Publications by authors named "Mario Colucci"

47 Publications

The Prothrombotic State Associated with SARS-CoV-2 Infection: Pathophysiological Aspects.

Mediterr J Hematol Infect Dis 2021 1;13(1):e2021045. Epub 2021 Jul 1.

Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, Bari, Italy.

Severe coronavirus disease-2019 (COVID-19) is frequently associated with microvascular thrombosis, especially in the lung, or macrovascular thrombosis, mainly venous thromboembolism, which significantly contributes to the disease mortality burden. COVID-19 patients also exhibit distinctive laboratory abnormalities that are compatible with a prothrombotic state. The key event underlying COVID-19-associated thrombotic complications is an excessive host inflammatory response to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection generating multiple inflammatory mediators, mainly cytokines and complement activation products. The latter, along with the virus itself, the increased levels of angiotensin II and hypoxia, drive the major cellular changes promoting thrombosis, which include: (1) aberrant expression of tissue factor by activated alveolar epithelial cells, monocytes-macrophages and neutrophils, and production of other prothrombotic factors by activated endothelial cells (ECs) and platelets; (2) reduced expression of physiological anticoagulants by dysfunctional ECs, and (3) suppression of fibrinolysis by the endothelial overproduction of plasminogen activator inhibitor-1 and, likely, by heightened thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Moreover, upon activation or death, neutrophils and other cells release nuclear materials that are endowed with potent prothrombotic properties. The ensuing thrombosis significantly contributes to lung injury and, in most severe COVID-19 patients, to multiple organ dysfunction. Insights into the pathogenesis of COVID-19-associated thrombosis may have implications for the development of new diagnostic and therapeutic tools.
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http://dx.doi.org/10.4084/MJHID.2021.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265369PMC
July 2021

A PPAR-α agonist protects the non-adrenergic, non-cholinergic inhibitory system of guinea pig trachea from the effect of inhaled ammonium persulphate: a pilot study.

G Ital Med Lav Ergon 2020 09;42(3):153-159

Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.

Summary: Aim of the study. Inhaled ammonium persulphate (AP) reduces non adrenergic, non cholinergic (NANC) relaxation in the guinea pig trachea, as a part of its inflammatory effects. Peroxisome Proliferator-Activated Receptor (PPAR) stimulation has shown anti-inflammatory properties. This study aimed at evaluating whether the PPAR-α agonist WY 14643 can prevent the reduction in NANC relaxation caused by inhaled AP in the guinea pig trachea. Materials and Methods. Four groups of ten male guinea pigs were treated for three weeks with inhaled AP (10 mg/m3, 30 min per day, group A), saline (group B), AP and WY 14643 (0.36 μM/die, per os, group C), and AP, WY 14643 and the PPAR-α antagonist GW 6471 (0.36 μM/die, per os, group D). NANC relaxations to electrical field stimulation (EFS) at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Results. The tracheal NANC relaxations were reduced by 90.3% in group A, as compared to group B. In group C, they were reduced by only 22.2%. In group D, they were reduced by 92.6 %. PPAR-α receptors were detected in inhibitory nerve fibers within the trachea as shown by immonohistochemical analysis. Conclusions. The PPAR-α agonist WY 14643 protects the NANC inhibitory system of the guinea pig trachea from the effect of inhaled ammonium persulphate and its protective effect is antagonized by GW 6471. PPAR-α might be exploited.
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September 2020

Extracellular histones promote fibrinolysis by single-chain urokinase-type plasminogen activator in a factor seven activating protease-dependent way.

Thromb Res 2020 12 23;196:193-199. Epub 2020 Aug 23.

Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, Bari, Italy.

Introduction: Extracellular histones inhibit tissue plasminogen activator (t-PA)-mediated fibrinolysis by modifying fibrin structure and rheological properties. However, other plasminogen activators involved in intravascular and extravascular fibrinolysis have not been considered yet.

Objectives: We investigated the effect of histones on fibrinolysis driven by different plasminogen activators.

Methods: Clot lysis induced by t-PA, urokinase (u-PA) and its single chain precursor (scu-PA) was evaluated by turbidimetry. Conversion of scu-PA to u-PA and activation of factor seven activating protease (FSAP) were assessed by fluorogenic and chromogenic assays, respectively.

