Atsushi Sawamura

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.

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.

Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase

BACKGROUND The aims of the present study were to confirm the consumption coagulopathy of disseminated intravascular coagulation with the fibrinolytic phenotype at an early phase of trauma and to test the hypothesis that thrombin-activatable fibrinolysis inhibitor, neutrophil elastase, and plasmin contribute to the increased fibrinolysis of this type of disseminated intravascular coagulation. Furthermore, we hypothesized that disseminated intravascular coagulation at an early phase of trauma progresses dependently to disseminated intravascular coagulation with a thorombotic phenotype from 3 to 5 days after injury. METHODS Fifty-seven trauma patients, including 30 patients with disseminated intravascular coagulation and 27 patients without disseminated intravascular coagulation, were studied prospectively. Levels of thrombin-activatable fibrinolysis inhibitor, tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase were measured on days 1, 3, and 5 after trauma. The prothrombin time, fibrinogen, fibrin/fibrinogen degradation product, antithrombin, and lactate also were measured. RESULTS Independent of the lactate levels, disseminated intravascular coagulation patients showed a prolonged prothrombin time, lesser fibrinogen and antithrombin levels, and increased levels of fibrin/fibrinogen degradation product on day 1. Disseminated intravascular coagulation diagnosed on day 1 continued to late-phase disseminated intravascular coagulation on days 3 and 5 after trauma. Increased levels of tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase but not thrombin-activatable fibrinolysis inhibitor were observed in the disseminated intravascular coagulation patients. No correlation was observed between plasmin alpha2 plasmin inhibitor complex and fibrin degradation product by neutrophil elastase in disseminated intravascular coagulation patients. Multiple regression analysis showed the disseminated intravascular coagulation score and the tissue-type plasminogen activator plasminogen activator inhibitor-1 complex levels on day 1 to correlate with the total volume of transfused blood. Patient prognosis deteriorated in accordance with the increasing disseminated intravascular coagulation severity. CONCLUSION Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase independent of hypoperfusion and continues to disseminated intravascular coagulation at a late phase of trauma. Increased fibrinolysis requires more blood transfusions, contributing to a poor patient outcome.

Systemic Inflammation and Disseminated Intravascular Coagulation in Early Stage of ALI and ARDS: Role of Neutrophil and Endothelial Activation

To determine the existence of a close link between inflammation and coagulation in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and to examine their prognostic value in the development of ARDS and clinical outcome, we made a prospective cohort study. The study subjects consisted of 57 patients: 19 patients with ARDS and 38 patients with ALI as defined by a Lung Injury Score of ≥2.5 and 1.0 to less than 2.5, respectively. According to the outcome, the patients were subdivided into the survivors and the nonsurvivors. Ten normal healthy volunteers served as control subjects. Plasma levels of soluble L-, P-, and E-selectins, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (sTM), and neutrophil elastase were measured within 24 h after the diagnosis of ALI or ARDS. The number of systemic inflammatory response syndrome (SIRS) criteria being met by the patients and the disseminated intravascular coagulation (DIC) scores were determined simultaneously. The number of SIRS criteria and the DIC scores of the patients with ALI or ARDS showed high values, and more than half of the patients were complicated by DIC. The levels of sL-selectin in both groups of the patients were significantly lower than those of the control subjects. All other soluble adhesion molecules, neutrophil elastase, and sTM in the patients with ALI and ARDS were markedly elevated than those in the control subjects. The levels sICAM-1, sVCAM-1, and sTM in the ARDS patients significantly increased compared with the ALI patients. The number of SIRS criteria and the DIC scores in the nonsurvivors showed higher values than those in the survivors. In addition, we found significant differences in the levels of soluble adhesion molecules, neutrophil elastase, and sTM between the survivors and the nonsurvivors. {In conclusion, we found a concurrent activation of both inflammation and coagulation in the patients with ALI or ARDS. The results also suggest that systemic activation of inflammation and coagulation associated with endothelial injury has prognostic value for the development of ARDS and poor outcome.}

Sivelestat (Selective Neutrophil Elastase Inhibitor) Improves the Mortality Rate of Sepsis Associated With Both Acute Respiratory Distress Syndrome and Disseminated Intravascular Coagulation Patients

Neutrophil elastase plays an important role in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) in sepsis. Sivelestat is a selective neutrophil elastase inhibitor. It is possible that sivelestat improves the outcome of septic patients associated with ARDS and DIC. A retrospective data analysis of septic patients associated with ARDS and DIC was conducted to investigate the effects of sivelestat. Observational period was 5 days after admission to intensive care unit (ICU). The study included 167 septic patients associated with ARDS and DIC. Control group included 133 patients without sivelestat, and sivelestat group included 34 patients started to deadministered sivelestat on the admission to ICU. The lung injury scores and PaO2/FiO2 ratio of the sivelestat group were significantly more severe than those of the control group from days 1 to 4. On day 5, the lung injury score and PaO2/FiO2 ratio of the sivelestat group improved to the same levels of those of the control group. The DIC score of sivelestat group improved on day 3 in comparison to day 1, and those of control group remained unchanged until day 4. The length of ICU stay of the sivelestat group was significantly shorter than that of the control group. A stepwise multiple logistic-regression analysis showed the sivelestat administration to be an independent predictor of survival of the septic patients associated with both ARDS and DIC. The length of ICU stay of the sivelestat group was significantly shorter than that of the control group. In addition, sivelestat administration was found to be an independent predictor of survival of those patients.

Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma

INTRODUCTION To validate the diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) at an early stage of trauma and to evaluate the hypothesis that the JAAM criteria can diagnose DIC with a higher sensitivity than the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. MATERIALS AND METHODS Based on a review of medical records, the data of 314 trauma patients were retrospectively obtained at 4 time points within 24 hr after arrival to the Emergency Department. RESULTS One hundred and forty-one JAAM DIC patients (44.9%) showed differences in the prevalence of massive bleeding and multiple organ dysfunction syndrome (MODS), and the outcome in comparison to the non-DIC patients. A stepwise logistic regression analysis showed that the maximum JAAM DIC scores independently predicted the patient death. All of the patients who developed ISTH overt DIC could be identified by the JAAM DIC criteria at early time points. The mortality rate and the incidence of massive bleeding and MODS of the patients with the ISTH overt DIC were higher than those only met the JAAM DIC criteria. Stepwise increases in the ISTH overt DIC scores and the incidence of the overt DIC were observed in accordance with the increases in the JAAM DIC scores. While the mortality rates were identical, there were marked differences in the incidence of MODS and Sequential Organ Failure Assessment scores between the DIC patients associated with trauma and sepsis. CONCLUSIONS The results show that the JAAM scoring system has acceptable validity for the DIC diagnosis at an early phase of trauma, and also that the scoring system can diagnose DIC with a higher sensitivity than the criteria of the ISTH overt DIC. Bleeding as well as MODS may affect the prognosis of the patients associated with DIC.

Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock.

BACKGROUND We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC. METHODS We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction. RESULTS Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients. CONCLUSION Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma : a retrospective observational study

In trauma, hemostatic functions should be maintained appropriately to prevent massive bleeding. This study elucidated the time-dependent changes in platelet count and coagulation variables, and the effects of disseminated intravascular coagulation (DIC) on these changes during the early phase of trauma. Trauma patients with an injury severity score ≥16 were enrolled. The critical levels of platelet count and coagulation variables were defined according to recent trauma guidelines. Massive transfusion was defined as >10 units red cell concentrate. The time from arrival at the emergency department to reaching the critical levels and meeting the criteria for massive transfusion were evaluated. Eighty trauma patients were enrolled; 35 were diagnosed with DIC on arrival. Among all patients, fibrinogen levels reached the critical level earliest among routine coagulation parameters; other routine coagulation parameters deteriorated after the patients met the criteria for massive transfusion. Routine coagulation parameters reached their critical levels earlier in DIC patients than patients without DIC. Massive transfusion was performed more frequently in DIC patients, who met the criteria earlier. During the early phase of trauma, fibrinogen levels deteriorate earlier than other routine coagulation parameters, especially in DIC patients.

Massive amounts of tissue factor induce fibrinogenolysis without tissue hypoperfusion in rats.

ABSTRACT Trauma-induced tissue factor (TF) release into the systemic circulation is considered to play an important role in the development of disseminated intravascular coagulation (DIC) immediately after severe trauma. However, the relationship between TF and hyperfibrinolysis, especially fibrinogenolysis, has been unclear. A total of 18 rats were divided into three groups: (a) the control group was infused with normal saline; (b) the low-dose group was infused with 4 U/kg TF; and (c) the high-dose group was infused with 16 U/kg TF. Arterial blood was drawn immediately and 2 and 4 h after the start of TF infusion. At each sampling point, arterial blood gases, platelet counts, and coagulation variables were measured. The fibrinogen degradation products were evaluated by a Western blot analysis. Hypotension, hypoxemia, and lactic acidosis were not observed in any of the three groups. In proportion to the doses of TF, the platelet counts, coagulation, and fibrinolysis variables deteriorated in line with DIC. The &agr;2-plasmin inhibitor levels significantly decreased in the high-dose group compared with the other groups. The amounts of fibrinogen degradation products increased in proportion to the doses of TF. The plasmin-&agr;2-plasmin inhibitor complex level in the high-dose group increased more than that of the other groups. In conclusion, TF can induce DIC associated with fibrinolysis and fibrinogenolysis without tissue hypoperfusion. The decrease in the &agr;2-plasmin inhibitor level and the significant increase in the plasmin level may be the two main factors underlying the pathogenesis of hyperfibrin(ogen)olysis after TF administration.

Effects of antithrombin III in patients with disseminated intravascular coagulation diagnosed by newly developed diagnostic criteria for critical illness.

A study was conducted to test the hypotheses that antithrombin III (antithrombin) improves disseminated intravascular coagulation (DIC) when applied to DIC patients diagnosed by sensitive criteria and that the administration of high-dose antithrombin is a beneficial treatment for DIC. Twenty-three DIC patients diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria were treated with either high-dose (60 IU/kg/day) or low-dose (30 IU/kg/day) antithrombin concentrates for 3 days. The clinical conditions that cause DIC were restricted to systemic inflammatory response syndrome (SIRS) and sepsis. Data of antithrombin activity, platelet counts, coagulation and fibrinolytic markers, and DIC scores before antithrombin administration (day 0), on days 1 to 3, and on day 7 were retrospectively collected from computer-based records. Patients who met the JAAM DIC criteria were administered either high-dose (12 patients) or low-dose (11 patients) antithrombin. The patients’ backgrounds and antithrombin activity (high dose, 51.5 ± 14.5%; low dose, 62.6 ± 19.3%; P = .153) on day 0 were identical in the 2 groups. The JAAM DIC score and prothrombin time ratio on day 7 significantly improved when compared with those on day 0. However, mortality at 28 days as well as interaction within the antithrombin doses administered showed no difference. There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups. The authors conclude that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients with SIRS/sepsis-associated DIC.