bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Consequences of the Initiation of Blood Coagulation
Authors: Camerer Eric , Røttingen John-Arne , Wiiger Merete Thune , Gjernes Elisabet , Prydz Hans 
Published: March 2018

IntroductionThis paper reviews some of the cell biological aspects of the consequences of blood clotting initiation. These intracellular events occur in cells carrying tissue factor (TF) when its ligand, factor VIIa, is bound to the receptor-like TF surface molecules. The intracellular signaling generated by this ligand/receptor binding and some of its consequences are described and parallel experiments with factor Xa are discussed.The role of TF as a major player in the initiation of blood coagulation has been known since the last century1,2 and is now characterized in molecular detail. Research on TF, for a long period and for obvious reasons, concentrated on its essential role as a cofactor in this process. Its importance in the development of clinical thrombosis, be it venous or arterial, has been appreciated since it was discovered that monocytes and macrophages3 and endothelial cells,4 under certain conditions, could be induced to synthesize TF. This contributed to answering the previously unresolved question about how TF got into contact with the flowing blood in the absence of any trauma. We later demonstrated that the TF induction process, in many cases, is subject to down-regulation by cAMP5,6 and that Ca2+ influx can induce the synthesis,5,6 along with a large number of other compounds.7 We also showed that protein kinase C was a mediator in at least some of these inducing pathways.8
The purification of TF in 19739 showed that TF was an integral membrane protein. By 1977 it was clear that TF likely participated in functions other than blood clotting.10 The cloning of the gene for TF11-14 suggested that, structurally, TF was a member of the Class II cytokine receptor family.15 To fulfil the criteria for being a true receptor, it also needed a specific and high-affinity ligand, which it has in factor VII. Also, to be classified as a true receptor, ligand binding should generate an intracellular signal. In 1992, we presented the first report of such a signal in the form of Ca2+ peaks. These peaks were triggered by the addition of factor VIIa to endothelial cells carrying TF on their surface as a result of exposure to interleukin 1β. These signals were characterized further16,17 and were thought to render final proof for the function of the TF receptor.This review discusses our findings with respect to TF/factor VIIa-induced intracellular Ca2+-signaling and concludes that there is likely a two-component receptor. The more consequential question—whether this intracellular signaling leads to altered gene expression and to other phenotypic changes—is also raised. The establishment of knockout mice18–20 and efforts to solve the three-dimensional structure of this complex by x-ray diffraction21–24 are not reviewed extensively.
Structure and Function of Fibrinogen: Insights from Dysfibrinogens
Authors: Sugo Teruko , Yoshida Nobuhiko , Terukina Shigeharu , Yamazumi Kensuke , Niwa Kazuki , Maekawa Hisato , Matsuda Michio 
Published: March 2018

SummaryThe structure-function relationships of dysfibrinogens and their clinical implications are discussed on the basis of the data provided from representative molecules.
Heparin-Induced Thrombocytopenia: A Clinicopathologic Syndrome
Authors: Warkentin Theodore 
Published: March 2018

IntroductionThe American vascular surgeons, Weismann and Tobin in 19581 and Roberts and colleagues in 1964,2 were the first to describe unusual thrombi affecting the lower limb arteries in some patients treated with heparin for 7 to 14 days. It was not until the mid-1970s however that Silver and colleagues3,4 identified the key elements of the heparin-induced thrombocytopenia (HIT) syndrome, namely thrombocytopenia associated with thrombosis beginning several days after starting heparin. Further, in vitro studies performed by these investigators suggested the presence of a heparin-dependent, platelet-aggregating factor in serum thought to be immunoglobulin G (IgG).In 1992, Amiral and colleagues5 identified the antigen target of HIT antibodies. The unusual nature of the HIT antigen, a multimolecular complex of heparin and platelet factor 4 (PF4),5,6 together with the remarkable, perhaps unparalleled, platelet- and endothelium-activating properties of the pathogenic HIT antibodies,7-10 are central to the thrombotic events that occur in these patients. From its obscure beginnings, HIT is now accepted as a common and distinct immunohematologic syndrome with broad implications ranging from public health prevention issues to fundamental questions of pathogenesis, which are leading to new insights into the molecular pathogenesis of thrombosis.
Treatment of Heparin-Induced Thrombocytopenia
Authors: Greinacher Andreas 
Published: March 2018

IntroductionUnfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the most widely used anticoagulants when parenteral anticoagulation with a short half-life is required. Both can be administered subcutaneously and intravenously, and both have been shown to be effective in a variety of clinical settings.1 UFH has several limitations. One is its poor bioavailability after subcutaneous injection and the marked variability in its anticoagulant response in patients with an acute thromboembolic complication.2,3 Another major issue associated with UFH is the induction of heparin-induced thrombocytopenia (HIT). Both limitations are closely linked,4 as the underlying cause is the high density of negative charges on the heparin molecule and its molecular weight. Both are responsible for the binding of heparin to plasma proteins other than antithrombin (AT), such as platelet factor 4 (PF4) and to several cell types. This leads to heparin-platelet interaction, the formation of HIT antigen (i.e., PF4/heparin complexes), and inhibition of the anticoagulant effect of heparin (aPTT-nonresponder).
Development of High-Capacity Adenoviral Vectors for Gene Therapy
Authors: Kochanek Stefan 
Published: March 2018

IntroductionArticles about mutations that cause genetic disorders frequently include a suggestion that gene therapy will likely provide a cure for the disease in the future. In fact, ongoing efforts to sequence the human genome, to understand the roles of genes during development, and to determine the molecular pathogenesis of disease will almost “naturally” lead to the use of nucleic acids for the treatment of diseases in the future.Somatic gene therapy can be defined as the treatment of inherited or acquired diseases by the introduction and expression of genetic information in somatic cells. Genetic disorders that are caused by loss-of-function mutations might be treated by introducing a functional copy of the mutated gene into the appropriate tissue. Good candidate disorders for somatic gene therapy include the many inborn errors of metabolism, such as hemophilia A or B, which are caused by either a low amount or the complete absence of a single functional gene product. These disorders have been characterized at the DNA level, and the disease-causing mutations can be relatively easily identified in individual patients.Many acquired diseases, such as different types of cancer, are less well-defined at the molecular level. However, because of their frequency and their impact on public health, interest in the development of gene therapy for these disorders is particularly high. In fact, most of the clinical gene therapy trials that have been conducted so far relate to the treatment of malignant tumors. Despite the many ongoing clinical trials, as yet, there have been no clear examples of the successful treatment of any human disease by gene transfer.Possibly the single most important reason preventing a broad application of gene transfer in the treatment of diseases, whether inherited or acquired, is the lack of both safe and effective gene transfer technologies. What are the requirements for the use of a vector as a vehicle for gene transfer in patients with inborn errors of metabolism? The vector should efficiently transport and deliver foreign genes to different cell types, both in vitro and in vivo. Following gene transfer, these genes should be permanently expressed at physiological levels. In many cases, expression will need to be tissue-specific and regulated. The vector should be safe, stable, and easily manufactured to high yields.While several nonviral and viral gene transfer vectors have been tested in different systems, currently, there is no vector system available that meets all of these requirements. With the realization that efficient delivery of genes into tissues is at the heart of successful somatic gene therapy, many research groups are concentrating their efforts on refining the different aspects of the multi-step process of gene transfer.
Effects of Hormone Replacement Therapy on Coagulation, Fibrinolysis, and Thrombosis Risk in Postmenopausal Women
Authors: Koh Kwang Kon , Horne McDonald , Cannon Richard 
Published: March 2018

IntroductionIn the United States and other developed countries, more women die from cardiovascular disease than from any other disease. The Nurses’ Health Study, among others, has suggested that postmenopausal women who take estrogen therapy have fewer cardiovascular events over time compared with untreated women.1,2 The favorable effects of orally-administered estrogen on lipoprotein levels, namely reductions in low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels, and increases in high-density lipoprotein (HDL) cholesterol levels, likely account for much of this apparent benefit. These effects have not yet, however, been proven in randomized clinical trials. Because estrogen has a multitude of biological effects, many other potential mechanisms by which estrogen provides protection against atherosclerosis and its consequences are currently being studied.Atherosclerosis is associated with chronic inflammation in response to injury and with a number of risk factors, such as elevated serum cholesterol, smoking, diabetes, and hypertension.3 Local activation of platelets and thrombus formation adjacent to atheromatous plaques, especially where ruptured or eroded, is now recognized to be of pathophysiological importance in the acute and chronic clinical expression of this disease.4 Thus, the favorable effects of estrogen on hemostasis may be relevant to the progression of atherosclerosis and associated clinical manifestations.In this regard, several groups have reported on the favorable effects of hormone replacement therapy on fibrinolysis in postmenopausal women. These results might be interpreted as protection by estrogen against the propagation of thrombi that could result in myocardial ischemia and infarction. On the other hand, coagulation activation and increased risk of thromboemboli and myocardial infarction have also been reported with hormone replacement therapy in postmenopausal women. In an effort to gain a better understanding of the complex effects of estrogen on hemostasis, this chapter will review a number of observational trials and treatment studies conducted in postmenopausal women receiving estrogen therapy.
Disseminated Intravascular Coagulation: Clinical Spectrum and Established as well as New Diagnostic Approaches
Authors: ten Cate Hugo , Levi Marcel , Müller-Berghaus Gert 
Published: March 2018