Results: Histones delayed t-PA- and u-PA-mediated fibrinolysis but strongly accelerated scu-PA-driven clot lysis through the enhancement of scu-PA to u-PA conversion. This effect required a plasma factor identified as FSAP by the following findings: 1) histones enhanced neither scu-PA activation nor scu-PA-mediated clot lysis under purified conditions; 2) in plasma, the enhancement of fibrinolytic activity by histones was abolished by a neutralizing anti-FSAP antibody; and 3) histones promoted the activation of plasma FSAP. The effect of the natural mixture of histones on scu-PA-driven fibrinolysis was differentially recapitulated by the individual recombinant histones, H4 displaying the strongest activity. When complexed to DNA, histones still accelerated scu-PA-mediated fibrinolysis but with a lesser efficiency due to a reduced FSAP activation. Finally, preincubation of histones with heparin or activated protein C, two known inhibitors of histones, further amplified histone-mediated boost of scu-PA-driven fibrinolysis.

Conclusions: Enhancement of FSAP-mediated scu-PA activity by histones may play yet unforeseen roles in intravascular fibrinolysis and contribute to extravascular proteolysis and tissue damage.
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http://dx.doi.org/10.1016/j.thromres.2020.08.034DOI Listing
December 2020

FVIII/VWF complex displays a greater pro-haemostatic activity than FVIII preparations devoid of VWF: Study in plasma and cell-based models.

Haemophilia 2020 Jul 23;26(4):e151-e160. Epub 2020 Apr 23.

Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.

Introduction: Plasma-derived FVIII/VWF complex was reported to be less sensitive to inhibitors than FVIII preparations devoid of VWF.

Aim: To compare the efficacy of FVIII/VWF complex (Fanhdi) and five different VWF-free FVIII preparations in restoring thrombin generation and activation of thrombin-activatable fibrinolysis inhibitor (TAFI) in haemophilic plasma, with and without inhibitor, and in cell-based models.

Methods: Experiments were performed in haemophilic plasma supplemented with inhibitory IgG or in plasma samples obtained from haemophilia A patients without (n = 11) and with inhibitor (n = 12). Thrombin generation was evaluated by calibrated automated thrombography (CAT) under standard conditions, in the presence of activated protein C (APC) or thrombomodulin (TM), and in cell-based models including endothelial cells, either alone or in combination with platelets or tissue factor-expressing blood mononuclear cells. The kinetics of TAFI activation was determined by a two-stage functional assay in the absence and in the presence of APC.

Results: In haemophilic plasma without inhibitor, Fanhdi enhanced thrombin generation and TAFI activation as well as recombinant (2nd-4th generation) and plasma-derived FVIII preparations devoid of VWF. On the contrary, in plasma with inhibitor, Fanhdi displayed a greater ability to restore thrombin generation and TAFI activation under all tested conditions. Notably, in cell-based models including endothelial cells, Fanhdi proved more efficient than all other preparations in improving thrombin generation even in the absence of inhibitor.

Conclusion: The greater pro-haemostatic activity of FVIII/VWF complex, either in haemophilic plasma with inhibitor or in the presence of endothelial cells, may offer therapeutic advantages.
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http://dx.doi.org/10.1111/hae.14008DOI Listing
July 2020

Microarray data and pathway analyses of peripheral blood mononuclear cells from healthy subjects after a three weeks grape-rich diet.

Data Brief 2020 Apr 12;29:105278. Epub 2020 Feb 12.

Institute for Biomedical Technology, National Research Council, 70126, Bari, Italy.

Using Human Gene Expression Microarrays (Agilent) technologies, we investigated changes of the level of gene expression in peripheral blood mononuclear cells of healthy subjects after 21 days of fresh table grape-rich diet and after an additional 28-day washout. Several hundreds of genes were differentially expressed after grape intake or after washout. The functional analysis of these genes detected significant changes in key processes such as inflammation and immunity, thrombosis, DNA and protein repair, autophagy and mitochondrial biogenesis. Moreover, fresh grape intake was found to influence the expression of many long non-coding RNA genes. The data can be valuable for researchers interested in nutrigenetics and nutrigenomics studies and are related to the research article "Gene expression signature induced by grape intake in healthy subjects reveals wide-spread beneficial effects on PBMCs" [1].
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http://dx.doi.org/10.1016/j.dib.2020.105278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036720PMC
April 2020

D-dimer corrected for thrombin and plasmin generation is a strong predictor of mortality in patients with sepsis.

Blood Transfus 2020 07 19;18(4):304-311. Epub 2019 Nov 19.

Department of Biomedical Sciences and Human Oncology, "Aldo Moro" University, Bari, Italy.

Background: D-dimer (DD) is the most used fibrin-related marker and has been proposed, either alone or in combination with other variables, as prognostic factor in patients with sepsis. However, DD generation depends on both coagulation and fibrinolysis, meaning that it may give false negative results in conditions associated with marked fibrinolytic inhibition such as sepsis. In this study, we tested whether correction of DD for thrombin and plasmin generation could improve its prognostic significance in septic patients.

