suppressed in the treatment groups (p < .05) Conclusions:Recombinant human activated protein C demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of inflammatory cytokine production.

Evaluation of New Japanese Diagnostic Criteria for Disseminated Intravascular Coagulation in Critically Ill Patients

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 × 103/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.

Association Between The Severity Of Sepsis And The Changes In Hemostatic Molecular Markers And Vascular Endothelial Damage Markers

It is well known that disorders of coagulation and fibrinolysis play a major role in the development of organ dysfunction during sepsis. Furthermore, the importance of the early initiation of anticoagulation therapy for severe cases has been emphasized based on the success of recent clinical trials. The purpose of this study is to search for useful markers for predicting organ dysfunction. Plasma samples were prospectively collected from 78 patients within 48 h after the onset of sepsis. Hemostatic markers and endothelial damage markers were compared between the patients with and without organ dysfunction. The WBC and platelet counts were not different between the groups. In contrast, fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex, plasmin α2-antiplasmin complex, soluble fibrin, and total plasminogen activator inhibitor-1 were significantly higher, and the antithrombin activity and protein C levels were lower in the patients with organ dysfunction. Thus, the changes in the hemostatic molecular markers were associated with organ dysfunction from an early stage of sepsis, and antithrombin and protein C activities were found to be the most reliable markers.

Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a prospective multicenter survey.

INTRODUCTION Although supplementation with antithrombin (AT) concentrates has been widely accepted for the treatment of disseminated intravascular coagulation (DIC) in Japan, the effects and adverse effects have not been investigated. MATERIALS AND METHODS We conducted a nonrandomized multi-institutional survey. A total of 729 septic DIC patients with AT activity levels of 70% or lower, who had undergone AT substitution at either 1500 IU/day or 3000 IU/day for consecutive 3 days were analyzed. Of these, 650 and 79 patients had received 1500 IU/day (AT1500 group) and 3000 IU/day (AT3000 group), respectively. RESULTS Bleeding events were observed in 6.52% of patients (severe bleeding, 1.71%). A significant decrease in initial AT level (below 50%) was observed in 69.6% of patients in AT3000 group and 48.2% in AT1500 group, and this difference was significant (P<0.01). A logistic-regression analysis conducted using age, gender, body weight, initial AT activity, and supplemented AT dose, revealed that higher initial AT activity (odds ratio (OR), 1.032; P<0.001), AT dose of 3000 IU/day (OR, 1.912; P=0.026), and age (OR, 0.985; P=0.023) were significant factors for improved survival. CONCLUSION The risk of severe bleeding is less than 2%, and concomitant administration of heparin did not increase the risk. The survival in AT1500 group was 65.2%, while that in AT3000 group was 74.7%.

Increased Plasma Levels of Soluble Thrombomodulin in Patients with Sepsis and Organ Failure

The fact that thrombomodulin (TM) is released into the bloodstream from damaged vascular endothelial cells led us to hypothesize that plasma levels of soluble TM could be an indicator of the development of organ failure. In this study, we examined the changes in plasma levels of TM in 60 septic patients and 13 postsurgical patients, and investigated the circulating levels of interleukin 6 (IL-6) and polymorphonuclear leukocyte elastase (PMN-E) to determine the mechanism causing the excess liberation of TM. The arterial ketone body ratio (AKBR) was also measured as an indicator of the hepatocyte energy state. Of the 60 septic patients, 26 developed organ failure, 10 of whom died. In contrast, none of the postsurgical patients developed organ failure. The mean plasma level of TM was significantly higher in the septic patients who developed organ failure compared to those without organ failure (P<0.001) or the postsurgical patients (P<0.001). Furthermore, those patients whose plasma TM values became elevated over 6.0ng/ml frequently developed complications. A positive correlation was also observed between the plasma TM levels and the IL-6 (P<0.01) and PMNE levels (P<0.01). In contrast, a negative correlation was seen between the plasma TM levels and the AKBR (P<0.01). These findings show that plasma TM could be a useful indicator of impending organ failure during sepsis.

Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model

IntroductionRecombinant human soluble thrombomodulin (rhsTM) is newly developed for the treatment of DIC. The purpose of this study was to evaluate the efficacy of the concomitant administration of rhsTM and antithrombin (AT).MethodsIn the first series, rats were treated with either 62.5, 125, 250 or 500 IU/kg (n = 6, each) of AT or 0.125, 0.25, 0.5 or 1.0 mg/kg (n = 6, each) of rhsTM followed by lipopolysaccharide (LPS) injection. 8 h later, the fibrinogen level was examined. In the second series, TM group was pretreated with 0.25 mg/kg of rhsTM, AT group was pretreated with 125 IU/kg of AT, AT/TM group was pretreated with both AT and rhsTM, and control group was pretreated with saline (n = 7, each). The platelet count, fibrinogen, ALT, LDH and high-mobility group box 1 (HMGB1) levels were measured. In addition, histologic changes in liver were examined. In the third series, survival was calculated up to 24 h.ResultsBoth AT and rhsTM produced a linear dose-response with regard to the fibrinogen level, with 125 IU/kg of AT and 0.25 mg/kg of rhsTM producing equivalent effects. The combined administration of AT and rhsTM significantly reduced the decrease in the platelet count and the fibrinogen level (P < 0.05, 0.01, respectively). The elevations in ALT and LDH were significantly suppressed in all treatment groups. The HMGB1 level and the histologic changes tended to indicate damage reduction. Survival was significantly better only in AT/TM group (P < 0.01).ConclusionsThe coadministration of AT and rhsTM might be effective for the treatment of severe sepsis.

SIRS-associated coagulopathy and organ dysfunction in critically ill patients with thrombocytopenia.

Backgrounds: Coagulopathy and thrombocytopenia often occur in critically ill patients, and disseminated intravascular coagulation (DIC) can lead to multiple organ dysfunction and a poor outcome. However, the relation between coagulopathy and systemic inflammatory response has not been thoroughly clarified. Thus, we evaluated coagulative activity, organ dysfunction, and systemic inflammatory response syndrome (SIRS) in critically ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation. Patients and Methods: Two hundred seventy-three patients, who were admitted to 13 critical care centers in Japan and fulfilled the criteria of platelet count of less than 150•109/L, were included. Coagulative variables (platelet count, fibrin/fibrinogen degradation products, and DIC scores), organ dysfunction index (Sequential Organ Failure Assessment [SOFA] score), and SIRS score in each patient were evaluated for 4 consecutive days after fulfilling the above entry criteria. The effect of SIRS on coagulopathy and organ dysfunction was evaluated in these patients. Results: Both the maximum SIRS score and entry SIRS score had significant relation to the maximum SOFA score during the observation period. Coagulation disorders indicated by the minimum platelet count, maximum DIC scores, and positivity for DIC worsened gradually with increases in SIRS scores. Both the minimum platelet count and maximum DIC scores were significantly correlated with the maximum SOFA score, indicating that a relation exists between coagulopathy and organ dysfunction. Conclusions: In critically ill patients with thrombocytopenia, coagulopathy and organ dysfunction progress with significant mutual correlation, depending on the increase in SIRS scores. The SIRS-associated coagulopathy may play a critical role in inducing organ dysfunction after severe insult.