scholarly journals SEPSIS-ASSOCIATED DISSEMINATED INTRAVASCULAR COAGULATION AND THROMBOEMBOLIC DISEASE

2010 ◽  
Vol 2 (3) ◽  
pp. e2010024 ◽  
Author(s):  
Nicola Semeraro ◽  
Concetta T. Ammollo ◽  
Fabrizio Semeraro ◽  
Mario Colucci
Keyword(s):  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Inflammatory Mediators ◽  
Infectious Agent ◽  
Plasminogen Activator Inhibitor ◽  
Multiple Organ ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inflammatory Reactions ◽  
Intravascular Coagulation ◽  
Microvascular Thrombosis

Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS), and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1) up-regulation of procoagulant molecules, primarily tissue factor (TF), which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2) impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor), which is orchestrated mainly by dysfunctional endothelial cells (ECs); and 3) suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated  activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones), are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the development of new therapeutic agents that could be potentially useful particularly for the management of severe sepsis.

scholarly journals Simvastatin improves the prognosis of endotoxin-induced disseminated intravascular coagulation by regulating the intestinal microenvironment

2020 ◽  
Author(s):  
Min Xu ◽  
Lili Luo ◽  
Mengyi Du ◽  
Lu Tang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Bacterial Translocation ◽  
Disseminated Intravascular Coagulation ◽  
Intestinal Barrier ◽  
Plasminogen Activator Inhibitor ◽  
Coagulation Factors ◽  
Organ Damage ◽  
Multiple Organ ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Coagulation Dysfunction

Abstract Background: Disseminated intravascular coagulation (DIC) is characterized by extensive endothelial injury and coagulation activation that is primarily caused by infection and can be aggravated by the gut due to increased permeability and bacterial translocation. Studies have shown that statins play an important role in reducing inflammation, protecting the endothelium and improving coagulation. In addition, statins regulate tight junction (TJ) proteins and gut microbes. Therefore, we aimed to investigate whether simvastatin improves DIC prognosis by regulating the intestinal microenvironment. Methods: Mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve hours later, cytokine release, coagulation dysfunction, multiple organ damage and survival were assessed. In addition, intestinal barrier and permeability and bacteria and bacteria translocation were evaluated. Results: We found that the severity of endotoxin-induced DIC was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition and an improved survival rate. In addition, simvastatin reduced epithelial apoptosis, increased TJ gene expression, and upregulated antimicrobial peptides, lysozyme and mucins. Simvastatin-pretreated mice showed increased Lactobacillales counts, while the LPS group had increased numbers of Desulfovibrio and Mucispirillum, which produce harmful toxins and damage the intestinal epithelium and mucosa. Finally, with the decreased intestinal permeability in the simvastatin group, bacterial translocation in the organs and blood was significantly reduced, both in quantity and species. Conclusions: Simvastatin improves DIC prognosis, and the intestinal microenvironment participates in this process.

scholarly journals The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1949-1957 ◽  
Author(s):  
Y Sakata ◽  
T Murakami ◽  
A Noro ◽  
K Mori ◽  
M Matsuda
Keyword(s):  
Plasminogen Activator ◽  
Acute Promyelocytic Leukemia ◽  
Disseminated Intravascular Coagulation ◽  
Specific Activity ◽  
Plasminogen Activator Inhibitor ◽  
Promyelocytic Leukemia ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Activator Inhibitor ◽  
Pai 1

In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.

Disseminated Intravascular Coagulation Is a Frequent Complication of Systemic Inflammatory Response Syndrome

1996 ◽  
Vol 75 (02) ◽  
pp. 224-228 ◽  
Author(s):  
Satoshi Gando ◽  
Takashi Kameue ◽  
Satoshi Nanzaki ◽  
Yoshimi Nakanishi
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Plasminogen Activator ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Systemic Inflammatory Response ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Activator Inhibitor

SummaryTo evaluate the role of disseminated intravascular coagulation (DIC) and to determine the influence of antithrombin, protein C, and plasminogen activator inhibitor 1 on multiple organ dysfunction syndrome (MODS) and outcome in patients with systemic inflammatory response syndrome (SIRS), we made a prospective cohort study. The study subjects consisted of thirty-five patients who exhibited two or more of the conditions of SIRS for more than three consecutive days. They were classified into subgroups of survivors (n = 13) and nonsurvivors (n = 22). The global coagulation and fibrinolytic markers, antithrombin, protein C, and plasminogen activator inhibitor 1 were measured on the day of the diagnosis of SIRS, and also on the 1st, 3rd, and 5th days. The results of these measurements, demographic data, criteria of severity, incidence of MODS were compared between the subgroups. For prediction of patient’s death, a receiver operating characteristic (ROC) curve analysis was made. DIC was frequently associated with SIRS patients (29/35, 82.9%). A significant decrease in the DIC score was found in the survivors (p = 0.0001). None of them suffered from DIC on the 5th day. In the nonsurvivors, low levels of protein C and antithrombin and markedly high values of plasminogen activator inhibitor 1 continued up to the 5th day, no improvement of the DIC was observed during the study period and the number of the dysfunctioning organs were significantly higher than in the survivors. Plasminogen activator inhibitor 1 on the 5th day had prognostic value for the prediction of death on the SIRS patients. In conclusion, DIC occurs commonly in patients with SIRS and may be the main determinant for the outcome of these patients. Changes in antithrombin, protein C, and plasminogen activator inhibitor 1 are one of the aggravating factors of MODS. Furthermore, plasminogen activator inhibitor 1 is a good predictor of death in these patients.

