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Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates.
Puy C, Tucker EI, Wong ZC, Gailani D, Smith SA, Choi SH, Morrissey JH, Gruber A, McCarty OJ
(2013) J Thromb Haemost 11: 1341-52
MeSH Terms: Animals, Antibodies, Neutralizing, Blood Coagulation, Factor XI, Factor XI Deficiency, Factor XII, Factor XIIa, Factor XIa, Humans, Plant Proteins, Polyphosphates, Prothrombin, Thrombin, Thrombosis, Time Factors
Show Abstract · Added May 19, 2014
BACKGROUND - Inorganic polyphosphates (polyP), which are secreted by activated platelets (short-chain polyP) and accumulate in some bacteria (long-chain polyP), support the contact activation of factor XII (FXII) and accelerate the activation of FXI.
OBJECTIVES - The aim of the present study was to evaluate the role of FXI in polyP-mediated coagulation activation and experimental thrombus formation.
METHODS AND RESULTS - Pretreatment of plasma with antibodies that selectively inhibit FXI activation by activated FXII (FXIIa) or FIX) activation by activated FXI (FXIa) were not able to inhibit the procoagulant effect of long or short-chain polyP in plasma. In contrast, the FXIIa inhibitor, corn trypsin inhibitor, blocked the procoagulant effect of long and short polyP in plasma. In a purified system, long polyP significantly enhanced the rate of FXII and prekallikrein activation and the activation of FXI by thrombin but not by FXIIa. In FXI-deficient plasma, long polyP promoted clotting of plasma in an FIX-dependent manner. In a purified system, the activation of FXII and prekallikrein by long polyP promoted FIX activation and prothombin activation. In an ex vivo model of occlusive thrombus formation, inhibition of FXIIa with corn trypsin inhibitor but not of FXI with a neutralizing antibodies abolished the prothrombotic effect of long polyP.
CONCLUSIONS - We propose that long polyP promotes FXII-mediated blood coagulation bypassing FXI. Accordingly, some polyp-containing pathogens may have evolved strategies to exploit polyP-initiated FXII activation for virulence, and selective inhibition of FXII may improve the host response to pathogens.
© 2013 International Society on Thrombosis and Haemostasis.
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15 MeSH Terms
Effect of zymogen domains and active site occupation on activation of prothrombin by von Willebrand factor-binding protein.
Kroh HK, Bock PE
(2012) J Biol Chem 287: 39149-57
MeSH Terms: Binding, Competitive, Blood Coagulation, Carrier Proteins, Catalytic Domain, Enzyme Precursors, Fibrin, HEK293 Cells, Humans, Kinetics, Platelet Membrane Glycoproteins, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Prothrombin, Recombinant Proteins, Staphylococcus aureus, Thermodynamics, Thrombin, Virulence Factors, von Willebrand Factor
Show Abstract · Added January 20, 2015
Prothrombin is conformationally activated by von Willebrand factor-binding protein (vWbp) from Staphylococcus aureus through insertion of the NH(2)-terminal residues of vWbp into the prothrombin catalytic domain. The rate of prothrombin activation by vWbp(1-263) is controlled by a hysteretic kinetic mechanism initiated by substrate binding. The present study evaluates activation of prothrombin by full-length vWbp(1-474) through activity progress curve analysis. Additional interactions from the COOH-terminal half of vWbp(1-474) strengthened the initial binding of vWbp to prothrombin, resulting in higher activity and an ∼100-fold enhancement in affinity. The affinities of vWbp(1-263) or vWbp(1-474) were compared by equilibrium binding to the prothrombin derivatives prethrombin 1, prethrombin 2, thrombin, meizothrombin, and meizothrombin(des-fragment 1) and their corresponding active site-blocked analogs. Loss of fragment 1 in prethrombin 1 enhanced affinity for both vWbp(1-263) and vWbp(1-474), with a 30-45% increase in Gibbs free energy, implicating a regulatory role for fragment 1 in the activation mechanism. Active site labeling of all prothrombin derivatives with D-Phe-Pro-Arg-chloromethyl ketone, analogous to irreversible binding of a substrate, decreased their K(D) values for vWbp into the subnanomolar range, reflecting the dependence of the activating conformational change on substrate binding. The results suggest a role for prothrombin domains in the pathophysiological activation of prothrombin by vWbp, and may reveal a function for autocatalysis of the vWbp·prothrombin complexes during initiation of blood coagulation.
