bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Plasminogen (Fibrinolytic) System
Authors: Collen Désiré 
Published: March 2018

IntroductionThe plasminogen (fibrinolytic) system (Fig. 1) comprises an inactive proenzyme, plasminogen, that can be converted to the active enzyme, plasmin. Plasmin degrades fibrin and activates matrix metalloproteinases (MMPs) that, in turn, degrade the extracellular matrix (ECM).1-3 Two physiological plasminogen activators (PAs) have been identified: tissue-type PA (t-PA) and urokinase-type PA (u-PA), which binds to a cellular u-PA receptor (u-PAR). Inhibition of the plasminogen/MMP system occurs at the level of the PA, by specific PA inhibitors (PAIs), at the level of plasmin, primarily by α2-antiplasmin, or at the level of MMPs, by tissue inhibitors of MMPs (TIMPs).The dual roles of the plasminogen system are presently well established. The t-PA-mediated pathway is primarily involved in fibrin homeostasis, and the u-PA-mediated pathway is primarily involved in phenomena, such as cell migration and tissue remodeling. Consequently, the terminology “fibrinolytic system” has become inadequate and, therefore, will be replaced by “plasminogen system” in the present review.In 1980, the state of knowledge concerning the plasminogen system was summarized.4 At that time, most of the components of the system (except the PAIs) were identified and biochemically characterized (except t-PA), but thrombolytic therapy was still in its infancy. The pathophysiologic role of the plasminogen system was deduced indirectly from correlations between levels of its components and clinical disease states, whereas its role in vascular biology, matrix remodeling, tumor growth and dissemination, wound healing, and infection was largely unknown. The last 20 years have witnessed a rapidly progressing elucidation of the biochemistry, (patho)physiology, and therapeutic applications of the plasminogen system. This development has been catalyzed by the emergence of powerful molecular biological technologies, including recombinant DNA techniques for the expression of heterologous proteins and targeted gene manipulation in vivo for the elucidation of the (patho)physiological role of their translation products.The aim of the present review is to summarize the main developments in the plasminogen field since the 1980s. This account will be incomplete, since references to much significant work were omitted due to space limitations. To alleviate this shortcoming, reference is made primarily to review articles, in which more details and citations to original work can be found.
Structural Studies of Fibrinolysis by Electron and Light Microscopy
Authors: Veklich Yuri , Collet Jean-Philippe , Francis Charles , Weisel John W. 
Published: March 2018

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6
Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15
To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.
Thrombopoietin-Induced Signal Transduction and Potentiation of Platelet Activation
Authors: Miyakawa Yoshitaka , Druker Brian , Ozaki Katsutoshi , Ohashi Hideya , Kato Takashi , Miyazaki Hiroshi , Handa Makoto , Ikebuchi Kenji , Ikeda Yasuo , Oda Atsushi 
Published: March 2018

IntroductionThe presence of thrombopoietin, a humoral regulator of megakaryopoiesis and thrombopoiesis, had been suggested for years,1 however, some investigators were skeptical about the existence of such a factor. Modern studies of thrombopoietin begin with the cloning of c-mpl (the cellular counterpart of the v-mpl oncogene) and its cognate ligand genes. Following the cloning of the c-mpl proto-oncogene,2 Methia et al3 found that, in the presence of oligonucleotides antisense to the gene, CD34+ cells developed into megakaryocytic precursors less efficiently. As the development into other lineage was nearly intact, it was reasonably argued that the c-mpl protein may be the receptor for a thrombopoietin-like factor.3 This study inspired numerous investigations, which culminated in the cloning of the thrombopoietin gene in 1994.1, 4-8
On the Role of Calpain and Rho Proteins in Regulating Integrin-induced Signaling
Authors: Fox Joan 
Published: March 2018

