Tomoko Ono

Plasminogen Activator Inhibitor 1 Promotes a Poor Prognosis in Sepsis-Induced Disseminated Intravascular Coagulation

Sepsis-induced disseminated intravascular coagulation (DIC) is a serious condition because it is closely linked to the development of multiple organ dysfunctions.We compared molecular fibrinolysis markers for 117 patients with sepsis-induced DIC and 1627 patients with nonseptic DIC. Levels of fibrinogen and fibrin degradation products and D-dimer were significantly lower in sepsis-induced DIC cases than in nonseptic DIC cases. In septic DIC cases, plasma plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in nonseptic DIC cases. D-dimer levels were negatively correlated with plasma PAI-1 levels in septic DIC cases. Multiple Organ Dysfunction Scores were significantly higher in septic DIC patients with PAI-1 levels >90 ng/mL than in the group with PAI-1 levels <30 ng/mL. The Kaplan-Meier survival functions until 28 days after DIC diagnosis were significantly lower in the group with PAI-1 levels >90 ng/mL than in the other groups. In a multivariate analysis, plasma PAI-1 levels at DIC diagnosis were an independent risk factor for mortality in sepsis-induced DIC (hazard ratio, 1.012; P = .008). These data suggest that plasma PAI-1 plays an important role in sustaining DIC in septic DIC cases and contributes to multiple organ failure and decreased survival in such patients.

Association between reduced ADAMTS13 and diabetic nephropathy

INTRODUCTION Deficiency of Von Willebrand factor (VWF)-cleaving protease (ADAMTS13) causes platelet thrombosis in the microcirculation. Intrarenal coagulation is thought to be associated with the development and progression of diabetic nephropathy. Our aim was to clarify the association between plasma ADAMTS13 antigen (ADAMTS13Ag) levels and diabetic nephropathy. MATERIAL AND METHODS We measured the plasma levels of VWF antigen (VWFAg) and ADAMTS13Ag, and calculated the VWF/ADAMTS13 ratio in 86 type 2 diabetic patients and 26 healthy volunteers, to investigate the relationship between these levels and renal function. With regard to diabetic macroangiopathy, the relationship between these levels and carotid intima-media thickness (IMT) was also investigated. RESULTS AND CONCLUSIONS A significant positive and negative correlation was noted between ADAMTS13Ag and the estimated glomerular filtration rate (eGFR), vWF/ADAMTS13 ratio and eGFR, respectively. The diabetic patients were divided into normoalbuminuria (n=50), microalbuminuria (n=8) and overt nephropathy (n=28) groups. Compared among these three groups and the 26 healthy volunteers, ADAMTS13Ag was significantly lower only in the overt nephropathy group. The mean carotid IMT was measured in 69 patients and was significantly negatively correlated with ADAMTS13Ag and positively correlated with VWF/ADAMTS13 ratio. When these 69 patients were divided into four groups according to eGFR and ADAMTS13 levels (ADAMTS13/eGFR; low/low: n=12; high/low: n=7; low/high: n=25; high/high: n=25), the mean carotid IMT was increased in patients with a low ADAMTS13Ag in the same eGFR group. The present study suggests that reduced ADAMTS13 might be associated with diabetic nephropathy.

Automated Latex Photometric Immunoassay for Total Plasminogen Activator Inhibitor-1 in Plasma

Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of the fibrinolytic system (1). The continuously high PAI-1 concentrations make fibrins resistant to dissolution by tissue-type plasminogen activator (tPA), which leads to multiorgan dysfunction and a bad prognosis in patients (2). Several methods have been developed for measuring the functional activity of PAI-1 in plasma samples based on the principle of adding a specified amount of tPA in excess of the PAI-1 and measuring residual tPA activity after a short incubation period (3). These methods, however, are neither completely specific nor accurate, and many other protease inhibitors in plasma inhibit tPA (4). Although several assays have also been described for PAI-1 antigen that are based on two-step enzyme immunoassays using monoclonal and/or polyclonal antibodies (5)(6), they have a narrow measurement range (0–40 μg/L) and are time-consuming (7). Because PAI-1 is a labile molecule, the utmost care is needed during blood collection and sample handling to ensure accurate measurement of PAI-1 and tPA. The half-life for the transformation from the active form of PAI-1 into the inactive latent form is ∼4 h in vitro and even shorter in vivo (8). It is therefore essential to correctly evaluate the amount of PAI-1 released from endothelial cells and adipose tissue (9) to make such methods clinically useful. We have developed a latex photometric immunoassay (LPIA) for total PAI-1 within a dynamic measurement range that can detect all forms of PAI-1 without the influence of conformational changes. Samples were obtained from 47 patients with myocardial infarction (29 men and 18 women) and 276 hospital employees, who volunteered for this study, as controls [100 men (age range, 23–63 years) and 168 women (age range, 21–57 years)]. After informed consent, blood samples were collected in a 1/10 volume of a solution containing 38 g/L sodium …

Prediction of Hepatocellular Carcinoma Development by Plasma ADAMTS13 in Chronic Hepatitis B and C

Background: Chronic liver injury evokes a wound healing response, promoting fibrosis and finally hepatocellular carcinoma (HCC), in which hepatic stellate cells play an important role. Although a blood marker of hepatic stellate cells is not known, those cells importantly contribute to the regulation of plasma a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) activity, a defect of which causes thrombotic thrombocytopenic purpura. Methods: Plasma ADAMTS13 was evaluated in chronic hepatitis B or C patients with or without HCC. Results: Plasma ADAMTS13 activity significantly correlated with serum aspartate aminotransferase and alanine aminotransferase, liver stiffness value, and aspartate aminotransferase-to-platelet ratio index, irrespective of the presence of HCC, suggesting that it may reflect hepatocellular damage and subsequent wound healing and fibrosis as a result of hepatic stellate cell action. During the three-year follow-up period for patients without HCC, it developed in 10 among 81 patients. Plasma ADAMTS13 activity was significantly higher in patients with HCC development than in those without and was a significant risk for HCC development by univariate and multivariate analyses. Furthermore, during the one-year follow-up period for patients with HCC treated with radiofrequency ablation, HCC recurred in 55 among 107 patients. Plasma ADAMTS13 activity or antigen level was significantly higher in patients with HCC recurrence than in those without and was retained as a significant risk for HCC recurrence by multivariate analysis. Conclusions: Higher plasma ADAMTS13 activity and antigen level was a risk of HCC development in chronic liver disease. Impact: Plasma ADAMTS13 as a potential marker of hepatic stellate cells may be useful in the prediction of hepatocarcinogenesis. Cancer Epidemiol Biomarkers Prev; 20(10); 2204–11. ©2011 AACR.

Inverse correlations between serum ADAMTS13 levels and systolic blood pressure, pulse pressure, and serum C-reactive protein levels observed at a general health examination in a Japanese population: A cross-sectional study

BACKGROUND Although a defect in ADAMTS13 activity is known to cause platelet thrombosis resulting in thrombotic thrombocytopenic purpura (TTP), recent evidence has revealed that low plasma ADAMTS13 concentrations may increase the risk of ischemic vascular diseases. Furthermore, reduced plasma ADAMTS13 activity has been reported in acute systemic inflammation or sepsis. These findings prompted us to examine whether ADAMTS13 may play a role in more diverse diseases, not limited to TTP. METHODS A cross-sectional study was conducted to examine ADAMTS13 concentrations in blood samples from 432 subjects who had undergone a general health examination. RESULTS Serum ADAMTS 13 concentrations were lower in men than in women and in older age, as previously reported. Of note, the serum ADAMTS13 concentration was significantly and inversely correlated with the systolic blood pressure, pulse pressure, and serum C reactive protein concentration in both men and women and with the serum γ-glutamyltransferase concentration in men only. In 88 subjects, who underwent a carotid artery evaluation, serum ADAMTS13 concentrations were significantly lower in the subjects with a thicker carotid intima-media. CONCLUSIONS ADAMTS13 may play a role in not only TTP, but also inflammation, oxidative stress, and atherosclerosis. The potentially diverse clinical significance of ADAMTS13 should be prospectively elucidated in a larger cohort.