bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binding of Abciximab to αVβ3 and Activated αMβ2 Receptors: With a Review of Platelet-Leukocyte Interactions
Authors: Coller Barry 
Published: March 2018

IntroductionMurine monoclonal antibody 7E3, as well as the derivatives of 7E3 used in vivo [7E3-F(ab’)2, 7E3 Fab’, mouse/human chimeric 7E3 Fab (c7E3 Fab; abciximab; ReoPro™)], inhibit platelet aggregation induced by physiologic and pathologic agonists by binding to the platelet glycoprotein (GP) IIb/IIIa receptor.1,2 This biological activity formed the basis of its development as an antithrombotic agent to prevent and treat plateletmediated ischemic cardiovascular disease. During its development, 7E3 was reported to also react with two other integrin receptors, the αVβ3 “vitronectin” receptor (CD51/CD61)3,4 and at least one activation-dependent conformation of the αMβ2 or “Mac-1” receptor (CD11b/CD18).5 Whereas both αVβ3 and αMβ2 have been implicated in a number of different physiologic and pathologic processes, it is possible that some effects of abciximab are due to its reactivity with one or the other of these receptors. Moreover, the reactivity of abciximab with these receptors opens up the possibility that abciximab, or other agents that inhibit these receptors, may be useful in preventing or treating disorders in which these receptors play a role. This review will address these issues.
Antiplatelet Therapy Using Cilostazol, a Specific PDE3 Inhibitor
Authors: Ikeda Yasuo 
Published: March 2018

IntroductionCilostazol, 6-[ 4-( l-cyclohexy l-IH-tetrazol-5yl ) butoxy ]-3, 4-dihydro-2 (1H)-quinolinone, is an antiplatelet/ antithrombotic agent that has been used since 1988 in several countries, including Japan, for treatment of chronic peripheral arterial occlusion. Cilostazol was also approved by the United States Food and Drug Administration (FDA) in 1999 for the treatment of intermittent claudication. Cilostazol not only inhibits platelet activation but also increases vasodilation.1,2 In addition, it has been also shown to inhibit vascular smooth muscle cell proliferation.3 These properties of cilostazol may also improve peripheral blood flow. The mechanism of these effects is mediated through elevated cyclic adenosine monophosphate (AMP), brought about by inhibition of cyclic nucleotide phosphodiesterase (PDE3) activity.4 In this chapter, the pharmacological properties, as well as the clinical efficacy of cilostazol, are briefly discussed.
CD4+ T Cell Response to Factor VIII in Hemophilia A, Acquired Hemophilia, and Healthy Subjects
Authors: Reding M.T. , Wu H. , Krampf M. , Okita D.K. , Diethelm-Okita B.M. , Key N.S. , Conti-Fine B.M. 
Published: March 2018

IntroductionIn spite of the significant advances in the treatment of hemophilia over the last 30 years, the development of antibodies that neutralize the procoagulant activity of factor VIII (factor VIII inhibitors) remains a serious complication of treatment with factor VIII products. Recent prospective studies of previously untreated patients with severe hemophilia have reported the incidence of inhibitor development to be approximately 20% to 25%.1-11 Factor VIII inhibitors may also develop in individuals without congenital factor VIII deficiency. Acquired autoimmune hemophilia occurs with an incidence of 0.2 to 1.0 per 1,000,000 per year in the general population.12,13 In both congenital and acquired hemophilia, anti-factor VIII antibody inhibitors are significant contributors to the morbidity and mortality of those affected. As such, these cases present difficult therapeutic challenges.Much work over the last decade has focused on defining the epitopes on factor VIII to which inhibitor antibodies bind. While this work has clarified some of the mechanisms by which inhibitors neutralize the procoagulant function of factor VIII, our knowledge of the factor VIII-specific CD4+ T helper cells, whose activation is crucial for the synthesis of factor VIII inhibitors, remains quite limited. This review will, first, discuss how a better understanding of the cellular mechanisms involved in the immune response to factor VIII may lead to improved methods of long-term inhibitor suppression and, perhaps, even prevention of inhibitor development. Lastly, this review will describe the work in our laboratory that has begun to characterize the CD4+ T cell response to factor VIII in patients with hemophilia and in normal subjects.
Immunology of the Antiphospholipid Syndrome: Antibodies, Antigens, and Autoimmune Response
Authors: Roubey Robert A. S. 
Published: March 2018