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20 MeSH Terms
New serum markers of hepatocellular carcinoma.
Masuzaki R, Karp SJ, Omata M
(2012) Semin Oncol 39: 434-9
MeSH Terms: Biomarkers, Biomarkers, Tumor, Carcinoma, Hepatocellular, Glypicans, Hepatocyte Growth Factor, Humans, Insulin-Like Growth Factor I, Liver Neoplasms, Osteopontin, Protein Precursors, Prothrombin, Vascular Endothelial Growth Factor A, alpha-Fetoproteins
Show Abstract · Added May 2, 2014
Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, usually develops in a liver already suffering from chronic damages, often cirrhosis. There has been marked progress in the treatment of HCC. However, effective treatments are limited to patients with less advanced HCC. The detection of HCC at an early stage is still a prerequisite for improved prognosis. To address this problem, a variety of screening modalities are used, including measurement of alpha-fetoprotein (AFP) and ultrasonography (US) at regular intervals in high-risk populations. Unfortunately, poor sensitivity and specificity of AFP and the operator-dependency of US limit the value of either test to diagnose early-stage lesions. Other tests, including Lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin (DCP), are currently being evaluated and may be superior to current tests. Recent developments in gene-expressing microarrays and proteomics promise even more potential diagnostic options. The strict application of the Early Detection Research Network methodology will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility.
Copyright © 2012 Elsevier Inc. All rights reserved.
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Persistent hypocoagulability in patients with septic shock predicts greater hospital mortality: impact of impaired thrombin generation.
Massion PB, Peters P, Ledoux D, Zimermann V, Canivet JL, Massion PP, Damas P, Gothot A
(2012) Intensive Care Med 38: 1326-35
MeSH Terms: Aged, Anticoagulants, Antithrombin III, Blood Coagulation Disorders, Blood Coagulation Factors, Female, Fibrin, Hospital Mortality, Humans, Intensive Care Units, Logistic Models, Longitudinal Studies, Male, Middle Aged, Partial Thromboplastin Time, Prospective Studies, Protein C, Prothrombin Time, Shock, Septic, Thrombin
Show Abstract · Added March 10, 2014
PURPOSE - Sepsis induces hypercoagulability, hypofibrinolysis, microthrombosis, and endothelial dysfunction leading to multiple organ failure. However, not all studies reported benefit from anticoagulation for patients with severe sepsis, and time courses of coagulation abnormalities in septic shock are poorly documented. Therefore, the aim of this prospective observational cohort study was to describe the coagulation profile of patients with septic shock and to determine whether alterations of the profile are associated with hospital mortality.
METHODS - Thirty-nine patients with septic shock on ICU admission were prospectively included in the study. From admission to day 7, analytical coagulation tests, thrombin generation (TG) assays, and thromboelastometric analyses were performed and tested for association with survival.
RESULTS - Patients with septic shock presented on admission prolongation of prothrombin time, activated partial thromboplastin time (aPTT), increased consumption of most procoagulant factors as well as both delay and deficit in TG, all compatible with a hypocoagulable state compared with reference values (P < 0.001). Time courses revealed a persistent hypocoagulability profile in non-survivors as compared with survivors. From multiple logistic regression, prolonged aPTT (P = 0.007) and persistence of TG deficit (P = 0.024) on day 3 were strong predictors of mortality, independently from disease severity scores, disseminated intravascular coagulation score, and standard coagulation tests on admission.
CONCLUSIONS - Patients with septic shock present with hypocoagulability at the time of ICU admission. Persistence of hypocoagulability assessed by prolonged aPTT and unresolving deficit in TG on day 3 after onset of septic shock is associated with greater hospital mortality.
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20 MeSH Terms
Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence.
Soroida Y, Ohkawa R, Nakagawa H, Satoh Y, Yoshida H, Kinoshita H, Tateishi R, Masuzaki R, Enooku K, Shiina S, Sato T, Obi S, Hoshino T, Nagatomo R, Okubo S, Yokota H, Koike K, Yatomi Y, Ikeda H
(2012) J Hepatol 57: 330-6
MeSH Terms: Aged, Biomarkers, Carcinoma, Hepatocellular, Creatine Kinase, Mitochondrial Form, Female, Humans, Isoenzymes, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Protein Precursors, Prothrombin, RNA, Messenger, alpha-Fetoproteins
Show Abstract · Added May 2, 2014
BACKGROUND & AIMS - Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno-inhibition method.
