Combination of thrombin-antithrombin complex,plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study

Introduction

Current criteria for early diagnosis of coagulopathy in sepsis are limited. We postulated that coagulopathy is already complicated with sepsis in the initial phase, and severe coagulopathy or disseminated intravascular coagulation (DIC) becomes overt after progressive consumption of platelet and coagulation factors. To determine early diagnostic markers for severe coagulopathy, we evaluated plasma biomarkers for association with subsequent development of overt DIC in patients with sepsis.

Methods

A single-center, prospective observational study was conducted in an adult ICU at a university hospital. Plasma samples were obtained from patients with sepsis at ICU admission. Fourteen biomarkers including global markers (platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen and fibrin degradation product (FDP)); markers of thrombin generation (thrombin-antithrombin complex (TAT) and soluble fibrin); markers of anticoagulants (protein C (PC) and antithrombin); markers of fibrinolysis (plasminogen, α₂-plasmin inhibitor (PI), plasmin-α₂-PI complex, and plasminogen activator inhibitor (PAI)-1); and a marker of endothelial activation (soluble E-selectin) were assayed. Patients who had overt DIC at baseline were excluded, and the remaining patients were followed for development of overt DIC in 5 days, and for mortality in 28 days.

Results

A total of 77 patients were enrolled, and 37 developed overt DIC within the following 5 days. Most patients demonstrated hemostatic abnormalities at baseline with 98.7% TAT, 97.4% FDP and 88.3% PC. Most hemostatic biomarkers at baseline were significantly associated with subsequent development of overt DIC. Notably, TAT, PAI-1 and PC discriminated well between patients with and without developing overt DIC (area under the receiver operating characteristic curve (AUROC), 0.77 (95% confidence interval, 0.64 to 0.86); 0.87 (0.78 to 0.92); 0.85 (0.76 to 0.91), respectively), and using the three together, significantly improved the AUROC up to 0.95 (vs. TAT, PAI-1, and PC). Among the significant diagnostic markers for overt DIC, TAT and PAI-1 were also good predictors of 28-day mortality (AUROC, 0.77 and 0.81, respectively).

Conclusions

Severe coagulation and fibrinolytic abnormalities on ICU admission were associated with subsequent development of overt DIC. A single measurement of TAT, PAI-1, and PC activity could identify patients with ongoing severe coagulopathy, early in the course of sepsis.     

A randomized,controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis

Introduction

To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals.

Methods

We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3.

Results

Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3.

Conclusions

Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis.

Trial registration

UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882     

A multicenter,prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis

Introduction

To validate the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scoring system in patients with severe sepsis, we conducted a multicenter, prospective study at 15 critical care centers in tertiary care hospitals.

Methods

This study included 624 severe sepsis patients. JAAM DIC was scored on the day of diagnosis of severe sepsis (day 1) and day 4. Scores for disease severity and organ dysfunction were also evaluated.

Results

The prevalence of JAAM DIC was 46.8% (292/624), and 21% of the DIC patients were scored according to the reduction rate of platelets. The JAAM DIC patients were more seriously ill and exhibited more severe systemic inflammation, a higher prevalence of multiple organ dysfunction syndrome (MODS) and worse outcomes than the non-DIC patients. Disease severity, systemic inflammation, MODS and the mortality rate worsened in accordance with an increased JAAM DIC score on day 1. The Kaplan-Meier curves demonstrated lower 1-year survival in the JAAM DIC patients than in those without DIC (log-rank test P <0.001). The JAAM DIC score on day 1 (odds ratio = 1.282, P <0.001) and the Delta JAAM DIC score (odds ratio = 0.770, P <0.001) were independent predictors of 28-day death. Dynamic changes in the JAAM DIC score from days 1 to 4 also affected prognoses. The JAAM DIC scoring system included all patients who met the International Society on Thrombosis and Haemostasis overt DIC criteria on day 1. The International Society on Thrombosis and Haemostasis scoring system missed a large number of nonsurvivors recognized by the JAAM scoring system.