IntroductionThe antiphospholipid syndrome (APS) is an autoimmune condition in which a group of autoantibodies are thought to play a direct role in the pathogenesis of thrombosis, fetal loss, and other clinical manifestations. This review will focus on the nature of these autoantibodies, the antigens they recognize, and mechanisms that may contribute to autoimmunity and the production of autoantibodies in patients with APS.
Disseminated Intravascular Coagulation
Authors: de Jonge Evert , van der Poll Tom , ten Cate Hugo , Levi Marcel 
Published: March 2018

IntroductionA quick literature search in the MEDLINE databases from 1966 to 1998 using the search term disseminated intravascular coagulation (DIC) and related key words yields an impressive 11,921 manuscripts. Most of the published literature concerns the pathophysiology of DIC, which in its main features is now well understood. Other aspects of DIC, however, particularly those related to the definition, the relevance of the syndrome, and clinical management, remain unclear. Taking an evidence-based approach to the appropriate diagnosis and treatment of patients with DIC is difficult, in view of the lack of sound clinical trials. This is probably due to the fact that DIC is a poorly-defined syndrome with a widely variable intensity, often complicating a diversity of severe disorders that are themselves related to extensive morbidity and mortality.1,2 This chapter briefly reviews the clinical setting, incidence, and relevance of DIC and current insights into the pathogenesis of DIC. It also discusses the available knowledge on the clinical management of patients with this syndrome.DIC is not a disease or a symptom but rather a syndrome, which is always secondary to an underlying disorder. The syndrome is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to the development of multiorgan failure. Consumption and subsequent exhaustion of coagulation proteins and platelets, due to the ongoing activation of the coagulation system, may induce severe bleeding complications, although microclot formation may occur in the absence of severe clotting factor depletion and bleeding.3 Derangement of the fibrinolytic system further contributes to intravascular clot formation (discussed later), but in some cases accelerated fibrinolysis (e.g., due to consumption of α2-antiplasmin) may cause severe bleeding. Hence, a patient with DIC can present with simultaneous thrombotic and bleeding problems, which obviously complicates treatment. Although there is no general consensus regarding the definition of DIC, the definition as put forward by Müller-Berghaus and colleagues in 1995 might be most appropriate: “Disseminated intravascular coagulation is an acquired syndrome characterized by the activation of intravascular coagulation up to intravascular fibrin formation. The process may be accompanied by secondary fibrinolysis or inhibited fibrinolysis.”4
The Role of Endothelial Cell-to-Cell Junctions in Vascular Morphogenesis
Authors: Bazzoni Gianfranco , Lampugnani Maria Grazia , Dejana Elisabetta 
Published: March 2018

IntroductionAdhesion of endothelial cells (ECs) to one another and to the extracellular matrix is mediated by various surface receptors These surface receptors belong to several families of ubiquitously expressed cell adhesion molecules, such as cadherins integrins, immunoglobulins, and proteoglycans. Besides merely providing attachment sites, most adhesive receptors interac with cytoskeletal and cytoplasmic molecules and, thus, contribute to the regulation of cell morphology and signaling.Adhesion requires refined modulation to sustain the process of new vessel formation or angiogenesis. Adjoining cells mus act in concert to finalize migration and proliferation and organize into a three-dimensional network of patent tubes. Some of the molecules involved in these cell-to-extracellular matrix and cell-to-cell interactions have now been characterized. The intracellular signaling pathways activated by these molecules are, on the contrary, still rather obscure. Moreover, the adhesive systems to matrix and neighboring cells can communicate,1-4 adding complexity and coordination to the process.
Diverse Roles of Macrophage Matrix Metalloproteinases in Tissue Destruction and Tumor Growth
Authors: Shapiro Steven 
Published: March 2018

SummaryIn the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.
Acute Coronary Syndromes: Pathophysiology and Preventive Priorities
Authors: Zaman Azfar , Helft Gerard , Fayad Zahi , Fuster Valentin , Badimon Juan Jose 
Published: March 2018