SummaryThe integrin family of transmembrane receptors plays an essential role in inducing the adhesion of cells to the extracellular matrix. In some cases, members of this family of receptors can bind soluble ligands or can bind receptors on other cells and, in this way, mediate interactions between cells. In all cases, once an integrin has bound, ligand signals are transmitted across the occupied integrin. These signals culminate in changes in the behavior of the cell appropriate for the adherent state of the cell. For example, in the case of platelets, an end result of the signaling induced by binding of fibrinogen to αIIbβ3 in a platelet aggregate is a reorganization of the cytoskeleton that leads to retraction of externally-bound fibrin by clots.1,2 In the case of neutrophils, cytoskeletal changes following the integrininduced interaction of neutrophils with endothelial cells lead to the migration of neutrophils into a site of injury.3,4 Other examples of the consequences of integrin-induced signaling in adherent cells include the trafficking of lymphocytes and migration of cells during development, angiogenesis, and metastasis.5-7
Numerous signaling molecules have been shown to be activated following integrin-ligand interactions.8 Many of these associate in complexes with ligand-occupied integrin and cytoskeletal proteins. However, in general, little is known about the key steps involved regarding integrin-induced changes in the behavior of adherent cells. The present chapter reviews steps involved in integrin-induced signaling, describes the evidence that calpain is one of the signaling molecules involved in this signal transduction, and discusses potential mechanisms by which cleavage of cytoskeletal proteins and signaling molecules by calpain may regulate the integrin-induced changes in cell behavior.
Inherited Abnormalities of Platelets
Authors: Nurden Alan 
Published: March 2018

IntroductionGenetic defects of platelets give rise to bleeding syndromes of varying severity. Affected areas of platelet function include the glycoprotein (GP) effectors of adhesion and aggregation, primary receptors for agonists, signaling pathways where messages are transmitted to targets elsewhere in the membrane or within the platelet, dense- and α-granule secretion, ATP production, and the expression of procoagulant activity. Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are the best-characterized platelet diseases and will have a major place in this review. GT is caused by abnormalities of platelet membrane GP IIb-IIIa (integrin αIIbβ3), resulting in absent platelet aggregation. BSS is caused by abnormalities of the GP Ib-IX-V complex, resulting in a loss of platelet adherence to vessel wall subendothelium. The disorders affecting platelet morphology, which give rise to the so-called giant platelet syndromes, are also considered.Studies on platelet disorders are significant because the knowledge gained has provided a better understanding of the molecular basis of primary hemostasis and has helped in the development of new drugs for use in antithrombotic therapy. In 1987, this author gave the inaugural State-of-the-Art lecture at an International Society of Thrombosis and Haemostasis meeting.1 At that time, the application of molecular biology procedures to the study of platelet disorders was just beginning. Now, 12 years later, some of these data will be reviewed and the recent advances discussed.
Surveillance for Bloodborne Infections
Authors: Chamberland Mary 
Published: March 2018

IntroductionSince blood is a biological product, it is a natural vehicle for transmission of infectious agents, and until an artificial blood substitute is developed, the risk of transfusion-transmitted infections will probably not be eliminated. Three agencies of the Department of Health and Human Services–the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and National Institutes of Health (NIH)–have collaborated with partners in local and state public health departments, academia, industry, and consumers to develop prevention strategies addressing emerging infectious disease threats to public health, including the safety of the U.S. blood supply. Four critical components of these prevention strategies are as follows: surveillance and response capabilities; integration of laboratory science and epidemiology (i.e., “applied research”) to optimize public health practice; prevention and control activities to enhance communication of public health information; and a strengthening of local, state, and federal infrastructures to support these activities.1
As highlighted by the Institute of Medicine, in its series of reports about the ongoing threat to health posed by emerging infectious diseases, surveillance is the critical lynchpin for the public health response to both known and unrecognized pathogenic threats.2 Surveillance data can be used to monitor and track temporal and demographic trends of disease, alert us to outbreaks or unexpected alterations in disease frequency or affected populations, serve as a basis for subsequent epidemiologic and laboratory investigations to describe the natural history of a disease or identify risk factors for its occurrence, and evaluate intervention strategies.2,3
This paper will review programs of surveillance in the U.S. to detect established and emerging infectious risks, with an emphasis on those that address blood safety. In addition, recent examples or case studies that illustrate the responsiveness of U.S. surveillance systems to blood safety issues will be presented.
Characterization of Factor VIII B-Cell Inhibitory Epitopes
Authors: Lollar Pete 
Published: March 2018