Conclusions

The JAAM DIC scoring system exhibits good prognostic value in predicting MODS and poor prognosis in patients with severe sepsis and can detect more patients requiring treatment. Conducting repeated daily JAAM scoring increases the ability to predict the patient''s prognosis.     

Time sequence of coagulation data in patients with decompensated liver cirrhosis and suspected disseminated intravascular coagulation

In patients with liver cirrhosis, especially in the advanced stage, the coexistence of low clotting factor levels, hypofibrinogenemia, thrombocytopenia and elevated fibrin(ogen) degradation product (FDP) and D-dimer levels may suggest the presence of disseminated intravascular coagulation (DIC). In this study we evaluated, in 21 patients with decompensated liver cirrhosis and elevated FDP and D-dimer levels, the time sequence of their coagulation data during a follow-up period of 15 days after the first observation; our aim was to clarify if these patients tend to develop during this time interval a severe consumption coagulopathy as an expression of overt DIC. We evaluated serum fibrinogen, platelet count, prothrombin activity, serum FDP and plasma D-dimer levels at days 1, 3, 6, 10 and 15. The coagulation data were fairly stable during the study period in all patients, even in the two patients who had upper digestive tract bleeding during the study time. Only two patients affected by infectious diseases showed a decrease of D-dimer and FDP levels after healing. Our data suggest that in decompensated liver cirrhosis the detection of elevated FDP and D-dimer levels is seldom related to the occurrence of an overt DIC, at least during a short time interval: in this condition heparin therapy seems therefore not advisable and even potentially dangerous.     

Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma‐shock (COT/ACOTS)

Two concepts have been proposed for the hemostatic changes occurring early after trauma. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype is characterized by activation of the coagulation pathways, insufficient anticoagulant mechanisms and increased fibrinolysis. Coagulopathy of trauma and acute coagulopathy of trauma‐shock (COT/ACOTS) occurs as a result of increased activation of the thrombomodulin and protein C pathways, leading to the suppression of coagulation and activation of fibrinolysis. Despite the differences between these two conditions, independent consideration of COT/ACOTS from DIC with the fibrinolytic phenotype is probably incorrect. Robust diagnostic criteria based on its pathophysiology are required to establish COT/ACOTS as a new independent disease concept. In addition, the independency of its characteristics, laboratory data, time courses and prognosis from DIC should be confirmed. Confusion between two concepts may be based on studies of trauma lacking the following: (i) a clear distinction of the properties of blood between the inside and outside of vessels, (ii) a clear distinction between physiologic and pathologic hemostatic changes, (iii) attention to the time courses of the changes in hemostatic parameters, (iv) unification of the study population, and (v) recognition that massive bleeding is not synonymous with coagulation disorders. More information is needed to elucidate the pathogenesis of these two entities, DIC with the fibrinolytic phenotype and COT/ACOTS after trauma. However, available data suggest that COT/ACOTS is not a new concept but a disease entity similar to or the same as DIC with the fibrinolytic phenotype.     

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study

Introduction  

It is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.     

Effects of antithrombin and gabexate mesilate on disseminated intravascular coagulation: a preliminary study

Purpose

We hypothesized that antithrombin is more effective for disseminated intravascular coagulation (DIC) than is gabexate mesilate, which is a protease inhibitor, suggested from the previous studies. Initially, we compared the effects of antithrombin and gabexate mesilate for treating infection-related DIC.

Methods

Sixteen adult patients with a diagnosis of DIC with infection who were assessed with an acute DIC score 4 or higher at the admission to the intensive care unit were divided into antithrombin-treated and gabexate mesilate–treated groups. White blood cell counts, C-reactive protein, platelet counts, antithrombin, fibrin and fibrinogen degradation product, d-dimer, fibrinogen, thrombin antithrombin complex, plasmin plasminogen complex, prothrombin time, and activated partial thrombin time were measured on the day of admission and on days 1, 3, 5, and 7 thereafter. Mortality over 28 days was also compared.