IntroductionCoronary atherosclerosis and its thrombotic complications are major causes of mortality and morbidity throughout the industrialized world. Atherosclerosis is a focal, pathological phenomenon characterized by the thickening and hardening of arteries due to accumulation of lipids, carbohydrates, blood products, fibrous tissue, and calcium deposits within the subendothelial space. Significant advances have been made in understanding the mechanisms underlying this disease process, and there is considerable evidence to show that plaque composition is a major determinant of the onset and severity of acute coronary syndromes. The ability to identify plaque composition and monitor its progression can, therefore, provide valuable information regarding the development of acute coronary syndromes and target areas for pharmacological intervention to reduce or prevent the socioeconomic impact of cardiovascular disease.This chapter will describe the pathogenesis of plaque formation and rupture and assess the role of thrombus and thrombosis in the progression of atherosclerotic disease. Furthermore, we shall briefly discuss therapeutic interventions and speculate on possible targets for future research.
The mRNAs of Prekallikrein, Factors XI and XII, and Kininogen, Components of the Contact Phase Cascade Are Differentially Expressed in Multiple Non-hepatic Human Tissues
Authors: Neth Peter , Arnhold Marianne , Nitschko Hans , Fink Edwin 
Published: March 2018

SummaryRecently RT-PCR studies had demonstrated the expression of plasma prekallikrein (PPK) mRNA in extrahepatic tissues. The questions arose whether that is illegitimate or regular expression, and whether the mRNAs of blood coagulation factors XI and XII, and high molecular weight kininogen, components of the contact activation cascade of blood coagulation are also expressed in non-hepatic tissues. These questions were addressed in the present study by employing quantitative RT-PCR. The relative mRNA levels of the respective proteins determined in 16 human tissues indicate legitimate extrahepatic transcription of at least three of the genes. Transcription of all genes was highest in the liver, but only PPK mRNA was detected in all 16 tissues, especially high levels in pancreas, kidney, testis, spleen and prostate. We conclude from these results that PPK is synthesized in significant amounts in non-hepatic tissues and that this locally synthesized PPK may have special local functions.
A New Approach in the Study of the Molecular and Cellular Events Implicated in Heparin-induced Thrombocytopenia
Authors: Khairy Mahnouch , Lasne Dominique , Brohard-Bohn Brigitte , Aiach Martine , Rendu Francine , Bachelot-Loza Christilla 
Published: March 2018

SummaryHeparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, results of platelet activation, via the receptor for the Fc domain of IgG (FcγRIIa), by heparin-dependentantibodies, commonly directed against the heparin-platelet factor 4 (H-PF4) antigenic complex. Our strategy was to use whole blood allowing the study of leukocyte-platelet interactions. Experiments were performed with blood from healthy donors incubated with HIT patients’ plasma and different concentrations of heparin. We showed that 75% of the HIT patients’ plasma induced the formation of leukocyteplatelet-aggregates in a heparin-dependent-manner. The formation of leukocyteplatelet-aggregates induced by HIT plasma in the presence of heparin was (i) independent of the healthy blood donor FcγRIIa polymorphism, (ii) correlated with the levels of anti H-PF4 IgG antibodies contained in the patients’ plasma, and to a lesser extent to anti H-PF4 IgM antibodies, and (iii) was mediated by P-selectin. This report opens new prospects in the study of the molecular and cellular events implicated in HIT.
Role of the 4G/5G Polymorphism of PAI-1 Gene Promoter on PAI-1 Levels in Obese Patients
Authors: Vettor Roberto , De Pergola Giovanni , De Mitrio Vito , Saggiorato Graziella , Mea Paolo Della , Patrassi Giovanni Maurizio , Lombardi Anna Maria , Fabris Roberto , Girolami Antonio , Sartori Maria Teresa 
Published: March 2018

