Satoshi Gando

Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome.

OBJECTIVES a) To investigate the relationships between tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), plasminogen activator inhibitor-1, and disseminated intravascular coagulation (DIC); b) to determine the influence of DIC on the mortality rate, adult respiratory distress syndrome (ARDS), and multiple organ dysfunction syndrome; and c) to find a useful prognostic index for outcome. DESIGN Prospective, case-control study. SETTING General intensive care unit (tertiary care center) in a city hospital serving a population of 1.5 million people. PATIENTS Fifty-eight trauma patients; 22 of the patients with DIC and 36 of the patients without DIC. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS TNF-alpha, IL-1 beta, plasminogen activator inhibitor-1 activity, and plasminogen activator inhibitor-1 antigen concentration were measured on the day of the injury, and on days 1, 3, and 5 after admission. The results of these measurements, demographic data, severity of illness score, mortality rate in the intensive care unit and frequencies of ARDS, multiple organ dysfunction syndrome, and sepsis were compared according to the occurrence of DIC. DIC patients were classified into subgroups of survivors and nonsurvivors, and the changes in plasminogen activator inhibitor-1 between subgroups were studied. The Acute Physiology and Chronic Health Evaluation II scores, the Injury Severity Scores, and the frequency of ARDS and multiple organ dysfunction syndrome were higher in the DIC patients. The mortality rate of the DIC patients was higher than the rate of the non-DIC patients (59.0% vs. 13.8%; p = .0009). TNF-alpha and IL-1 beta concentrations increased more in the DIC patients than in the non-DIC patients. Plasminogen activator inhibitor-1 activity and plasminogen activator inhibitor-1 antigen concentrations in the DIC patients, especially those values in the nonsurvivors, continued to be markedly high up to day 5 of admission. The most favorable prognostic value of plasminogen activator inhibitor-1 for the prediction of death in all of the trauma patients and the DIC patients was determined on days 3 and 5, respectively. No significant correlation was noted between the two cytokines and plasminogen activator inhibitor-1. CONCLUSIONS In the patients with trauma, DIC is a predictor of ARDS, multiple organ dysfunction syndrome, and death. TNF-alpha and IL-1 beta might be one of the causes of DIC, while plasminogen activator inhibitor-1 may be one of the aggravating factors of ARDS and multiple organ dysfunction syndrome. Plasminogen activator inhibitor-1 is a good predictor of death for posttrauma DIC patients.

Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines

Three guidelines have recently been published for the diagnosis and treatment of disseminated intravascular coagulation (DIC) in adults. This communication seeks to harmonize the recommendations in these guidelines using a modified GRADE system. The scoring system for diagnosis of DIC using global coagulation tests is known to correlate with key clinical observations and outcomes (Moderate quality). The cornerstone of DIC treatment is the treatment of the underlying condition (Moderate quality). In general, transfusion of platelets or plasma (components) in patients with DIC should be reserved for patients who are bleeding (Low quality). Therapeutic doses of heparin should be considered in cases of DIC where clinical features of thrombosis predominate. Heparin is not recommended in those patients with a high risk of bleeding, (Moderate quality). However, prophylactic doses of unfractionated heparin or low molecular we ight heparin is recommended in critically ill and non-bleeding patients with DIC for prevention of venous thromboembolism (Moderate to High quality). Although further prospective evidence from randomized controlled trials is required, administration of antithrombin or recombinant thrombomodulin may be considered in certain patients with DIC. In general, patients with DIC should not be treated with antifibrinolytic agents (Low quality). However those who present with severe bleeding, that is characterized by a markedly hyperfibrinolytic state such as leukemia (Low quality) and trauma (Moderate quality), may be treated with antifibrinolytic agents.

Posttrauma coagulation and fibrinolysis.