IntroductionAlthough disseminated intravascular coagulation (DIC) is an “intermediary mechanism of disease”1 that has been intensively studied during the last three decades,2-4 several aspects relating to the clinical problem of DIC are still under debate. For example, a standardized definition of disseminated intravascular coagulation has not yet been agreed upon. A diagnosis can be accurately made using the facilities of a specialized laboratory, but time constraints make the diagnosis of DIC by the general laboratory difficult. Since DIC can be prevented if the right therapy is initiated early, the ability to quickly and accurately diagnose DIC and to monitor the involved dynamic processes are essential prerequisites for the effective management patients with DIC.Due to the problems associated with defining DIC, making an early diagnosis, and effectively treating the condition following diagnosis, the clinical management of DIC can be difficult. The transition from an activated hemostatic system to a well-defined state of DIC is indistinct, and the borderlines cannot easily be distinguished. In addition, different underlying diseases mediating DIC induce different clinical symptoms associated with DIC and demand different therapeutic approaches.
The Pathophysiology of Disseminated Intravascular Coagulation
Authors: Timmerman Janneke , Levi Marcel , ten Cate Hugo 
Published: March 2018

IntroductionDisseminated intravascular coagulation (DIC) can be defined as “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.”1 Being an acquired disorder, DIC occurs in a wide range of underlying disease states, including sepsis (both by Gram positive and Gram negative bacteria), burns, preeclampsia, malignancy, and polytrauma.1 In the majority of conditions, the pathogenesis of DIC remains only partly understood, an exception is Gram negative septicemia. In the following chapter, we will discuss the presumed mechanism by which DIC is elicited in different pathological states. The initiation of DIC follows the presentation of the glycoprotein tissue factor (TF) at a cellular surface, being either an intact or perturbed cell, or a cell membrane remnant.2 The extracellular TF molecules may interact with circulating factor VIIa to form a catalytic complex. The complex binds the coagulation zymogen factors IX and X. This leads to proteolytic cleavage of these molecules, yielding enzymatically active factors IXa and Xa and promoting the activation of prothrombin to thrombin (Fig. 1).
Hemostatic Gene Expression and Vascular Disease in Obesity: Insights from Studies of Genetically Obese Mice
Authors: Samad Fahumiya , Loskutoff David 
Published: March 2018

IntroductionObesity is a major public health problem in Western societies with substantial economic consequences. In the United States alone, over 30% of the population is defined as clinically obese, and thereby, are subject to increased risk for obesity-associated disorders, including cardiovascular disease (CVD), hypertension, insulin resistance, and non-insulin dependent diabetes mellitus (NIDDM).1,2 In spite of the magnitude of this problem, the molecular changes in obesity that promote these conditions are far from resolved. The fact that human obesity is a polygenic disorder with complex environmental and behavioral characteristics has made obesity research one of the more difficult areas of investigation in the medical sciences.1,3 However, recent studies of genetically obese mice and rats have produced breakthroughs in several areas of obesity-related research, primarily because obesity in these animals appears to be monogenic (i.e., to result from mutations in single genes). In this regard, five different genes, all mapped to different chromosomal locations, have been shown to cause distinct syndromes of spontaneous obesity with severe insulin resistance in mice.3 These include the obese (ob), diabetes (db), tubby (tub), lethal yellow (Ay) and fat (fat) mutations. Genes encoding intercellular adhesion molecule 1 (ICAM-1) and the leukocyte integrin αmβ2 (MAC-1) also have been implicated in the regulation of adipose tissue mass.4 These animal studies, together with studies of cultured adipocytes, have provided fundamental new information about the factors and cells that may be responsible for the altered hemostatic balance leading to increased cardiovascular risk in obesity/NIDDM.In this chapter, we summarize our studies on plasminogen activator inhibitor 1 (PAI-1), tissue factor, and transforming growth factor (TGF)-β expression in obesity, using genetically obese mice as a model. These studies emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also implicate multiple cytokines, hormones, and growth factors in the abnormal expression of these and perhaps other hemostatic genes by adipocytes in obesity/NIDDM (Fig. 1). These studies emphasize the key role played by tumor necrosis factor (TNF)-α in the expression of hemostatic genes in this disorder.
Why Atherosclerotic Vessels Narrow: The Fibrin Hypothesis
Authors: Yee Karen , Schwartz Stephen 
Published: March 2018