SummaryAs PAI-1, a cardiovascular risk factor linked to insulin-resistance, may be influenced by a 4G/5G gene polymorphism in disease states, we studied both PAI-1 plasma concentration (PAI-1:Ag) and 4G/5G polymorphism, and their relationship with anthropometric and endocrine-metabolic parameters in 93 obese patients and 79 lean normal subjects. In obese patients PAI-1:Ag levels were significantly increased, namely in males and in those with central obesity, and tightly related to the insulin-resistance parameters.In obese patients the 4G/5G polymorphism was a determinant of PAI-1:Ag levels, which were highest in 4G/4G, intermediate in 4G/5G and lowest in 5G/5G genotype carriers. PAI-1:Ag levels were significantly associated with most of anthropometric and endocrine-metabolic parameters only in 4G allele obese carriers. Moreover, only in patients with central obesity was the relationship between genotype and PAI-1 concentration maintained, with the highest levels in the 4G/4G patients. In each genotype subset of patients with central, but not peripheral, obesity PAI-1:Ag levels were significantly increased compared to their lean counterparts.In conclusion, the 4G/5G polymorphism may influence PAI-1 expression in obesity, with a crucial role in central but not peripheral adiposity. Since subjects with central obesity are at high risk for cardiovascular disease, the effects of the 4G/5G polymorphism on PAI-1 concentration may further enhance this risk.
Treatment of Intermittent Claudication with Mesoglycan – A Placebo-controlled, Double-blind Study
Authors: Gresele Paolo , Ferrari Gianni , Santoro Luigi , Gianese Francesco , Nenci Giuseppe ,   for the Mesoglycan Intermittent Claudication Group
Published: March 2018

Summary
Objective: To assess the effect of treatment with mesoglycan, a sulphated polysaccharide compound, on the walking capacity of patients with stage II peripheral arterial disease. Methods: Non-diabetic out-patients with intermittent claudication, duplex ultrasound evidence of peripheral atherosclerosis, ankle/arm index <0.80, systolic ankle pressure >50 mmHg, and absolute walking distance (AWD) between 100 and 300 m (standardised treadmill test) were eligible. After a 5-week run-in on single-blind placebo, patients were randomised to double-blind treatment with mesoglycan, 30 mg/day intramuscularly for 3 weeks followed by 100 mg/day orally for 20 weeks, or matching placebo. All patients received low-dose aspirin and lifestyle instructions. Clinical response was defined as an AWD increase at Week 23 >50% over baseline. Health-related quality of life and ischaemic events were assessed as secondary efficacy variables. Results: 242 patients were randomised and 237 were assessed for clinical response. Patients achieving clinical response were 59/118 with mesoglycan (50.0%) and 31/119 with placebo (26.1%; p <0.001). Geometric mean AWD increased from 192 to 298 m with mesoglycan, and from 192 to 238 m with placebo (p <0.001). Pain-free walking distance showed a non-significant increase with mesoglycan (p = 0.057). Changes in quality of life scores were in favour of mesoglycan. The rate of ischaemic events was 1/120 on mesoglycan and 6/122 on placebo (p = 0.053). The rate of non-ischaemic adverse events leading to treatment discontinuation was 7/120 and 4/122, respectively. Conclusion: Treatment with mesoglycan improves the walking capacity of patients with intermittent claudication, and might confer additional antithrombotic protection over that of aspirin.
The Fibrin Assay Comparison Trial (FACT): Correlation of Soluble Fibrin Assays with D-dimer
Authors: Zips Sybille , Ergül Hanimsah , Heene Dieter , Dempfle Carl-Erik ,   the FACT study group
Published: March 2018