METHODS - Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled.
RESULTS - Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC ≤ 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues.
CONCLUSIONS - Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power.
Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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15 MeSH Terms
Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors.
Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, Asaoka Y, Sato T, Masuzaki R, Kondo Y, Goto T, Yoshida H, Omata M, Koike K
(2012) Am J Gastroenterol 107: 569-77; quiz 578
MeSH Terms: Aged, Biomarkers, Biomarkers, Tumor, Carcinoma, Hepatocellular, Catheter Ablation, Disease Progression, Female, Follow-Up Studies, Humans, Lectins, Liver Neoplasms, Male, Multivariate Analysis, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Prospective Studies, Protein Precursors, Prothrombin, Reoperation, Risk Factors, Survival Rate, Tomography, X-Ray Computed, Treatment Outcome, alpha-Fetoproteins
Show Abstract · Added May 2, 2014
OBJECTIVES - Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center.
METHODS - We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database.
RESULTS - Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7-63.9%) and 27.3% (95% CI: 21.5-34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1-4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8-77.8%) and 80.8% (95% CI: 77.4-84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%).
CONCLUSIONS - RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.
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25 MeSH Terms
Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times.
Enooku K, Tateishi R, Kanai F, Kondo Y, Masuzaki R, Goto T, Shiina S, Yoshida H, Omata M, Koike K
(2012) J Gastroenterol 47: 71-8
MeSH Terms: Aged, Antineoplastic Agents, Biomarkers, Biomarkers, Tumor, Carcinoma, Hepatocellular, Disease Progression, Female, Humans, Indoles, Liver Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Propionates, Protein Kinase Inhibitors, Protein Precursors, Prothrombin, Time Factors, Treatment Outcome, Tumor Burden, alpha-Fetoproteins
Show Abstract · Added May 2, 2014
BACKGROUND - We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.
METHODS - Twenty-five patients with advanced hepatocellular carcinoma (HCC) received TSU-68, a multiple tyrosine kinase inhibitor. Exponential increase in HCC-specific tumor marker levels (alpha-fetoprotein or des-gamma-carboxyprothrombin) was seen in 15 of them prior to TSU-68 administration. The relationship between tumor marker DT and tumor volume DT was evaluated. Next, tumor marker DT in the first 8 weeks of TSU-68 administration was compared with tumor marker DT before treatment. Efficacy evaluation based on changes in tumor marker DT was compared with Response Evaluation Criteria In Solid Tumors (RECIST).
RESULTS - Tumor marker DT and tumor volume DT were almost identical (r(2) = 0.94, P < 0.001) in each patient before TSU-68 administration. Efficacy evaluation based on changes in tumor marker DT on TSU-68 administration was in accordance with RECIST in 12/15 cases. Discordance was observed in three cases, for which RECIST indicated disease progression in spite of elongated tumor marker DT. Those cases showed substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions.
CONCLUSIONS - Serum tumor marker DT can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis which can compromise radiographic evaluation. This approach may be applicable to the evaluation of responses to chemotherapy, particularly to cytostatic agents (ClinicalTrials.gov number, NCT00784290).
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21 MeSH Terms
In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation.
Panizzi P, Nahrendorf M, Figueiredo JL, Panizzi J, Marinelli B, Iwamoto Y, Keliher E, Maddur AA, Waterman P, Kroh HK, Leuschner F, Aikawa E, Swirski FK, Pittet MJ, Hackeng TM, Fuentes-Prior P, Schneewind O, Bock PE, Weissleder R
(2011) Nat Med 17: 1142-6
MeSH Terms: Animals, Coagulase, Endocarditis, Bacterial, Mice, Microscopy, Fluorescence, Positron-Emission Tomography, Protein Engineering, Prothrombin, Quorum Sensing, Staphylococcus aureus
Show Abstract · Added January 20, 2015
Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.
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10 MeSH Terms
Active site-labeled prothrombin inhibits prothrombinase in vitro and thrombosis in vivo.