IntroductionFactor VIII contains three epitopes that are the usual targets of clinically significant antibody inhibitors. Two of these epitopes are located in the A2 and C2 domains of factor VIII. The third epitope appears to be in the A3 domain. Ongoing studies continue to provide higher resolution maps of these epitopes and to understand the mechanism by which inhibitors produce a bleeding diathesis. The manipulation of inhibitor epitopes using recombinant DNA technology may lead to improved forms of factor VIII that have lower antigenicity and/or lower immunogenicity.
Prophylactic Infusion Regimens in the Management of Hemophilia
Authors: Ljung Rolf 
Published: March 2018

IntroductionThe goal of prophylactic treatment of hemophilia is to convert the severe form of the disorder into a milder form by administration of factors VIII or IX. The rationale behind this is that chronic arthropathy, the hallmark of hemophilia after repeated bleedings, is less frequent and less severe in moderate hemophilia (i.e., factor VIII or factor IX concentrations of 1% to 4% of normal) than in severe hemophilia (i.e., factor VIII/factor IX concentrations lower than 1% of normal).1 Keep in mind, however, that prophylactic treatment also provides protection from all other forms of hemorrhage that may occur spontaneously or as a result of trivial trauma in the untreated hemophilic child. Today, prophylactic treatment is available to only a few hemophilia patients in the world, although it is recommended by the World Health Organization (WHO) and the World Federation of Haemophilia (WFH): “Since the main goal is to prevent joint bleeding and its sequelae, prophylaxis should be considered optimal management for persons with severe hemophilia A or B (i.e., with basal factor VIII and/or factor IX levels <1% of normal). Treatment should be started at the age of 1-2 years and be continued indefinitely. Where prophylaxis is not feasible or appropriate, on-demand therapy should be given.”2 In the United States, the Medical and Scientific Advisory Council of the National Hemophilia Foundation has recommended that “prophylaxis should be considered the optimal therapy for children with severe hemophilia A or B.”3 The aim of this chapter is to discuss prophylactic infusion regimens in the management of hemophilia.
P-Selectin-β2-Integrin Cross-Talk: A Molecular Mechanism For Polymorphonuclear Leukocyte Recruitment At The Site Of Vascular Damage
Authors: Evangelista Virgilio , de Gaetano Giovanni , Cerletti Chiara 
Published: March 2018

IntroductionPlatelets activated at the site of vascular damage play a pivotal role in polymorphonuclear (PMN) leukocyte accumulation in a growing thrombus2,3 and may substitute endothelial cells in the recruitment and migration of leukocytes through damaged vessel wall.4 Leukocytes, accumulated in a platelet thrombus, can contribute to further platelet activation5 and to increased fibrin deposition.6 These events, on the one hand, may contribute to the maintenance of vascular and tissue integrity. They may, however, play a pathogenic role in inflammatory and thrombotic disease, providing some biological plausibility to the epidemiological evidence of significant association between leukocyte count and the incidence of coronary heart disease.7,8
We shall focus our attention on the molecular mechanisms involved in the recruitment of PMN leukocytes on activated platelets as it occurs at the site of vascular damage, with particular attention to P-selectin- β2-integrin cross-talk.
Gene Trap, Gene Knockout, Gene Knock-In, and Transgenics in Vascular Development
Authors: Sato Thomas 
Published: March 2018