ObjectiveTo determine the effects of disseminated intravascular coagulation (DIC) and headinjury on posttrauma coagulation and fibrinolysis. DesignCase-control study. SettingGeneral ICU (tertiary care center) in a city hospital serving a population of 150 million people. PatientsForty trauma victims: 15 with DIC; 25 without DIC. InterventionsMeasurement of six types of coagulation and fibrinolytic molecular markers (fibrinopeptide A, fibrinopeptide Bβ15–42, plasmin antiplasmin complex, D-dimer, tissue plasminogen activator antigen concentration, tissue plasminogen activator activity) immediately after trauma, 3 days later, and 6 days later. Anticoagulant treatment with gabexate mesilate at 1.45 ±PT 0.06 mg/kg/hr. Measurements and Main ResultsFibrinopeptide A, fibrinopeptide Bβ15–42, plasmin antiplasmin complex, and D-dimer showed high values immediately after trauma and exceeded normal activity for the first 6 days. When trauma was complicated with DIC, the molecular markers showed significantly higher values than those for non-DIC patients on all days. In the head-injured patients, such effect was not noted. Tissue plasminogen activator antigen concentration and tissue plasminogen activator activity were within a normal physiologic range of variation. By contrast, tissue plasminogen activator antigen concentration increased significantly after trauma in patients with DIC. When anticoagulant treatment was found effective, it caused a reduction in fibrinopeptide A. Conclusionsa) Fibrinolytic shut-down and its reactivation cannot be confirmed after trauma. b) Head injury does not lead to an increase in posttrauma coagulation or fibrinolytic activity. c) DIC enhances posttrauma coagulation and fibrinolytic activity and plasminogen activator inhibitor activity can be inferred in DIC patients. d) Increase in tissue plasminogen activator antigen concentration without tissue plasminogen activator activation may be a prognostic factor indicative of DIC and its chances of improvement, and fibrinopeptide A as an assessment criterion for the effectiveness of anticoagulant treatment. (Crit Care Med 1992; 20:594–600)

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.

Trauma, Shock, and Disseminated Intravascular Coagulation: Lessons from the Classical Literature

A trauma patients survival depends on the ability to control 2 opposing conditions, bleeding at the early phase and thrombosis at a late phase of trauma. The mixed existence of physiological responses for hemostasis and wound healing and pathological hemostatic responses makes it difficult to understand the mechanisms of the 2 stages of coagulopathy after trauma.Traumatic coagulopathy is multifactorial but disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype is the predominant and initiative pathogenesis of coagulopathy at the early stage of trauma. High levels of inflammatory cytokines and severe tissue injuries activate the tissue-factor–dependent coagulation pathway followed by massive thrombin generation and its activation. Low levels of protein C and antithrombin induce insufficient coagulation control and the inhibition of the anticoagulation pathway. Primary and secondary fibrin(ogen)olysis is highly activated by the shock-induced tissue hypoxia and disseminated fibrin formation, respectively. Consumption coagulopathy and severe bleeding are subsequently observed in trauma patients. Persistently high levels of plasminogen activator inhibitor-1 expressed in the platelets and endothelium then change the DIC with the fibrinolytic phenotype into the thrombotic phenotype at approximately 24 to 48 hours after the onset of trauma. All of these changes coincide with the definition of DIC, which can be clearly distinguished from normal responses for hemostasis and wound healing by using sensitive molecular markers and DIC diagnostic criteria such as those outlined by the Japanese Association for Acute Medicine and the International Society on Thrombosis and Haemostasis.Treatments of DIC with the fibrinolytic phenotype involve the surgical repair of the trauma, improvement of shock, and the rapid and sufficient replacement of platelet concentrate, fresh frozen plasma, and depleted coagulation factors. The administration of an antifibrinolytic agent (tranexamic acid) may reduce the risk of death in bleeding trauma patients associated with this type of DIC.

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.

Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock

OBJECTIVES To obtain systematic information on the extrinsic coagulation pathway, as well as to investigate the time course of the coagulation abnormalities in sepsis. DESIGN Prospective observational study. SETTING General intensive care unit. PATIENTS Nineteen patients with the diagnosis of severe sepsis or septic shock and nine control patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Tissue factor antigen concentration (tissue factor antigen), prothrombin fragment F1+2, thrombin antithrombin III complex, fibrinopeptide A, D-dimer, and antithrombin III concentrations were measured on the day of diagnosis of severe sepsis and septic shock, and on days 1, 2, 3, and 4 after diagnosis. The concentrations of tissue factor antigen, prothrombin fragment F1+2, fibrinopeptide A, and D-dimer were significantly increased in patients with severe sepsis and septic shock compared with control subjects. However, the concentrations of thrombin antithrombin III complex showed no statistical differences between the septic patients and the control subjects. Significantly, low antithrombin III concentrations were observed in the septic patient groups compared with control subjects. With the exception of D-dimer, the concentrations of the hemostatic markers were similar between severe sepsis and septic shock patients. Significant correlations were noted between tissue factor antigen and the disseminated intravascular coagulation score (r2=.236, p< .0001) and the number of dysfunctioning organs (r2=.229, p=.035). CONCLUSIONS We systematically elucidated coagulation disorders in newly defined sepsis. The extrinsic coagulation pathway is activated in patients with severe sepsis and septic shock. In these patients, enhanced thrombin generation and activation, and fibrin formation were demonstrated when compared with the control subjects. Furthermore, the thrombin generated appears not to be fully neutralized by antithrombin III.

Microvascular thrombosis and multiple organ dysfunction syndrome.