Material And Methods: We performed a nested study in 269 septic patients from the ALBIOS trial. DD, prothrombin fragment 1+2 (F1+2) and plasmin-antiplasmin complex (PAP) were assayed at day 1. Corrected DD (DD) was calculated by the formula DD×PAP/F1+2, such that the lower the DD the greater the imbalance in favour of fibrin formation over fibrin lysis, and vice-versa. Primary outcome was 90-day mortality.

Results: DD showed a J-shaped relationship with mortality, which was highest in the first DD tertile (low fibrinolysis), intermediate in the 3 (high fibrinolysis), and lowest in the 2 (balanced fibrinolysis), suggesting an increased risk whenever the coagulation-fibrinolysis balance is tilted (p<0.0001). Neither DD, nor PAP or F1+2 showed a comparable association with mortality. DD was an independent prognostic factor in multivariable Cox models and significantly improved risk stratification (cNRI≥0.28). Finally, by combining DD and SOFA tertiles, we developed a score with high discriminatory power.

Discussion: DD is a good marker of the in vivo coagulation-fibrinolysis balance and displays a prognostic value in sepsis much higher than DD.
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http://dx.doi.org/10.2450/2019.0175-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375887PMC
July 2020

Thrombin activatable fibrinolysis inhibitor pathway alterations correlate with bleeding phenotype in patients with severe hemophilia A.

J Thromb Haemost 2020 02 15;18(2):381-389. Epub 2019 Oct 15.

Dipartimento di Scienze Biomediche e Oncologia Umana, Università degli Studi di Bari Aldo Moro, Bari, Italy.

Background: Patients with severe hemophilia A display varied bleeding phenotypes despite similar factor VIII (FVIII) activity levels.

Objective: We investigated different thrombin activatable fibrinolysis inhibitor (TAFI)-related variables in patients with severe hemophilia A and their possible correlation with bleeding tendency.

Patients/methods: Sixty-one patients with severe hemophilia A (FVIII:C <1%], treated on demand, were included. Patients were categorized as mild, moderate, and severe bleeders according to number of bleeds per year (≤2, 3-24, ≥25, respectively). Thirty healthy males served as controls. Clot lysis time was assessed by turbidimetric assay, TAFI activation by two-stage functional assay, and response to TAFIa as the prolongation of fibrinolysis time upon addition of purified TAFIa. Circulating levels of activated TAFI (TAFIa/ai) were measured by specific enzyme-linked immunosorbent assay.

Results: As compared to controls, hemophilic patients displayed shorter lysis time, less TAFIa generation, and reduced response to TAFIa, but similar TAFIa/ai levels. Clot lysis time was similar in mild, moderate, and severe bleeders, whereas TAFIa generation and response to TAFIa decreased with the increase in bleeding tendency; moreover, circulating TAFIa/ai levels were highest in severe bleeders. Patients with markedly impaired TAFIa generation or TAFIa response (below median) displayed 3-fold to 4-fold higher bleeding rate and factor consumption than patients whose TAFI-related values approached the control ones.

Conclusion: The TAFI pathway impairment correlates with bleeding phenotype in severe hemophilia and may represent a promising tool to stratify the bleeding risk.
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http://dx.doi.org/10.1111/jth.14656DOI Listing
February 2020

Randomised trial of chronic supplementation with a nutraceutical mixture in subjects with non-alcoholic fatty liver disease.

Br J Nutr 2020 01;123(2):190-197

Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli (IS), Italy.

A mixture of natural ingredients, namely, DHA, phosphatidylcholine, silymarin, choline, curcumin and d-α-tocopherol, was studied in subjects with non-alcoholic fatty liver disease (NAFLD). Primary endpoints were serum levels of hepatic enzymes, and other parameters of liver function, the metabolic syndrome and inflammation were the secondary endpoints. The coagulation-fibrinolysis balance was also thoroughly investigated, as NAFLD is associated with haemostatic alterations, which might contribute to increased cardiovascular risk of this condition. The present study involved a double-blind, randomised, multicentre controlled trial of two parallel groups. Subjects with NAFLD (18-80 years, either sex) received the active or control treatment for 3 months. All assays were performed on a total of 113 subjects before and at the end of supplementation. The hepatic enzymes aspartate aminotransferase (AST), alanine aminotransferase and γ-glutamyl transpeptidase decreased from 23·2 to 3·7 % after treatment, only the AST levels reaching statistical significance. However, no differences were found between control and active groups. Metabolic and inflammatory variables were unchanged, except for a slight (less than 10 %) increase in cholesterol and glucose levels after the active treatment. Coagulation-fibrinolytic parameters were unaffected by either treatment. In conclusion, chronic supplementation with the mixture of dietary compounds was well tolerated and apparently safe in NAFLD subjects. The trial failed to demonstrate any efficacy on relevant physiopathological markers, but its protocol and results may be useful to design future studies with natural compounds.
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http://dx.doi.org/10.1017/S0007114519002484DOI Listing
January 2020

Low D-dimer levels in sepsis: Good or bad?