Results

Platelet counts and antithrombin were significantly higher in the antithrombin group on day 7 and on days 5 and 7, respectively. Antithrombin increased to the normal level on day 1 in the antithrombin group but on day 7 in the gabexate mesilate group. C-reactive protein, fibrinogen degradation product, d-dimer, thrombin antithrombin complex, plasmin plasminogen complex, and prothrombin time were lower in the antithrombin group; but the differences were not significant. The 28-day mortality was 2 of 8 in the antithrombin group and 3 of 8 in the gabexate mesilate group, but they were not significantly different.

Conclusions

Antithrombin may be a more effective treatment for coagulation and fibrinolysis disorders than gabexate mesilate in infection-related DIC, but there was no difference in 28-day mortality.     

Disseminated intravascular coagulation is associated with the neurologic outcome of cardiac arrest survivors

Purpose

We aimed to examine the serial changes in coagulofibrinolytic markers that occurred after the restoration of spontaneous circulation (ROSC) in cardiac arrest patients, who were treated with targeted temperature management (TTM). We also evaluated the association between the disseminated intravascular coagulation (DIC) score and clinical outcomes.

Screening tests of disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis

OBJECTIVE: To study the clinician's ordering pattern in the diagnosis of disseminated intravascular coagulation (DIC) and to analyze the utility of selected tests by assessing their sensitivity, specificity, and overall efficiency. DESIGN: Retrospective, nonrandomized, clinical study. SETTING: University hospital intensive care units. PATIENTS: A total of 82 inpatients treated in our intensive care units were identified from the hospital computer system as having been tested for DIC in a 3-month period. INTERVENTION: Screening tests for DIC were ordered for the suspected patients. MEASUREMENTS AND MAIN RESULTS: Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen/fibrin degradation products (FDP), and fibrinogen were used most frequently as DIC diagnostic tests. The FDP and D-dimer combination (n = 39) had the highest diagnostic efficiency of 95%, with sensitivity being 91% and specificity 94%. This is followed by FDP (n = 71), efficiency 87%, sensitivity 100%, and specificity 67%; PT/PTT and FDP combination (n = 71), efficiency 86%, sensitivity 91%, and specificity 71%; and D-dimer (n = 44), efficiency 80%, sensitivity 91%, and specificity 68%. The rest of the commonly used tests, such as PT, PTT, thrombin time, platelet count, fibrinogen, and the presence of schistocytes (n = 80), had individually either low specificity or low sensitivity and, therefore, low efficiency scores (57%, 57%, 70%, 67%, 65%, and 51%, respectively). CONCLUSIONS: The D-dimer and FDP tests offered the best test panel in the diagnosis of DIC. We propose the use of D-dimer, FDP, and antithrombin as the DIC diagnostic test panel, with D-dimer and FDP providing a rapid and specific diagnosis, antithrombin providing insight to the severity and prognosis, and FDP (rapid and less expensive than D-dimer) to follow-up the progress of the condition once the diagnosis is established.     

Disseminated intravascular coagulation (DIC).