IntroductionConventional wisdom holds that atherosclerosis narrows vessels simply by growth of the plaque.1 We now know, however, that this is incorrect. Morphological studies from the last 10 years have shown that there is no correlation between lesion size and lumen diameter. This lack of correlation is also true in the lesions found in the apolipoprotein E (apoE)-deficient mouse model.2 Pathologic studies in the mouse model and in humans suggest that the media remodels as the plaque enlarges to maintain normal blood flow through the vessel.3,4 This normal ability of the vessel to adapt to changes in lumen diameter has been called either “adaptive remodeling” or “compensatory enlargement.” We will use the former term since “remodeling” has long been used by physiologists to describe adaptive changes of vessels to pressure or flow.The mechanism for adaptive remodeling is not known. Critical processes may include shear stress caused by the lesion, signaling in response to medial attenuation by proteases, or poorly defined apoptotic processes.3-5 This chapter will review the evidence for adaptive remodeling and propose a mechanism for the ultimate failure of remodeling and subsequent narrowing of the affected vessel. We will suggest that the critical processes in vascular narrowing are the same processes seen in wound healing, with fibrin playing a role as a provisional matrix.
Gene-Environment Interaction in the Determination of Levels of Plasma Fibrinogen
Authors: Luong Le-Anh , Montgomery Hugh , Day Ian , Mohamed-Ali Vidya , Yudkin John , Humphries Steve 
Published: March 2018

IntroductionThis review will focus on the inflammatory risk factors that may influence changes in plasma fibrinogen levels and that may influence an individual’s risk of ischemic heart disease (IHD). These inflammatory risk factors occur to a different extent in individuals as their environment changes. Although a specific genotype may be associated, in healthy subjects, with modest differences in levels of a risk factor for thrombosis, this effect may be larger or smaller in subgroups of subjects. Documenting such gene-environment interactions is important if genotype information is ever to be used in a clinical or diagnostic setting. Understanding the molecular mechanisms of such interactions is vital to the development of novel therapeutic approaches to reduce risk of myocardial infarction (MI).We review some of the gene-environment interactions detected to date for the G-455A β-fibrinogen gene promoter polymorphism. Carriers of the A allele, representing roughly 20% of the population, consistently have, on average, 7% to 10% higher fibrinogen levels than those with the genotype GG. Data will be presented to demonstrate interaction between situations of inflammatory stimulation (e.g., smoking habit, presence of ischemic disease, and level of physical exercise) in the determination of the magnitude of the effect of the A allele on plasma fibrinogen levels.The cytokine interleukin-6 (IL-6) is the likely link between inflammatory processes and IHD. Recently we have identified a functional G/C polymorphism at -174bp in the IL-6 promoter, with the G allele being a 2 to 4 times stronger promoter upon stimulation with interleukin-1 (IL-1) or lipopolysaccharide (LPS). In a small study of healthy subjects, the C allele was associated with significantly lower mean plasma levels of IL-6, an effect which may be protect against the development of IHD. Finally, we describe a rapid throughput genotyping method that is useful for large-scale genetic epidemiology studies.
Regulation of Fibrinolysis in the Development of Atherothrombosis: Role of Adipose Tissue
Authors: Alessi M.C. , Juhan-Vague I. 
Published: March 2018

IntroductionAmong the list of coronary risk factors, it has recently been proposed that fibrinolytic system impairment, due to increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma, could predict complications of atherosclerosis. The fibrinolytic system1 is regulated by a balance between activators and inhibitors. PAI-1, which inhibits t-PA and u-PA, is the main inhibitor of plasminogen activation. An increased PAI-1 concentration induces a reduction in plasmin formation and leads to fibrin accumulation.2-5 PAI-1 also induces changes in vessel wall remodeling through the activation of metalloproteinases and growth factors and the degradation of the extracellular matrix.4 In addition to its antiprotease activity, PAI-1 also participates in the cellular adhesion and migration processes. Because it binds to vitronectin in the same part of the molecule as vitronectin receptor or u-PA receptor, it mediates the release of cells from their substrate.6,7 All of these properties indicate that PAI-1 can be involved in tissue remodeling and thrombotic processes and, therefore, participates in the development of atherothrombosis.In plasma, an elevated PAI-1 concentration is presently considered a risk factor for coronary vascular events. It appears that PAI-1 is an inducible target controlled for in insulin resistance and obesity, which are situations that favor the development of atherothrombosis. It has been postulated that PAI-1 could contribute to an increased susceptibility to atherothrombosis in insulin-resistant patients. The production of PAI-1 by adipose tissue has recently been demonstrated. The elucidation of the regulation of PAI-1 synthesis and the identification of factors responsible for increased plasma PAI-1 concentration in the insulin-resistant state might lead to therapeutic concepts for the prevention of atherothrombosis.