Thromb Res 2019 02 5;174:13-15. Epub 2018 Dec 5.

Dipartimento di Scienze e Biomediche ed Oncologia Umana, Università degli Studi di Bari Aldo Moro, Bari, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2018.12.003DOI Listing
February 2019

Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis.

Crit Care Med 2018 03;46(3):e221-e228

Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Germany.

Objective: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis.

Design: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial).

Setting: Forty ICUs in Italy.

Patients: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95).

Interventions: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1.

Measurements And Main Results: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality.

Conclusions: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.
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http://dx.doi.org/10.1097/CCM.0000000000002919DOI Listing
March 2018

Grape intake reduces thrombin generation and enhances plasma fibrinolysis. Potential role of circulating procoagulant microparticles.

J Nutr Biochem 2017 12 1;50:66-73. Epub 2017 Sep 1.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Phytochemicals contained in grapes down-regulate several prothrombotic pathways in vitro. We evaluated the effect of grape consumption on coagulation and fibrinolysis in healthy volunteers. Thirty subjects were enrolled: 20 were given grape (5 g/kg body weight/day for 3 weeks), while 10 served as controls. Blood samples were taken at baseline (T0), at the end of the grape diet (T1) and after 4-week wash-out (T2). Grape intake caused a significant decrease of the procoagulant and inflammatory responses of whole blood and/or mononuclear cells to bacterial lipopolysaccharide at both T1 and T2. At plasma level, grape diet decreased thrombin generation at T1 and T2, largely through a reduction in the number and/or activity of procoagulant microparticles. This anticoagulant effect resulted in the formation of clots that were more susceptible to fibrinolysis, mainly because of a lesser activation of thrombin activatable fibrinolysis inhibitor. No difference in any variables was detected in controls at the time points considered. In conclusion, chronic grape consumption induces sustained anticoagulant and profibrinolytic effects with potential benefits for human health.
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http://dx.doi.org/10.1016/j.jnutbio.2017.08.012DOI Listing
December 2017

Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors.

Endocrine 2017 May 22;56(2):298-307. Epub 2016 Jul 22.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.

Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis.
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http://dx.doi.org/10.1007/s12020-016-1027-1DOI Listing
May 2017

Dabigatran but not rivaroxaban or apixaban treatment decreases fibrinolytic resistance in patients with atrial fibrillation.

Thromb Res 2016 Feb 24;138:22-29. Epub 2015 Dec 24.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Introduction: Most anticoagulants stimulate fibrinolysis in vitro through mechanisms dependent on and independent of thrombin activatable fibrinolysis inhibitor (TAFI). We evaluated the effect of dabigatran, rivaroxaban and apixaban treatment on plasma fibrinolysis in patients with non-valvular atrial fibrillation.

Methods And Results: Patients treated with dabigatran etexilate (n=22), rivaroxaban (n=24) or apixaban (n=22) were studied. Plasma was obtained before (trough) and 2h after drug intake (peak). Fibrinolytic resistance of clots exposed to exogenous tissue plasminogen activator was significantly lower in peak than in trough samples and correlated with drug concentration only in dabigatran group. Moreover, fibrinolytic resistance at peak was lower in dabigatran than in rivaroxaban and apixaban groups. This difference disappeared if the TAFI pathway was inhibited. Thrombin generation and TAFI activation were markedly lower in peak than in trough samples in all three groups. However, TAFIa levels in trough and peak samples were significantly lower in dabigatran group than in rivaroxaban and apixaban groups. Circulating levels of prothrombin fragment F1+2 (reflecting in vivo thrombin generation) and plasmin-antiplasmin complex (reflecting plasmin generation) were not or barely influenced by drug levels in all groups.

Conclusions: Our data suggest that dabigatran, contrary to rivaroxaban and apixaban, reduces fibrinolytic resistance by virtue of its greater impact on TAFI activation. The profibrinolytic effect of dabigatran may play a role locally, at sites of fibrin formation, by making the nascent thrombus more susceptible to plasminogen-dependent degradation.
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http://dx.doi.org/10.1016/j.thromres.2015.12.023DOI Listing
February 2016

Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran.

J Pharmacol Exp Ther 2016 Feb 17;356(2):305-13. Epub 2015 Nov 17.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology (C.T.A., N.S., M.C., F.S.), and Section of Pharmacology (M.R.C), University of Bari "Aldo Moro," Bari, Italy

The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator-mediated clot lysis by turbidimetry, and thrombin-activatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins.
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http://dx.doi.org/10.1124/jpet.115.229823DOI Listing
February 2016

Coagulopathy of Acute Sepsis.