DIC is a life-threatening complication of several disease states. It is characterized by systemic activation of the hemostasis system. In many instances the release of tissue factor (TF) from endothelial cells or other circulating cells triggers the system. Initially, the increased activation can be compensated for by the natural inhibitor systems, a state referred to as compensated DIC. As the trigger persists, inhibitors will be consumed leading to more coagulation. In this process many clotting factors, most notably fibrinogen and platelets are consumed, resulting eventually in a complete breakdown of the hemostasis system. This results in a profuse and diffuse bleeding tendency or decompensated DIC. The term consumptive coagulopathy denotes this process. Of crucial importance is the fate of fibrin that is formed from fibrinogen by thrombin. If the fibrinolytic system is insufficiently activated, fibrin will be deposited in the microcirculation leading to MODS. This will not occur if the fibrinolytic system is fully activated. The clinical suspicion of DIC must be confirmed by laboratory tests and decreasing fibrinogen levels and platelet counts support the diagnosis. The determination of D-dimer, fibrin(ogen) split products (FSP) and soluble fibrin monomer (FM) further support the diagnosis. FM suggest the presence of thrombin, FSP the generation of plasmin, and D-dimer, both thrombin and plasmin. While the tests are not specific for DIC, they can be helpful, in the proper clinical setting, to diagnose decompensated or acute DIC. The tests are not useful for the diagnosis of compensated DIC, except for D-dimer, FSP, and FM if elevated. Compensated DIC can be diagnosed by molecular markers of in vivo hemostasis activation, such as thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F 1 + 2), or plasmin-antiplasmin (PAP) complexes. For the treatment of DIC it is imperative to remove the triggering underlying disease. The consumption of coagulation constituents can be corrected by cryoprecipitate, platelet concentrates, and fresh frozen plasma, if needed. This may reduce the bleeding tendency. Arrest of the activated hemostasis system by heparins, either subcutaneous in low doses or intravenous in therapeutic doses, is only recommended in patients with compensated DIC. If the patient bleeds, heparins should not be given. The administration of concentrates of natural anticoagulants, i.e., antithrombin, protein C, or tissue factor pathway inhibitor are safer than heparins since they do not exacerbate the bleeding tendency. These concentrates were found to be very effective in animal models of DIC; human experience is still limited. Generally, the earlier treatment is initiated, the better the patient's prognosis.     

Recombinant human soluble thrombomodulin improves mortality in patients with sepsis especially for severe coagulopathy: a retrospective study

Background

Disseminated intravascular coagulation (DIC) is associated with high mortality in patients with sepsis. Several studies reporting that recombinant human soluble thrombomodulin (rhTM) reduced mortality in sepsis patients. This retrospective cohort study aimed to evaluate the efficacy of rhTM for patients with mild coagulopathy compared with those with severe coagulopathy.

Methods

We evaluated about 90-day mortality and SOFA score. SOFA score was also evaluated for the following components: respiratory, cardiovascular, hepatic, renal and coagulation.

Results

All 69 patients were diagnosed with sepsis, fulfilled Japanese Association for Acute Medicine criteria for DIC, and were treated with rhTM. Patients were assigned to either the mild coagulopathy group (did not fulfill the International Society on Thrombosis and Haemostasis overt DIC criteria) or the severe coagulopathy group (fulfilled overt DIC criteria). The 90-day mortality was significant lower in severe coagulopathy group than mild coagulopathy group (P?=?0.029). Although the SOFA scores did not decrease in the mild coagulopathy group, SOFA scores decreased significantly in the severe coagulopathy group. Furthermore the respiratory component of the SOFA score significant decreased in severe coagulopathy group compared with mild coagulopathy group.

Conclusions

rhTM administration may reduce mortality by improving organ dysfunction especially for respiratory in septic patients with severe coagulopathy.

     

Posttrauma coagulation and fibrinolysis.

OBJECTIVE: To determine the effects of disseminated intravascular coagulation (DIC) and head injury on posttrauma coagulation and fibrinolysis. DESIGN: Case-control study. SETTING: General ICU (tertiary care center) in a city hospital serving a population of 150 million people. PATIENTS: Forty trauma victims: 15 with DIC; 25 without DIC. INTERVENTIONS: Measurement of six types of coagulation and fibrinolytic molecular markers (fibrinopeptide A, fibrinopeptide B beta 15-42, 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 +/- 0.06 mg/kg/hr. MEASUREMENTS AND MAIN RESULTS: Fibrinopeptide A, fibrinopeptide B beta 15-42, 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. CONCLUSIONS: a) 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.     

Rule out of acute aortic dissection with plasma matrix metalloproteinase 8 in the emergency department

Introduction

Matrix metalloproteinases (MMPs) are involved in aortic pathophysiology. Preliminary studies have detected increased plasma levels of MMP8 and MMP9 in patients with acute aortic dissection (AAD). However, the performance of plasma MMP8 and MMP9 for the diagnosis of AAD in the emergency department is at present unknown.