This paper will review the involvement of disseminated intravascular coagulation-induced microvascular thrombosis in the pathogenesis of multiple organ dysfunction syndrome and the interaction between disseminated intravascular coagulation and systemic inflammatory response syndrome in critically ill patients. The published literature on clinical and experimental studies are the data sources of the study. Histologic evidence of microvascular thrombosis and tissue injury in disseminated intravascular coagulation has been reported in clinical, experimental, and autopsy findings. Proinflammatory cytokine-evoked neutrophil–endothelial activation and interplay between inflammation and coagulation through protease-activated receptors contribute to enhanced microvascular fibrin deposition in organs. In a clinical setting, systemic inflammatory response syndrome and disseminated intravascular coagulation synergistically play pivotal roles in the development of multiple organ dysfunction syndrome and in the poor prognosis of critical illness. Disseminated intravascular coagulation contributes to microvascular thrombosis and subsequent multiple organ dysfunction syndrome. Recent knowledge on the relationship between disseminated intravascular coagulation and systemic inflammatory response syndrome gives further insight into the pathogenic mechanisms of multiple organ dysfunction syndrome in critically ill patients.

Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload

1 The present work was carried out in order to determine whether a decrease in cardiac Na+‐Ca2+ exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [Ca2+]i homeostasis in diabetic cardiomyocytes. 2 The NCX current was significantly reduced in ventricular myocytes freshly isolated from streptozotocin‐induced diabetic rat hearts, and its current density was about 55 % of age‐matched controls. 3 Diabetes resulted in a 30 % decrease in cardiac protein and mRNA levels of NCX1, a NCX isoform which is expressed at high levels in the heart. 4 The reduced NCX current and the decreased protein and mRNA levels of NCX1 in diabetes were prevented by insulin therapy. 5 Although both diastolic and peak systolic [Ca2+]i were not different between the two groups of myocytes, increasing external Ca2+ concentration to high levels greatly elevated diastolic [Ca2+]i in diabetic myocytes. Inhibition of NCX by reduction in extracellular Na+ by 50 % could produce a marked rise in diastolic [Ca2+]i in control myocytes in response to high Ca2+, as seen in diabetic myocytes. However, cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca2+ pump ATPase, did not modify the high Ca2+‐induced changes in diastolic [Ca2+]i in either control or diabetic myocytes. 6 Only in papillary muscles from diabetic rats did the addition of high Ca2+ cause a marked rise in resting tension signifying a partial contracture that was possibly due to an increase in diastolic [Ca2+]i. 7 In conclusion, the diminished NCX function in diabetic myocytes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA. We suggest that this impaired NCX function may play an important role in alterations in Ca2+ handling when [Ca2+]i rises to pathological levels.

Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality

INTRODUCTION Disseminated intravascular coagulation (DIC) with an antifibrinolytic phenotype is characterized by microvascular thrombosis leading to poor outcome at the late-stage of trauma. To test the hypothesis that DIC with a fibrinolytic phenotype at an early stage of trauma also contributes to a poor outcome due to severe bleeding, we conducted a retrospective, cohort study. MATERIALS AND METHODS The subjects included 314 consecutive severe trauma patients. A systematic review of medical records of the patients was conducted to provide the base line characteristics and DIC-related variables. The data of these variables were obtained at 4 time points within 24 hr after arrival to the emergency department (ED); Time Point 1, immediately after arrival to the ED to 4 hr after arrival; Time Point 2, 4 to 8 hr after arrival; Time Point 3, 8 to 16 hr after arrival; Time Point 4, 16 to 24 hr after arrival. RESULTS Nonsurvivors (87.3%, 48/55) met the Japanese Association for Acute Medicine (JAAM) DIC criteria showing lower fibrinogen levels, a prolonged prothrombin time, and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels in comparison to those of the 289 survivors. The FDP/D-dimer ratio and lactate level were significantly higher in the nonsurvivors than those of the survivors. Lower fibrinogen levels and higher FDP/D-dimer ratio suggest fibrinogenolysis in DIC of the nonsurvivors. Furthermore a stepwise logistic regression analysis showed that the JAAM DIC score, levels of fibrinogen, FDP and lactate at Time Point 1 are independent predictors of death. Low levels of fibrinogen and high FDP but not D-dimer predict massive bleeding at an early stage of trauma. The optimal cutoff points for the prediction of death and massive bleeding were fibrinogen (1.90, 1.90 g/L) and FDP (35.2, 68.7 mg/L), respectively. CONCLUSIONS DIC with a fibrinolytic phenotype modified through fibrinogenolysis at an early phase of trauma contributes to poor prognosis due to massive bleeding. Tissue hypoperfusion may be involved in the pathogenesis of this type of DIC.