Semin Thromb Hemost 2015 Sep 25;41(6):650-8. Epub 2015 Aug 25.

Section of Experimental and Clinical Pathology, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis-ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools.
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http://dx.doi.org/10.1055/s-0035-1556730DOI Listing
September 2015

A modified prothrombin time to measure the anticoagulant activity of dabigatran.

Thromb Res 2014 Dec 28;134(6):1368-9. Epub 2014 Sep 28.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University of Bari, Bari, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2014.09.027DOI Listing
December 2014

Influence of cell-associated tissue factor concentration on the anticoagulant activity of dabigatran. A possible explanation for the reduced incidence of intracranial bleeding.

Br J Haematol 2015 Mar 4;168(6):911-3. Epub 2014 Oct 4.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, University Aldo Moro, Bari, Italy.

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http://dx.doi.org/10.1111/bjh.13168DOI Listing
March 2015

How a β-D-glucoside side chain enhances binding affinity to thrombin of inhibitors bearing 2-chlorothiophene as P1 moiety: crystallography, fragment deconstruction study, and evaluation of antithrombotic properties.

J Med Chem 2014 Oct 14;57(20):8563-75. Epub 2014 Oct 14.

Institute of Crystallography, Consiglio Nazionale delle Ricerche , Via Amendola 122/o, 70126 Bari, Italy.

The β-d-glucose-containing compound 3, bearing 2-chlorothiophene and 1-isopropylpiperidine moieties as binders of the S1 and S4 pockets, respectively, proved to be potent competitive inhibitor of factor Xa (fXa, Ki = 0.090 nM) and thrombin (fIIa, Ki = 100 nM). The potency of 3 increases, over the parent compound 1, against fIIa (110-fold), much more than against fXa (7-fold). Experimental deconstruction of 3 into smaller fragments revealed a binding cooperativity of the P3/P4 and propylene-linked β-d-glucose fragments, stronger in fIIa (15.5 kJ·mol(-1)) than in fXa (2.8 kJ·mol(-1)). The crystal structure of human fIIa in complex with 3 revealed a binding mode including a strong H-bond network between the glucose O1', O3', and O5' and two critical residues, namely R221a and K224, belonging to the Na(+)-binding site which may allosterically perturb the specificity sites. The potential of 3 as antithrombotic agent was supported by its ability to inhibit thrombin generation and to stimulate fibrinolysis at submicromolar concentration.
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http://dx.doi.org/10.1021/jm5010754DOI Listing
October 2014

The paradoxical antifibrinolytic effect of dabigatran and argatroban in the presence of soluble thrombomodulin is unrelated to protein C-dependent increase of thrombin generation.

Thromb Res 2014 Nov 23;134(5):1110-6. Epub 2014 Aug 23.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy. Electronic address:

Background: Anticoagulants stimulate fibrinolysis in vitro, mainly by inhibiting thrombin-mediated TAFI activation. Surprisingly, however, direct thrombin inhibitors (DTIs) inhibit fibrinolysis and enhance thrombin generation in vitro when tested in the presence of high thrombomodulin (TM) concentrations. Because the paradoxical effect on thrombin generation was shown to be protein C (PC)-dependent, we investigated the role of PC in the antifibrinolytic effect of two DTIs, dabigatran and argatroban.

Methods And Results: In the presence of 10 nM TM, both dabigatran (0.5 μM) and argatroban (1 μM) prolonged clot lysis time and enhanced thrombin generation. This notwithstanding, the DTIs inhibited thrombin-mediated TAFI activation, peak TAFIa activity being reduced by >60%. A specific feature of TAFI activation curve in the presence of DTIs was a much slower disappearance of TAFIa activity, which was likely the cause of fibrinolysis inhibition. The addition of an anti-PC antibody (αPC) nullified the paradoxical effect of DTIs on thrombin generation but influenced neither TAFI activation nor the fibrinolysis time.

Conclusions: Our results suggest that the inhibition of PC activation by DTIs in the presence of TM, while enhancing thrombin generation, has no effect on thrombin-mediated TAFI activation. The inhibition of fibrinolysis by DTIs can be explained by the prolonged activation of TAFI resulting from the sustained release of thrombin from thrombin-DTI complex. While the clinical relevance of these findings needs to be investigated by in vivo studies, our data might help understanding the role of the different players in the regulation of thrombin generation, TAFI activation and fibrinolysis resistance.
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http://dx.doi.org/10.1016/j.thromres.2014.08.010DOI Listing
November 2014

Co-administration of low molecular weight heparin enhances the profibrinolytic effect of warfarin through different mechanisms.