Methods

The levels of MMP8 and MMP9 were measured by ELISA on plasma samples obtained from 126 consecutive patients evaluated in the emergency department for suspected AAD. All patients were subjected to urgent computed tomography (CT) scan for final diagnosis.

Results

In the study cohort (N = 126), AAD was diagnosed in 52 patients and ruled out in 74 patients. Median plasma MMP8 levels were 36.4 (interquartile range 24.8 to 69.3) ng/ml in patients with AAD and 13.2 (8.1 to 31.8) ng/ml in patients receiving an alternative final diagnosis (P <0.0001). Median plasma MMP9 levels were 169.2 (93.0 to 261.8) ng/ml in patients with AAD and 80.5 (41.8 to 140.6) ng/ml in patients receiving an alternative final diagnosis (P = 0.001). The area under the curve (AUC) on receiver-operating characteristic (ROC) analysis of MMP8 and MMP9 for the diagnosis of AAD was respectively 0.75 and 0.70, as compared to 0.87 of D-dimer. At the cutoff of 3.6 ng/ml, plasma MMP8 had a sensitivity of 100.0% (95% CI, 93.2% to 100.0%) and a specificity of 9.5% (95% CI, 3.9% to 18.5%) and ruled out AAD in 5.6% of patients. Combination of plasma MMP8 with D-dimer increased the AUC on ROC analysis to 0.89. Presence of MMP8 <11.0 ng/ml and D-dimer <1.0 or <2.0 µg/ml provided a negative predictive value of 100% and ruled out AAD in 13.6% and 21.4% of patients respectively.

Conclusions

Low levels of plasma MMP8 can rule out AAD in a minority of patients. Combination of plasma MMP8 and D-dimer at individually suboptimal cutoffs could safely rule out AAD in a substantial proportion of patients evaluated in the emergency department.     

Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a secondary survey

Introduction

In a previous report, we demonstrated a favorable trend for supplementation with antithrombin (AT) concentrate at a dosage of 3,000 IU/day over 1,500 IU/day for the treatment of sepsis-associated disseminated intravascular coagulation (DIC) in patients with an AT activity of 70% or less. Since the survival difference did not reach statistical significance, we planned to examine the effects in a larger number of cases with severer disease.

Methods

We performed a non-randomized multi-institutional survey. In total, 307 septic DIC patients who had AT activity less than 40% and who had undergone AT substitution at a dose of either 1,500 IU/day or 3,000 IU/day for three consecutive days were analyzed. Of these, 259 patients received 1,500 IU/day (AT1500 group) and 48 patients received 3,000 IU/day (AT3000 group). The primary efficacy endpoints were recovery from DIC by day 7 and an all-cause mortality on day 28. Adverse bleeding events were also examined. A logistic regression analysis was conducted by using age, sex, body weight, initial AT activity, DIC score, platelet count, coadministration of heparin, recombinant thrombomodulin, suspected source of infection, surgery, and supplemented AT dose.

Results

Supplementation significantly decreased the DIC score in the AT3000 group, leading to the superior resolution of DIC, compared with the results in the AT1500 group (66.7% versus 45.2%, P = 0.007). In addition, the AT3000 group exhibited a better survival than the AT1500 group (77.1% versus 56.4%, P = 0.010). Bleeding events were observed in 6.96% (severe bleeding: 3.04%) in the AT1500 group and 6.52% (severe bleeding, 4.35%) in the AT3000 group (P = 1.000; severe bleeding, P = 0.648). A logistic regression analysis revealed that the use of AT3000 (odds ratio (OR), 2.419; P = 0.025), a higher initial platelet count (OR, 1.054; P = 0.027), and patient age (OR, 0.977; P = 0.045) were significantly correlated with an improved survival.

Conclusions

The AT3000 group exhibited significantly improved rates of survival and recovery from DIC without an increased risk of bleeding, compared with the AT1500 group, among the patients with sepsis-associated DIC and an AT activity of less than 40%.     

A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria

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.     

Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy

Purpose

Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course.

Methods

One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score.

Results

Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis.

