Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure

Abstract High Mobility Group Box chromosomal protein 1 (HMGB1) is a nuclear DNA-binding protein acting as a proinflammatory cytokine when released in the extracellular space from necrotic cells, activated macrophages and dendritic cells. HMGB1 acts on a specific receptor, RAGE (receptor for advanced glycation end-products), and induces prolonged inflammation, organ failure, septicaemia and death. The aim of the study was to determine the diagnostic value of plasma HMGB1 concentration and its role in the development of organ failure in patients with disseminated intravascular coagulation (DIC). Plasma HMGB-1 levels were measured in patients with suspected DIC by ELISA and their relationships with DIC, organ failure and clinical outcome were determined. The study group included 201 patients suspected of having DIC (79 females and 122 males, age; 52.1±16.5 years, mean±SD). The study group represented all such patients admitted to the Second Department of Internal Medicine and Intensive Care Unit (ICU) of Mie University Hospital between January 1, 2002 and December 31, 2003. The underlying diseases were infectious diseases (n=40), hematopoietic diseases (n=58), solid cancers (n=16), trauma (n=21), aneurysm (n=12), autoimmune diseases (n=8), liver diseases (n=7), post-operation (n=32) and other diseases (n=7). Results: Plasma HMGB1 was below the detection limit in normal subjects, but moderately elevated in patients with infectious diseases (4.54 ± 8.18 ng/ml, mean±SD), malignancies (2.15 ± 5.34 ng/ml), and traumas (6.47 ± 13.13 ng/ml). DIC was associated with significantly high plasma HMGB1 (14.05 ± 12.56 ng/ml) in these patients. The highest HMGBI levels were in patients with organ failure (8.29 ± 10.99 ng/ml) and non-survivors (16.58 ± 11.01 ng/ml). HMGB1 plasma levels correlated with the DIC score and sepsis-related organ failure assessment (SOFA) score. Plasma levels of HMGB1 were significantly higher in patients with PAI-I of >50 ng/ml (3.66 ± 6.36 ng/ml) than in those with PAI-I <50 ng/ml (1.38 ± 2.97 ng/ml) (p< 0.05) but there was no significant difference in HMGB1 levels between patients with TNF-a of >1.5 (3.04 ± 5,56 ng/ml) and those with less than 1.5 pg/ml (2.44 ± 5.36 ng/ml). Our data suggest that HMGB-1 is a potentially suitable prognostic marker of OF or DIC.

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Plasma Levels of Total Plasminogen Activator Inhibitor-I (PAI-I) and tPA/PAI-1 Complex in Patients With Disseminated Intravascular Coagulation and Thrombotic Thrombocytopenic Purpura

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602960100700309 ◽

2001 ◽

Vol 7 (3) ◽

pp. 229-233 ◽

Cited By ~ 22

Author(s):

Rika Watanabe ◽

Hideo Wada ◽

Youichi Miura ◽

Youichi Murata ◽

Yasuyuki Watanabe ◽

...

Keyword(s):

Organ Failure ◽

Plasminogen Activator ◽

Thrombotic Thrombocytopenic Purpura ◽

Disseminated Intravascular Coagulation ◽

Plasma Levels ◽

Plasminogen Activator Inhibitor ◽

Thrombocytopenic Purpura ◽

Intravascular Coagulation ◽

Activator Inhibitor ◽

Pai 1

In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure, The plasma levels of total PAI-I and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-1, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.

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Plasma Levels of Thrombomodulin and Active Plasminogen Activator Inhibitor Increase in Disseminated Intravascular Coagulation with Multiple Organ Failure

Hemostasis and Circulation ◽

10.1007/978-4-431-66925-8_33 ◽

1992 ◽

pp. 200-206

Author(s):

H. Asakura ◽

H. Jokaji ◽

M. Saito ◽

C. Uotani ◽

I. Kumabashiri ◽

...

Keyword(s):

Multiple Organ Failure ◽

Organ Failure ◽

Plasminogen Activator ◽

Disseminated Intravascular Coagulation ◽

Plasma Levels ◽

Plasminogen Activator Inhibitor ◽

Multiple Organ ◽

Intravascular Coagulation ◽

Activator Inhibitor

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The Glycosaminoglycan of Recombinant Human Soluble Thrombomodulin Affects Antithrombotic Activity in a Rat Model of Tissue Factor-Induced Disseminated Intravascular Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648448 ◽

1992 ◽

Vol 67 (03) ◽

pp. 366-370 ◽

Cited By ~ 16

Author(s):

Katsuhiko Nawa ◽

Teru Itani ◽

Mayumi Ono ◽

Katsu-ichi Sakano ◽

Yasumasa Marumoto ◽

...

Keyword(s):

Tissue Factor ◽

Disseminated Intravascular Coagulation ◽

Rat Model ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Soluble Thrombomodulin ◽

Intravascular Coagulation ◽

Platelet Counts ◽

Recombinant Human Soluble Thrombomodulin

SummaryPrevious studies on recombinant human soluble thrombomodulin (rsTM) from Chinese hamster ovary cells revealed that rsTM was expressed as two proteins that differed functionally in vitro due to the presence (rsTMp) or absence (rsTMa) of chondroitin-4-sulfate. The current study evaluates the in vivo behavior of rsTM in rats and in a rat model of tissue factor-induced disseminated intravascular coagulation (DIC). rsTMp was more potent than rsTMa for prolongation of the activated partial thromboplastin time (APTT) and their in vivo half-lives determined by ELISA were 20 min for rsTMp and 5.0 h for rsTMa. Injection of a tissue factor suspension (5 mg/kg) resulted in DIC as judged by decreased platelet counts and fibrinogen concentrations, prolonged APTT, and increased fibrin and fibrinogen degradation products (FDP) levels. A bolus injection of either rsTM (0.2 mg/kg) 1 min before induction of DIC essentially neutralized effects on platelets, fibrinogen, and FDP levels, and had only a moderate effect on APTT prolongation. The dose of anticoagulant to inhibit the drop in platelet counts by 50% (ED50) was 0.2 mg/kg rsTMa, 0.07 mg/kg rsTMp, and 7 U/ kg heparin. The effect of increasing concentrations of rsTM and heparin on bleeding times were compared in experiments involving incision of the rat tail. Doubling of the bleeding times occurred at 5 mg/kg rsTMa, 3 mg/kg rsTMp or 90 U/kg heparin. These values represent a 25-fold increase over the ED50 for rsTMa, 43-fold for rsTMp and 13-fold for heparin. These results suggest that rsTMp is a potent anticoagulant to inhibit the platelet reduction when injected prior to the induction of DIC in rats.

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Changes in Plasma Levels of Prothrombin Fragment F1+2 in Cases of Disseminated Intravascular Coagulation

Acta Haematologica ◽

10.1159/000204477 ◽

1993 ◽

Vol 89 (1) ◽

pp. 22-25 ◽

Cited By ~ 11

Author(s):

Hidesaku Asakura ◽

Yoshimune Shiratori ◽

Hiroshi Jokaji ◽

Masanori Saito ◽

Chika Uotani ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Plasma Levels ◽

Prothrombin Fragment ◽

Intravascular Coagulation

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Early Changes in the Sequential Organ Failure Assessment Score Among Patients With Sepsis-Induced Disseminated Intravascular Coagulation

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618814346 ◽

2018 ◽

Vol 24 (9_suppl) ◽

pp. 332S-339S

Author(s):

Katsunori Mochizuki ◽

Kotaro Mori ◽

Yuta Nakamura ◽

Ryo Uchimido ◽

Hiroshi Kamijo ◽

...

Keyword(s):

Infection Control ◽

Sequential Organ Failure Assessment ◽

Organ Failure ◽

Disseminated Intravascular Coagulation ◽

Sofa Score ◽

Early Improvement ◽

Initial Infection ◽

Soluble Thrombomodulin ◽

Failure Assessment ◽

Recombinant Human Soluble Thrombomodulin

It is unclear whether initial infection control or anticoagulant therapy exerts a greater effect on early changes in the Sequential Organ Failure Assessment (SOFA) score among patients with sepsis-induced disseminated intravascular coagulation (DIC). This retrospective propensity score cohort study aimed to evaluate whether adequacy of infection control or anticoagulation therapy had a greater effect on early changes in the SOFA scores among 52 patients with sepsis-induced DIC. Inadequate initial infection control was associated with a lower 28-day survival rate among patients with sepsis-induced DIC (odds ratio [OR]: 0.116, 95% confidence interval [CI]: 0.022-0.601; P = .010); however, the adequacy was not associated with an early improvement in the SOFA score. However, despite adjusting for inadequate initial infection control, administration of recombinant human soluble thrombomodulin was associated with an early improvement in the SOFA score (OR: 5.058, 95% CI: 1.047-24.450; P = .044). Therefore, early changes in the SOFA score within 48 hours after the DIC diagnosis were more strongly affected by the administration of recombinant human soluble thrombomodulin than the adequacy of initial infection control.

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