Thromb Res 2014 Apr 4;133(4):634-9. Epub 2014 Jan 4.

Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.

Background And Objective: Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance.

Patients And Methods: Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively.

Results: In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis.

Conclusions: Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings.
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http://dx.doi.org/10.1016/j.thromres.2013.12.035DOI Listing
April 2014

Factor IX-Padua enhances the fibrinolytic resistance of plasma clots.

Thromb Haemost 2014 Feb 17;111(2):226-32. Epub 2013 Oct 17.

Paolo Simioni, MD, PhD, Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Via Giustiniani 2 - 35100 Padua, Italy, Tel./Fax: +39 049 8212667, E-mail:

Hypercoagulable conditions may determine a hypofibrinolytic state by increasing the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Factor (F)IX-Padua is a mutated FIX with an eight-fold increased clotting activity and associates with a higher venous thrombotic risk. We evaluated the influence of FIX-Padua on TAFI-mediated regulation of fibrinolysis. A subject hemizygous for FIX-Padua, two family members (heterozygous and normal) and six healthy controls were studied. Clot lysis, TAFI activation and thrombin generation were evaluated in contact-inhibited plasma challenged with low concentrations of tissue factor. Fibrinolysis times were significantly longer in FIX-Padua carriers than controls. The difference disappeared when activated TAFI (TAFIa) was inhibited, when TAFI activation was avoided or when clotting was made independent of FIX. TAFIa generation was markedly enhanced in FIX-Padua carriers as compared to controls, and this could be explained by a greater thrombin generation in the former. Hyperactive FIX, but not wild-type FIX, enhanced fibrinolytic resistance also when the FXI-dependent positive feedback was blocked by a neutralising anti-FXI antibody. This thrombin-mediated, TAFI-dependent down-regulation of fibrinolysis provides new clues for explaining the heightened thrombotic risk in subjects carrying the FIX-Padua mutation.
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http://dx.doi.org/10.1160/TH13-06-0489DOI Listing
February 2014

Antithrombotic activity of 12 table grape varieties. Relationship with polyphenolic profile.

Food Chem 2013 Oct 10;140(4):647-53. Epub 2012 Nov 10.

Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124 Bari, Italy.

The synthesis of tissue factor (TF) by monocytes/macrophages activated by inflammatory agents is of utmost importance in the pathogenesis of thrombotic diseases and substances inhibiting TF synthesis represent novel and promising antithrombotics. We investigated the effect of 12 table grape varieties (white, red and black) on TF synthesis and the possible relation with the phenolic profile. The ability of grape skin extracts (GSEs) to inhibit TF was evaluated in whole blood and isolated mononuclear cells challenged with endotoxin. TF expression was assayed by functional and immunological assays. All GSEs inhibited TF synthesis but with a different efficiency, red grapes being the most active. By correlation analysis, the compounds showing the strongest association with TF-inhibiting activity were quercetin and cyanidin. However, no single polyphenol was able to inhibit TF synthesis as efficiently as the crude grape extracts, unless it was combined with at least another compound, suggesting a synergism.
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http://dx.doi.org/10.1016/j.foodchem.2012.10.132DOI Listing
October 2013

Does inhibiting Sur1 complement rt-PA in cerebral ischemia?

Ann N Y Acad Sci 2012 Sep;1268:95-107

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA-associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA-associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA-associated HT in stroke.
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http://dx.doi.org/10.1111/j.1749-6632.2012.06705.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507518PMC
September 2012

Skin extracts from 2 Italian table grapes (Italia and Palieri) inhibit tissue factor expression by human blood mononuclear cells.

J Food Sci 2012 Aug;77(8):H154-9

Research Unit for Grape and Wine Growing in the Mediterranean Environment, CRA-UTV Agricultural Research Council, Turi, Bari, Italy.

Unlabelled: Grape and its products such as red wine and grape juice have well-known antithrombotic properties, which have been attributed to their high content in polyphenolic compounds. Most studies on the mechanisms underlying these beneficial effects, among which the suppression of tissue factor (TF) synthesis in blood mononuclear cells (MNC) and vascular endothelium is a prominent one, have been performed with purified polyphenols, while little is known about the effect of fresh grapes which contain a multitude of phytochemicals whose interaction may lead to different cell responses. In this study, we investigated the effect of grape skin extracts (GSEs) on TF expression in isolated blood MNC and in whole blood. Alcoholic extracts from skins of 2 grape varieties (Palieri and Italia) inhibited TF expression in lipopolysaccharide (LPS)-stimulated MNC in a concentration-dependent manner with ≥90% inhibition of TF activity and antigen at 6 μg/mL of gallic acid equivalents. Noteworthy, GSEs were also able to inhibit the appearance of TF in whole blood challenged with LPS. The 2 grape varieties displayed a fairly similar TF-inhibiting capacity despite marked differences in phenolic profile. When selected purified polyphenols were tested, their ability to inhibit TF expression was markedly lower as compared to grape extracts, whereas a mixture of some representative polyphenols was much more efficient, supporting the occurrence of a synergistic effect. Given the key role of cell TF in thrombotic diseases, the inhibition of MNC-mediated clotting activation, if confirmed by in vivo studies, might represent an important antithrombotic mechanism.