SummarySoluble fibrin (SF) is regarded as an indicator of acute fibrin formation and a precursor of fibrin thrombi. Using a set of clinical plasma samples, and fibrin derivatives, five assays for measurement of SF, including two chromogenic assays, two ELISA systems, and one latex-enhanced photometric immunoassay were compared. Correlation between SF assays was moderate (Spearman’s rho values between 0.344 and 0.805). Re-calibration with serial dilutions of desAABBfibrin monomer resulted in adjustment of the numerical scale of the assays without improving correlation.All SF assays reacted with purified crosslinked fibrin derivatives. Using clinical plasma samples, Spearman’s rho of SF assays with D-dimer consensus values based upon results of 23 quantitative D-dimer assays were between 0.491 and 0.911.Although all SF assays react with desAABB-fibrin monomer complexes, SF assays are heterogeneous concerning reactivity with fibrin compounds observed in clinical plasma samples. The prospect of a common calibrator for SF assays therefore seems to be remote.Since SF assays react with crosslinked fibrin derivatives, it is not possible to clearly distinguish between acute fibrin formation, and fibrin dissolution on the basis of the results of current SF assays.
Attenuation by Fibrates of Plasminogen Activator Inhibitor Type-1 Expression in Human Arterial Smooth Muscle Cells
Authors: Lutzi Steffen , Ruef Johannes , Peter Karlheinz , Klar Ernst , Kübler Wolfgang , Sobel Burton , Bode Christoph , Nordt Thomas 
Published: March 2018

SummaryHuman atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells.Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-β (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-β -induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less.Gemfibrozil specifically attenuates TGF-β -induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.
Increased Expression of Serine Palmitoyltransferase (SPT) in Balloon-injured Rat Carotid Artery
Authors: Carton Jill , Argentieri Dennis , Damiano Bruce , D’Andrea Michael , Uhlinger David 
Published: March 2018

SummaryThe response to vascular injury is a complex wound healing response involving cell proliferation, migration, remodeling and inflammation. In the present studies we employed a rat balloon angioplasty model of vascular injury to investigate the potential role of sphingolipid signaling in the response to vascular injury. The enzyme serine palmitoyltransferase (SPT) catalyzes the first committed step in de novo sphingolipid biosynthesis. We observed marked upregulation of expression of both SPT subunits in actively proliferating cells in injured vessels. This enhanced SPT expression occurs in de-differentiated fibroblasts and proliferating vascular smooth muscle cells. The upregulation is particularly apparent in the proliferating luminal edge of the neointima and the adventitial de-differentiated fibroblasts and may serve as a hallmark of this process. The possible functional consequences of this enzyme upregulation and its role in the response to vascular injury are suggested but remain to be determined.
Antiphospholipid Syndrome: Diagnostic Aspects of Lupus Anticoagulants
Authors: Arnout J. 
Published: March 2018

SummaryAntiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies (aPL) are thought to be involved in the development of venous and/or arterial thrombosis. APL found in this syndrome are antibodies directed against a variety of phospholipid (PL) binding-proteins of which β2-glycoprotein I (β2GPI) and prothrombin are considered to be the major antigens. Some of these antibodies prolong PL-dependent clotting reactions and are termed lupus anticoagulants (LA). Autoimmune aPL which bind through β2GPI to cardiolipin are called anticardiolipin antibodies (aCL). Clinical studies indicate that LA is a stronger risk factor for thrombosis than aCL. The production of monoclonal antibodies against β2GPI and prothrombin has enabled us to understand the mechanism by which LA prolong coagulation in vitro. LA form bivalent antigen-antibody complexes with increased affinity for PL which compete with coagulation factors for the same catalytic surface. These LA positive monoclonal antibodies may be helpful in further improving the laboratory diagnosis of LA.
Protease Crosstalk with Integrins: the Urokinase Receptor Paradigm
Authors: Wei Ying , Chapman Harold 
Published: March 2018

SummaryMigratory cells use both adhesion receptors and proteolytic enzymes to regulate their interaction with and response to extracellular matrices. Cooperation between integrins and proteases operates at several levels: integrin signaling induces proteases, proteases co-localize with integrins, and proteases regulate the interface between integrins and the intracellular cytoskeleton. One protease system intimately connected to integrins is the urokinase/urokinase receptor(uPAR)/plasmin system. Recent studies indicate urokinase promotes the ligand-like binding of its receptor to a set of β1 and β2 integrins, this binding in turn affecting integrin signaling and cell migration. The glycolipid anchor of uPAR associates with cholesterol-rich membrane rafts. Binding of uPAR to integrins may enrich integrin clusters with signaling molecules such as src-family kinases that localize to rafts and are important to integrin function. Signals derived from integrin/uPAR complexes promote the function of other integrins. Thus the urokinase/plasmin system coordinates with integrins to regulate cell: matrix interactions.