Changes in Plasma Levels of Natural Anticoagulants in Disseminated Intravascular Coagulation: High Prognostic Value of Antithrombin and Protein C in Patients with Underlying Sepsis or Severe Infection

Choi, Qute; Hong, Ki Ho; Kim, Ji Eun; Kim, Hyun Kyung

doi:10.3343/alm.2014.34.2.85

Cited by 37 publications

(27 citation statements)

References 19 publications

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“…Thus, we think that AT is an excellent discriminator of the severity of sepsis. Recently, Choi et al [ 54 ] reported a significant correlation between AT and the DIC score in patients with sepsis, suggesting that AT is a good indicator of DIC severity. Indeed, AT had a significant prognostic power in a Kaplan-Meier analysis, showing a higher hazard ratio than conventional coagulation markers, such as D-dimer.…”

Section: Reviewmentioning

confidence: 99%

Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

Iba

Saitoh

2014

j intensive care

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Antithrombin (AT) is known as an important physiological anticoagulant. AT inactivates thrombin and multiple other coagulation factors, thereby strongly inhibiting the over-activation of the coagulation system during disseminated vascular coagulation (DIC). AT also suppresses the pro-inflammatory reactions that are promoted through protease-activated receptor-1 during sepsis. One of the unique characteristics of AT is the conformational change it undergoes when binding to heparin-like molecules. The anticoagulant function is greatly accelerated after AT binds to externally administered heparin in the circulating blood. Meanwhile, AT also binds to syndecan-4 on the cell surface under physiological conditions, thereby contributing to local antithrombogenicity. The binding of AT and syndecan-4 upregulates prostaglandin I2 production, downregulates pro-inflammatory cytokine production, and suppresses the leukocyte-endothelial interaction. Other than these activities, recent preclinical studies have reported that AT might inhibit neutrophil necrotic cell death and the ejection of neutrophil extracellular traps. Together, these effects may lead to the attenuation of inflammation by decreasing the level of damage-associated molecular patterns. Although a number of animal studies have demonstrated a survival benefit of AT, the clinical benefit has long been argued since the effect of high-dose AT was denied in 2001 in a large-scale randomized controlled trial targeting patients with severe sepsis. However, recent clinical studies examining the effects of a supplemental dose of AT in patients with sepsis-associated DIC have revealed that AT is potentially effective for DIC resolution and survival improvement without increasing the risk of bleeding. Since DIC is still a major threat during sepsis, the optimal method of identifying this promising drug needs to be identified.

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Section: Reviewmentioning

confidence: 99%

Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

Iba

Saitoh

2014

j intensive care

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“…big-h3 (also known as TGF-bi) is a secreted protein found in the ECM and it has an N-terminal secretory signal (aa 1-23), four FAS1 homologous internal domains, and a cell attachment site (RGD) at its C terminus (4). big-h3 binds to the ECM through interaction of the YH motif in its FAS1 domains with collagens I, II, IV, and VI (5,6). Its FAS1 domain interacts with its a3b1, aVb3, and aVb5 integrins on the cell surface.…”

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confidence: 99%

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

et al. 2015

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big-h3/TGF-bi is a secreted protein capable of binding to both extracellular matrix and cells. Human genetic studies recently revealed that in the tgfbi gene encoding for big-h3, three single nucleotide polymorphisms were significantly associated with type 1 diabetes (T1D) risk. Pancreatic islets express big-h3 in physiological conditions, but this expression is reduced in b-cell insult in T1D. Since the integrity of islets is destroyed by autoimmune T lymphocytes, we thought to investigate the impact of big-h3 on T-cell activation. We show here that big-h3 inhibits T-cell activation markers as well as cytotoxic molecule production as granzyme B and IFN-g. Furthermore, big-h3 inhibits early T-cell receptor signaling by repressing the activation of the early kinase protein Lck. Moreover, big-h3-treated T cells are unable to induce T1D upon transfer in Rag2 knockout mice. Our study demonstrates for the first time that T-cell activation is modulated by big-h3, an islet extracellular protein, in order to efficiently avoid autoimmune response.Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by smoldering inflammatory response directed against the insulin-producing b-islet cells of the pancreas. Both CD4 + and CD8 + T cells are involved in the destruction of b-cells (shed by a prior insult). CD4 + T cells are insulin reactive, and CD8 + T cells play a major role as b-cell killers (1,2). Although both in vitro and in vivo evidence point to a role for regulatory T cells in T-cell-mediated regulation controlling diabetes in mouse models (3), the influence of the inflammatory environment in which they function remains poorly understood. The cross talk between the inflammatory milieu and the immune response during insulitis is likely to be communicated in large part through the extracellular matrix (ECM). big-h3 (also known as TGF-bi) is a secreted protein found in the ECM and it has an N-terminal secretory signal (aa 1-23), four FAS1 homologous internal domains, and a cell attachment site (RGD) at its C terminus (4). big-h3 binds to the ECM through interaction of the YH motif in its FAS1 domains with collagens I, II, IV, and VI (5,6). Its FAS1 domain interacts with its a3b1, aVb3, and aVb5 integrins on the cell surface. Previous studies demonstrated that recombinant big-h3 could preserve the integrity and enhance the function of cultured pancreatic islet cells (7). Conversely, big-h3 knockout (KO) islet function was compromised in vivo after transplantation in recipients with diabetes (8). These studies point out that big-h3 might play an active role in the protection of b-cells against T-cell cytotoxic insult in T1D. The effect of big-h3 on T-cell function and activation relative to its roles in islet b-cell-ECM destruction in T1D in mice has never been investigated and it is the focus of our project. RESEARCH DESIGN AND METHODS MiceFemale C57Bl/6 NOD mice were bred and housed in specific pathogen-free conditions. T1D was chemically induced inC57Bl/6 using a standard low-dose (35 mg/kg) streptozotoci...

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“…While 40% activity of AT III is seen in full blown DIC. Choi et al 16 reported a correlation between AT and the DIC scores in septic patients. This suggests that AT level is a good indicator of DIC severity.…”

Section: Discussionmentioning

confidence: 96%

Comparison of Antithrombin III and Pentoxifylline Treatments in Gram Negative Sepsis Patients Developing DIC

Ozden¹,

Köksal²,

Öz³

2019

MMJ

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The aim of this study was to evaluate the effects of antithrombin III (AT III) and pentoxifylline treatments on the gram negative septic patients with disseminated intravascular coagulation (DIC). Method: For six days after plasma AT III activity dropped lower than 80% in Gram-patients who developed DIC were treated with AT III (90-120 IU/kg/day in 6 hours) or pentoxifylline (1.5 mg/ kg/h in 6 hours) Fibrinogen, FDP, D-dimer, complete blood count, AT III activity, and DIC scores were calculated and recorded. Results: The coagulation tests, AT III activity and FDP started to improve from the second day of treatment with both treatments (p<0.05). D-Dimer started to decrease on the second day of treatment with pentoxifylline (p<0.001) and fourth day of AT III treatment (p<0.05). Fibrinogen levels decreased on the second day of pentoxifylline treatment (p<0.05) and on the last day of AT III treatment (p<0.001). DIC scores started to decrease on the last day of treatment with AT III treatment (p<0.001) and on the third day of treatment with pentoxifylline (p<0.05). Conclusion: Both ATIII and pentoxifylline treatments had positive effects on fibrinogen, FDP, D-Dimer, AT III activity and DIC scores in patients with Gram-negative sepsis who developed DIC.

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Changes in Plasma Levels of Natural Anticoagulants in Disseminated Intravascular Coagulation: High Prognostic Value of Antithrombin and Protein C in Patients with Underlying Sepsis or Severe Infection

Cited by 37 publications

References 19 publications

Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

Comparison of Antithrombin III and Pentoxifylline Treatments in Gram Negative Sepsis Patients Developing DIC

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