Practical Application: Our data indicate that the combination of different polyphenols, as in grape extracts, is much more efficient than the single constituents, a finding that might be useful as starting point for the development of new antithrombotic nutraceutics. In addition, our study validated a simple, inexpensive, and physiologically relevant in vitro method on whole blood that allows the evaluation of one of the most important antithrombotic activities of food and food-derived products. The simplicity of the method makes it suitable also for screening purposes in large-scale studies.
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http://dx.doi.org/10.1111/j.1750-3841.2012.02818.xDOI Listing
August 2012

Evidence that fibrinolytic changes in paediatric obesity translate into a hypofibrinolytic state: relative contribution of TAFI and PAI-1.

Thromb Haemost 2012 Aug 28;108(2):311-7. Epub 2012 Jun 28.

Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Patologia Generale e Sperimentale, Bari, Italy.

Paediatric obesity, like adulthood obesity, is associated with an increase of fibrinolysis inhibitors. No study, however, has evaluated the impact of these changes on plasma fibrinolytic capacity. We investigated plasma fibrinolysis and the role therein of the fibrinolytic changes associated with obesity in 59 obese children (body mass index > 95th percentile) and 40 matched controls. Fibrinolysis was investigated by measuring 1) the plasma levels of relevant fibrinolytic factors; 2) the in vitro fibrinolytic capacity under different conditions, using a microplate plasma clot lysis assay; 3) the circulating levels of markers of clotting and fibrinolysis activation. Plasminogen activator inhibitor 1 (PAI-1), total thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen levels were higher in obese children as compared to controls (p<0.01). Plasma clots from obese children lysed significantly slower than control clots when exposed to exogenous plasminogen activator, indicating a greater resistance to fibrinolysis. By the use of a selective inhibitor of activated TAFI and by regression analyses we found that fibrinolysis resistance in obese samples was attributable to PAI-1 increase and to enhanced TAFI activation. The ratio between the circulating levels of D-dimer and thrombin-antithrombin complex, a marker of in vivo fibrinolysis, was significantly lower in obese children, suggesting a reduced fibrinolytic efficiency. These data indicate that paediatric obesity is associated with a hypofibrinolytic state which might contribute to the increased thrombotic risk associated with this condition.
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http://dx.doi.org/10.1160/TH11-12-0864DOI Listing
August 2012

Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model.

Auton Neurosci 2012 Aug 16;169(2):77-86. Epub 2012 May 16.

Department of Legal Medicine, Forensic Sciences and Pharmaco-Toxicology, University of Pavia, Pavia, Italy.

Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson's disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens. Four weeks post 6-OHDA injection, lesioned rats showed a significant increase of vasoactive intestinal polypeptide (VIP) concomitant with the reduced expression of nNOS in the myenteric plexus of distal ileum and proximal colon; in particular VIP increased in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT) was not modified in any of the intestinal segments analyzed. Interestingly, we found a reduced expression of dopamine receptor type 2 (D2R) in proximal (-66.8%) and distal (-54.5%) colon, together with reduced peristalsis efficiency (decrease in intraluminal pressure and frequency of peristaltic events) in the 6-OHDA-lesioned rats. The selective depletion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters, as well as of the D2R in intestinal specific regions. Moreover, 6-OHDA-lesioned rats demonstrated altered colon propulsive activity referable to the D2R decrease. Our findings unveil subtle mechanisms underlying the enteric neurochemical plasticity events evoked by disruption of the normal brain-gut cross-talk, giving a peculiar point of view on the pathophysiology of the severe constipation that frequently affects PD patients.
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http://dx.doi.org/10.1016/j.autneu.2012.04.005DOI Listing
August 2012

Determination of ethyl glucuronide in nails by liquid chromatography tandem mass spectrometry as a potential new biomarker for chronic alcohol abuse and binge drinking behavior.

Anal Bioanal Chem 2012 Feb 23;402(5):1865-70. Epub 2011 Dec 23.

Department of Legal Medicine, Forensic and Pharmaco-Toxicological Science, University of Pavia, Via Forlanini, 12, 27100 Pavia, Italy.