scholarly journals The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1949-1957 ◽  
Author(s):  
Y Sakata ◽  
T Murakami ◽  
A Noro ◽  
K Mori ◽  
M Matsuda
Keyword(s):  
Plasminogen Activator ◽  
Acute Promyelocytic Leukemia ◽  
Disseminated Intravascular Coagulation ◽  
Specific Activity ◽  
Plasminogen Activator Inhibitor ◽  
Promyelocytic Leukemia ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Activator Inhibitor ◽  
Pai 1

Abstract In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.

Dysregulation of Inflammatory and Hemostatic Markers In Disseminated Intravascular Coagulation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3656-3656
Author(s):  
Debra Hoppensteadt ◽  
Josephine Cunanan ◽  
Nasiredin Sadeghi ◽  
Inder Kaul ◽  
Jawed Fareed
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Inflammatory Mediators ◽  
Protein C ◽  
Control Group ◽  
Normal Male ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Hemostatic Markers ◽  
Circulating Levels ◽  
Pai 1

Abstract Abstract 3656 Disseminated intravascular coagulation (DIC) represents a complex polypathologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are upregulated through multiple mechanisms. The upregulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO) and c reactive protein (CRP), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), prothrombin fragment1.2 (F1.2), thrombin antithrombin complex (TAT), antithrombin (AT), activated protein C (APC) and protein C (Pr C) were evaluated in the baseline samples of an initial cohort of provisionally diagnosed DIC and sepsis patients enrolled in an ongoing clinical trial designed to assess the safety and efficacy of r-thrombomodulin (ART-123) (n=100). The control group consisted of normal male and female volunteers (n=30). Commercially available ELISA methods were used to measure the various mediators. Marked deviations in the circulating levels of these markers, as compared to controls, were noted as shown in the following table. Compared with normal volunteers, patients showed a 5–10 fold increase in the circulating level of most inflammatory markers, with the exception of PCT, IL-6 and CRP, where the increase was over 50 fold. PCI, Pr C and AT exhibited slight decreases. Wide individual variations were obvious. These results clearly indicate that inflammation, thrombin generation, impairment of fibrinolysis and impairment of endogenous anticoagulants play a key role in the pathogenesis of DIC. Marker Normal Human Volunteers (n=30) DIC with Sepsis Patients (n=100) Fold Change PCT (ng/ml) 0.1 ± 0.04 (0.01) 18.7 ± 31.2 (3.1) 187× Increase C5a (ng/ml) 6.7 ± 1.7 (0.5) 15.5.7 ± 14.9 (1.5) 2× Increase PCI (% NHP) 138.9 ± 71.1 (8.8) 106.9 ± 33.4 (7.1) 1.3× Decrease IL-6 (pg/ml) 2.5 ± 1.2 (0.3) 522.5 ± 881.5 (88.2) 210× Increase IL-10 (pg/ml) 9.8 ± 5.23 (1.7) 46.9 ± 73.3 (8.8) 5× Increase MPO (ng/ml) 15.1 ± 10.1 (2.7) 111.4 ± 74.9 (7.5) 7× Increase PAI-1 (ng/ml) 31.7 ± 8.9 (3.1) 130.2 ± 178.1 (22.1) 4× Increase F1.2 (pM) 108.6 ± 46.2 (12.3) 473.7 ± 320.2 (32.0) 4× Increase TAT (ng/ml) 4.4 ± 1.1 (0.3) 17.0 ± 30.8 (3.1) 5× Increase AT (% NHP) 94.2 ± 10.3 (2.7) 80.4 ± 30.7 (3.1) 1.2× Decrease APC (ratio) 2.23 ± 0.3 (0.1) 2.48 ± 0.4 (0.04) 1.1× Increase CRP (ug/ml) 0.5 ± 1.1 (0.3) 38.4 ± 3.9 (0.4) 76× Increase Pr. C (% NHP) 78.3 ± 13.3 (3.6) 41.3 ± 17.4 (1.7) 2× Decrease Disclosures: Kaul: Artisan Pharma: Employment.

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