Kroh HK, Panizzi P, Tchaikovski S, Baird TR, Wei N, Krishnaswamy S, Tans G, Rosing J, Furie B, Furie BC, Bock PE
(2011) J Biol Chem 286: 23345-56
MeSH Terms: Amino Acid Substitution, Animals, Blood Coagulation, Catalytic Domain, Enzyme Activation, Humans, Kinetics, Mice, Mutation, Missense, Protein Structure, Tertiary, Prothrombin, Thromboplastin, Thrombosis
Show Abstract · Added January 20, 2015
Mouse and human prothrombin (ProT) active site specifically labeled with D-Phe-Pro-Arg-CH(2)Cl (FPR-ProT) inhibited tissue factor-initiated thrombin generation in platelet-rich and platelet-poor mouse and human plasmas. FPR-prethrombin 1 (Pre 1), fragment 1 (F1), fragment 1.2 (F1.2), and FPR-thrombin produced no significant inhibition, demonstrating the requirement for all three ProT domains. Kinetics of inhibition of ProT activation by the inactive ProT(S195A) mutant were compatible with competitive inhibition as an alternate nonproductive substrate, although FPR-ProT deviated from this mechanism, implicating a more complex process. FPR-ProT exhibited ∼10-fold more potent anticoagulant activity compared with ProT(S195A) as a result of conformational changes in the ProT catalytic domain that induce a more proteinase-like conformation upon FPR labeling. Unlike ProT and ProT(S195A), the pathway of FPR-ProT cleavage by prothrombinase was redirected from meizothrombin toward formation of the FPR-prethrombin 2 (Pre 2)·F1.2 inhibitory intermediate. Localization of ProT labeled with Alexa Fluor® 660 tethered through FPR-CH(2)Cl ([AF660]FPR-ProT) during laser-induced thrombus formation in vivo in murine arterioles was examined in real time wide-field and confocal fluorescence microscopy. [AF660]FPR-ProT bound rapidly to the vessel wall at the site of injury, preceding platelet accumulation, and subsequently to the thrombus proximal, but not distal, to the vessel wall. [AF660]FPR-ProT inhibited thrombus growth, whereas [AF660]FPR-Pre 1, lacking the F1 membrane-binding domain did not bind or inhibit. Labeled F1.2 localized similarly to [AF660]FPR-ProT, indicating binding to phosphatidylserine-rich membranes, but did not inhibit thrombosis. The studies provide new insight into the mechanism of ProT activation in vivo and in vitro, and the properties of a unique exosite-directed prothrombinase inhibitor.
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13 MeSH Terms
Activation of factor XI by products of prothrombin activation.
Matafonov A, Sarilla S, Sun MF, Sheehan JP, Serebrov V, Verhamme IM, Gailani D
(2011) Blood 118: 437-45
MeSH Terms: Amino Acid Sequence, Blood Coagulation, Blood Coagulation Tests, Catalytic Domain, Cells, Cultured, Factor XI, Humans, Models, Biological, Molecular Sequence Data, Peptide Hydrolases, Prothrombin, Recombinant Proteins, Sequence Homology, Amino Acid
Show Abstract · Added May 19, 2014
The prothrombinase complex converts prothrombin to α-thrombin through the intermediate meizothrombin (Mz-IIa). Both α-thrombin and Mz-IIa catalyze factor (F) XI activation to FXIa, which sustains α-thrombin production through activation of FIX. The interaction with FXI is thought to involve thrombin anion binding exosite (ABE) I. α-Thrombin can undergo additional proteolysis to β-thrombin and γ-thrombin, neither of which have an intact ABE I. In a purified protein system, FXI is activated by β-thrombin or γ-thrombin, and by α-thrombin in the presence of the ABE I-blocking peptide hirugen, indicating that a fully formed ABE I is not absolutely required for FXI activation. In a FXI-dependent plasma thrombin generation assay, β-thrombin, γ-thrombin, and α-thrombins with mutations in ABE I are approximately 2-fold more potent initiators of thrombin generation than α-thrombin or Mz-IIa, possibly because fibrinogen, which binds to ABE I, competes poorly with FXI for forms of thrombin lacking ABE I. In addition, FXIa can activate factor FXII, which could contribute to thrombin generation through FXIIa-mediated FXI activation. The data indicate that forms of thrombin other than α-thrombin contribute directly to feedback activation of FXI in plasma and suggest that FXIa may provide a link between tissue factor-initiated coagulation and the proteases of the contact system.
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13 MeSH Terms