A liquid chromatography tandem mass spectrometry method for ethyl glucuronide (EtG) detection and quantification in nails was developed and fully validated. Nails were extracted in 700 μL double-distilled water. EtG-d(5) was used as an internal standard. Reversed-phase separation was obtained with an isocratic mobile phase composed of 0.1% formic acid and acetonitrile (99:1) for 10 min. Quantification was performed by multiple reaction monitoring of two transitions per compound (EtG and internal standard). The assay was linear from 10 to 500 pg/mg. Validation parameters were studied at three different quality control levels (10, 50, and 300 pg/mg). Intraday, interday, and total imprecision had a coefficient of variation of less than 9.5%. Ion suppression and ion enhancement were negligible (less than 20%). No carryover was detected. The method was applied to several real cases, among teetotalers, social drinkers, and heavy drinkers. A questionnaire, together with the informed consent form, was given to all the participants in order to evaluate alcohol intake in the one month before sample collection. Nail EtG levels in a social drinker were much higher than the concentrations of EtG in hair provided by the same subject, thus suggesting potential high sensitivity in evaluating both chronic excessive alcohol consumption and binge drinking habits.
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http://dx.doi.org/10.1007/s00216-011-5609-8DOI Listing
February 2012

Coagulation activation is associated with nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species generation in hemodialysis patients.

Antioxid Redox Signal 2012 Mar 22;16(5):428-39. Epub 2011 Dec 22.

Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Aims: This study investigated on (i) the role of gp91(phox)/NOX2 in reactive oxygen species (ROS) generation in hemodialysis (HD) patients, and (ii) the link between clotting activation and ROS production in this setting.

Results: The study was performed on peripheral blood mononuclear cells (PBMCs) isolated from HD patients randomized to polysulphon/polyamide (S-group, n=30) or ethylene-vinyl-alcohol (EVAL) membrane (E-group, n=30) treatment and from healthy subjects (control group, n=15). ROS generation was increased in PBMCs of HD patients compared with healthy subjects. S-group showed higher levels of intracellular ROS generation than control, whereas E-group did not. In addition, S-group displayed an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity compared with E-group and healthy subjects. A further increase in NADPH activity shortly after HD treatment was observed only in S-group. The plasma levels of the prothrombin fragment F1+2, a marker of in vivo clotting activation, were significantly higher in S-group than in E-group. Moreover, a heightened thrombin generation was recorded in the plasma of S-group. Intracellular ROS production correlated with NADPH oxidase activity and coagulation priming in HD patients. The in vitro validation study demonstrated that incubation of PBMCs with activated FX induced a significant increase in intracellular ROS production, superoxide generation, and gp91(phox)/NOX2 expression.

Innovation: The pivotal role of NADPH oxidase in the upregulation of ROS in HD patients makes this enzyme a potential target for therapeutic intervention in the treatment of HD-related oxidative stress.

Conclusion: The EVAL membrane, by reducing clotting activation, inhibits gp91(phox)/NOX2-related ROS production in HD patients.
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http://dx.doi.org/10.1089/ars.2011.4062DOI Listing
March 2012

Thrombin activatable fibrinolysis inhibitor: at the nexus of fibrinolysis and inflammation.

Thromb Res 2012 Mar 21;129(3):314-9. Epub 2011 Nov 21.

Department of Biomedical Sciences and Human Oncology – Section of General and Experimental Pathology, University Aldo Moro, Bari, Italy.

TAFI (thrombin activatable fibrinolysis inhibitor) is the precursor of a basic carboxypeptidase (TAFIa) with strong antifibrinolytic and anti-inflammatory activity. Compelling evidence indicates that thrombin, either alone or in complex with thrombomodulin, is the main physiological activator of TAFI. For this reason derangements of thrombin formation, whatever the cause, may influence the fibrinolytic process too. Experimental models of thrombosis suggest that TAFI may participate in thrombus development and persistence under certain circumstances. In several models of pharmacological thrombolysis, the administration of TAFI inhibitors along with the fibrinolytic agent leads to a marked improvement of thrombus lysis, underscoring the potential of TAFI inhibitors as adjuvants for thrombolytic therapy. The role of TAFI in inflammatory diseases is more complex as it may serve as a defense mechanism, exacerbate the disease, or have no influence, depending on the nature of the model and the role played by the mediators controlled by TAFIa. Finally, the numerous clinical studies in patients with thrombotic disease support the idea that increased levels of TAFI and/or the enhancement of TAFI activation may represent a new risk factor for venous and arterial thrombosis.
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http://dx.doi.org/10.1016/j.thromres.2011.10.031DOI Listing
March 2012
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