Conclusion

Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.     

Platelet Kinetics in Idiopathic Thrombocytopenic Purpura Patients Treated with Thrombopoietin Receptor Agonists

Aim

Thrombopoietin receptor agonists (Tpo RA) increase platelet counts in the majority of chronic autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura; ITP) patients. It is unknown whether this treatment may also improve platelet survival (PS) in these patients.

Methods

In order to determine platelet survival (PS), autologous platelets were labeled with ¹¹¹In oxine and retransfused in six patients under treatment with Tpo RA (romiplostim n = 3; eltrombopag n = 3).

Results

Stable platelet counts of greater than 100 × 10³/μl were observed in all 6 patients. Platelet survival was decreased in all cases (mean 2.10 days; range 0.13–3.73 days). No correlation was found between platelet count and PS. Similarly, there was no significant relationship between platelet turnover and platelet count. However, a high platelet turnover, exceeding 25 or three times the norm was observed in 2 patients who presented the lowest PS (0.13 or 0.83 days). Two patients had a moderately shortened PS (1.91 or 2.42 days), and, correspondingly, a moderately increased platelet turnover rate (63,072 or 72,872 platelets/μl/day).

Conclusion

These results indicate that Tpo RA may not only overcompensate platelet destruction in ITP, but may interfere with other mechanisms, which, in some cases, results in a reduced platelet destruction rate.     

D-二聚体／FDP比值在急性与陈旧性脑梗死诊断中的意义

目的研究急性与陈旧性脑梗死时患者血浆凝血、纤溶活性的变化,探讨D-二聚体／FDP比值在急性与陈旧性脑梗死时的应用价值。方法比较40例急性脑死塞患者与40例陈旧性脑梗死患者血浆凝血、纤溶活性。检测血浆中的纤维蛋白原（Fbg）、D-二聚体（D-dimer）、纤维蛋白（原）降解产物（FDP）三个参数。对三个参数分别进行组合分析：评价不同组合在鉴别急性与陈旧性脑梗死时的应用价值。结果急性脑梗死组血浆D-二聚体／FDP比值明显高于陈旧性脑梗死组（P〈0．05）;而单独Fbg、FDP比较两组差别无显著性（P〉0．05）;两组单独D-dimer结果均与正常参考值有差别（P〈0．05）,但两组相比较,D-dimer值差别无显著性（P〉0．05）。结论急性脑梗死的发生存在血液高凝状态大于纤溶状态,D-二聚体／FDP比值可以作为诊断急性与陈旧性脑梗死的快速简便实验室指标。     

Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma

ABSTRACT: INTRODUCTION: Disseminated intravascular coagulation (DIC) is characterized by the concomitant activation of coagulofibrinolytic disorders and systemic inflammation associated with endothelial dysfunction-induced microvascular permeability. Angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC after severe trauma. MATERIALS AND METHODS: A total of 57 patients with severe trauma were divided into two subgroups; 30 DIC patients and 27 non-DIC patients. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. The serum levels of angiogenic factors were measured at the time of admission (Day 1), Day 3 and Day 5. This study compared levels of these angiogenic factors between the two DIC groups, and evaluated their predictive value for organ dysfunction. RESULTS: DIC patients, especially those with ISTH DIC, showed higher Sequential Organ Failure Assessment (SOFA) scores and lactate levels. There were lower levels of VEGF, Ang1 and the soluble Tie2 in the ISTH DIC patients than the non-DIC patients. The levels of soluble VEGF receptor-1 (sVEGFR1), Ang2 and the Ang2/Ang1 ratio in the ISTH DIC patients were higher than in non-DIC patients. The relationship between the presence of massive transfusion and angiogenic factors indicated the same results. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA scores. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2. The decrease in the platelet counts also independently predicted the increase in Ang2 levels in DIC patients. CONCLUSIONS: Angiogenic factors and their soluble receptors, particularly sVEGFR1 and Ang2, are considered to play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. DIC-induced tissue hypoxia and platelet consumption may play crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction.