Increased Serum Levels and Sinusoidal Expression of Thrombomodulin in Acute Liver Damage

Takatori, Masao; Iwabuchi, Shogo; Ro, Shinsei; Murayama, Masahiro; Maeyama, Shiro; Uchikoshi, Toshiyuki; Nakano, Masahiko; Ishii, Hidemi

doi:10.1016/s0049-3848(98)00167-4

Cited by 21 publications

(12 citation statements)

References 19 publications

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“…Thrombomodulin (TM) is an endothelial cell glycoprotein that is expressed as a result of tissue injury [10–12]. The Imubind Thrombomodulin enzyme kit, an enzyme‐linked immunosorbent assay (ELISA), was used for the quantitation of thrombomodulin.…”

mentioning

confidence: 99%

Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFκB and nitric oxide in responders and nonresponders to IFNα therapy

George

Baluch

Thiel

2003

Journal of Viral Hepatitis

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Hepatitis C virus (HCV) infects hepatocytes and utilizes the hepatocyte to replicate. In so doing, many hepatocyte activities are shifted from their native state to one reflecting liver cell stress. Thrombomodulin and tissue factor are endothelial cell proteins that are expressed as a result of tissue injury or stress. Urokinase is a serine protease, which has been implicated in a number of physiologic and pathologic processes related to cellular stress and or injury. Nitric oxide is produced by cells in response to injury and functions both as a vasodilator and as an activator of a large number of cytokine cascades. NFkappaB is a transcription factor that forms one of the first lines of cellular defense against infection and hepatocellular stress. The levels of these four factors in plasma, hepatocyte cytosol and hepatocyte nuclear extracts provide a precise panoramic measure of cellular stress. Plasma, hepatocyte cytosol and nuclear extracts of hepatocytes were assayed for these four factors in 17 patients treated with alphaIFN for chronic hepatitis C. Five of the 17 were responders while 12 were nonresponders. Ten normal controls and 1 normal control liver were assayed also for each parameter. Nonresponders had 2x the plasma urokinase levels of responders and normals. The cytosol prepared from hepatocytes of nonresponders had a urokinase level 15-fold that of the controls and responders to IFN therapy. Plasma thrombomodulin levels in nonresponders were sixfold greater than those of responders and controls. The levels of all of the other measures in plasma, cytosol and nuclear extracts of liver tissue varied minimally between responders and nonresponders and the normal controls. These data demonstrate that: (i) urokinase levels in plasma and more clearly in cytosol are greater in nonresponders than responders, and (ii) plasma thrombomodulin levels in nonresponders are sixfold greater than those of responders and controls. These data suggest that urokinase and thrombomodulin may be unique markers of cellular and endothelial stress present in individuals with chronic hepatitis C. These markers might be useful during the clinical course of chronic hepatitis C, as a means of gauging the tissue response to therapy.

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confidence: 99%

Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFκB and nitric oxide in responders and nonresponders to IFNα therapy

George

Baluch

Thiel

2003

Journal of Viral Hepatitis

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“…First, although elevated sTM level has been widely associated with endothelial injury, compromised hepatic or renal function can also cause elevation in sTM levels due to decreased degradation and elimination. Diseases such as acute liver damage, chronic viral hepatitis, liver failure, and renal failure have all been documented to elevate sTM levels [1, 4, 10, 12, 14]. Therefore, high sTM levels do not always signify endothelial damage.…”

Section: Discussionmentioning

confidence: 99%

Serological Tests for Diagnosis and Staging of Hand–Arm Vibration Syndrome (HAVS)

Kao

Yan

Zhang

et al. 2007

Hand (New York, N,Y.)

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The current gold standard for the diagnosis and staging of hand-arm vibration syndrome (HAVS) is the Stockholm workshop scale, which is subjective and relies on the patient's recalling ability and honesty. Therefore, great potentials exist for diagnostic and staging errors. The purpose of this study is to determine if objective serum tests, such as levels of soluble thrombomodulin (sTM) and soluble intercellular adhesion molecule-1 (sICAM-1), may be used in the diagnosis and staging of HAVS. Twenty two nonsmokers were divided into a control group (n=11) and a vibration group (n=11). The control group included subjects without history of frequent vibrating tool use. The vibration group included construction workers with average vibrating tool use of 12.2 years. All were classified according to the Stockholm workshop scale (SN, sensorineural symptoms; V, vascular symptoms. SN0, no numbness; SN1, intermittent numbness; SN2, reduced sensory perception; SN3, reduced tactile discrimination; V0, no vasospasmic attacks; V1, intermittent vasospasm involving distal phalanges; V2, intermittent vasospasm extending to middle phalanges; V3, intermittent vasospasm extending to proximal phalanges; V4, skin atrophy/necrosis). All control subjects were SN0 V0. Seven out of 11 vibration subjects were SN1 V1, and 4 out of 11 were SN1 V2. A 10-cm 3 sample of venous blood was collected from each subject. The sTM and sICAM-1 levels were determined by enzyme-linked immunosorbent assay. The mean plasma sTM levels were as follows: control group=2.93±0.47 ng/ml, and vibration group=3.61±0.24 ng/ml. The mean plasma sICAM-1 levels were as follows: control group=218.8±54.1 ng/ml, and vibration group= 300.3±53.2 ng/ml. The sTM and sICAM-1 differences between control and vibration groups were statistically significant (p<0.0002 and p<0.001, respectively). When reference ranges provided by Hemostasis Reference Lab were used as cut-off values, all sTM and sICAM-1 levels were within range, except three vibration individuals (27%) who had sICAM-1 levels greater than the reference range. This was not statistically significant (p=0.08). When subjects were compared based on the Stockholm workshop scale, mean plasma sTM levels were SN0 V0 group=2.93± 0.47 ng/ml, SN1 V1 group=3.59±0.25 ng/ml, and SN1 V2 group=3.65±0.27 ng/ml, and mean plasma sICAM-1 levels were SN0 V0=219±54.1 ng/ml, SN1 V1=275± 33.5 ng/ml, and SN1 V2=345±54.6 ng/ml. The difference in sTM level among the three groups was statistically significant (p<0.001). The difference in sICAM-1 level among the three groups was also statistically significant (p<0.002). The sTM and sICAM-1 levels are statistically higher in subjects with HAVS, with levels proportional to the disease severity. However, large population studies are needed to determine the "real-life" standard reference ranges for sTM and sICAM-1.

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“…Increased serum levels and sinusoidal expression of thrombomodulin, as seen in the present investigation, have been reported previously in cases of acute and chronic liver disease and have been reported to represent a manifestation of endothelial cell stress or injury. Soluble thrombomodulin is a truncated form of thrombomodulin that lacks the transmembrane and cytoplasmic domains of tissue thrombomodulin 28–31 . The rapid consumption of soluble thrombomodulin with an infusion of rhFVIIa has not been reported previously and should reduce the anticoagulant actions of thrombomodulin by depleting soluble thrombomodulin and enhancing its procoagulant action by enabling thrombomodulin to interact with thrombin generated at the surface of endothelial cells and platelets.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human factor VIIa‐induced alterations in tissue factor and thrombomodulin in patients with advanced liver cirrhosis

Thiel

Farr

Mindikoğlu

et al. 2005

J of Gastro and Hepatol

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These data demonstrate that rhFVIIa administration to individuals with liver disease results in (i) a transient improvement in the prothrombin time; (ii) no change in the activated partial thromboplastin time; and (iii) a marked reduction in the levels of thrombomodulin and tissue factor. These data suggest that rhFVIIa binds tissue factor and enhances tissue factor and thrombomodulin clearance from the circulation.

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Increased Serum Levels and Sinusoidal Expression of Thrombomodulin in Acute Liver Damage

Cited by 21 publications

References 19 publications

Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFκB and nitric oxide in responders and nonresponders to IFNα therapy

Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFκB and nitric oxide in responders and nonresponders to IFNα therapy

Serological Tests for Diagnosis and Staging of Hand–Arm Vibration Syndrome (HAVS)

Recombinant human factor VIIa‐induced alterations in tissue factor and thrombomodulin in patients with advanced liver cirrhosis

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