IntroductionThe vascular system is one of the first organ systems to develop in our bodies. Normal development and maturation of the physiological functions of almost all of the other organs are critically dependent on the accurate and tightly controlled establishment of the vascular system. Our understanding of the mechanisms underlying the formation of the vascular system during development is still in its infancy. With further understanding of these mechanisms, we may eventually be able to correct the abnormal development and the malfunctioning of many organs by therapeutically modulating the morphology and/or physiological function of the vascular system.Our further understanding of the vascular development can, in part, be achieved by discovering the molecules that play critical roles in this process. We could also achieve this goal by learning more about the functions of previously identified molecules in the vascular system. Discovery of new processes underlying the development of the vascular system will also contribute to further understanding of these molecular mechanisms.Recent advances, using the whole genome approach, have resulted in a flood of new information. This trend will continue, and fortunately, a number of molecular reagents will become available. Therefore, the field will likely experience an exponential growth in terms of novel biological insights and discovering the mechanisms of vascular system development.Occasionally, reductionistic approaches help to systematically address a number of biological problems, including the problems associated with vascular system development. One such approach is to choose an organism that allows us to systematically address these biological questions. The choice of animal models that are well-suited for the study of a particular question has led to a large number of discoveries. To address questions in vascular system development, current research has focused on animal models, including fish, frog, bird, and mouse, and also studies involving humans. It is also worthwhile to note that the branching morphogenesis of the fly trachea system has been utilized to address fundamental questions of vascular morphogenesis.This chapter will summarize the genomic manipulation of the murine vascular system to address questions regarding vascular development. In addition, the advances that have been made in this field using such methods will be summarized.
The Effect of Unfractionated vs. Low Molecular Weight Heparin on Tissue Factor Pathway Inhibitor Levels in Hospital Inpatients
Authors: Kuter David , Brown Jennifer 
Published: March 2018

SummaryAlthough heparin is widely used as an antithrombotic agent, its multiple mechanisms of action are not fully defined. Recent work has suggested that tissue factor pathway inhibitor (TFPI) may contribute to the antithrombotic activity of heparin by inhibiting the extrinsic pathway of coagulation. We have investigated the effect of heparin on TFPI and have found that when unfractionated heparin is given by continuous intravenous infusion to hospitalized inpatients, TFPI levels increase 2.3-fold and remain high as long as heparin is continued, but return to baseline levels soon after the infusion is stopped. In contrast, therapeutic doses of the low molecular weight heparin, dalteparin, resulted in significantly less TFPI induction. Given the increasing number of studies establishing the clinical efficacy of low molecular weight heparins as antithrombotic agents, these results suggest that TFPI may not be a major contributor to the antithrombotic effect of heparin.
Signal Transduction Pathways Underlying the Expression of Tissue Factor and Thrombomodulin in Promyelocytic Cells Induced to Differentiate by Retinoid Acid and Dibutyryl cAMP
Authors: Dobado-Berrios Pablo , Ros Rosa , Torres Antonio , García-Navarro Socorro , Jardí Mercé , Félez Jordi , Velasco Francisco , López-Pedrera Chari 
Published: March 2018

SummaryAcute promyelocytic leukaemia (APL) may be associated with disseminated intravascular coagulation, as a result of increased tissue factor (TF) expression and reduced thrombomodulin (TM) expression by APL blast cells. During retinoid acid (RA)- and dibutyryl cAMP (dbcAMP)-induced differentiation of the APL cells, there is a marked up-modulation of both the protein kinase A (PKA) and C (PKC) activities. In order to further assess whether these kinases are intimately associated with both the differentiation process and the regulation of TF and TM expression, we have correlated the modulation of their respective pathways with the extent of differentiation and modulation of these cellular receptors. NB4 cells were incubated with all-trans-RA (ATRA) or dbcAMP for up to 48 h. The contribution of phospholipase C (PLC), inositol phosphate (IP), PKC and PKA in the expression of CD11b, TF and TM was studied by the use of specific inhibitors. Myo-inositol uptake and PKC activity increased in cells induced to differentiate by ATRA but the retinoid did not affect cAMP levels or PKA activity. Under treatment with dbcAMP, PKA activity was increased while inositol uptake and PKC activity remained unchanged. Our results show that the effects of ATRA and dbcAMP on promyelocytic cells are closely related, respectively, to the PLC/IP/PKC and the cAMP/PKA pathways. In cells induced to differentiate by ATRA, CD11b expression seems more closely related to inositol uptake than to PKC activity while the expression of TF and TM show the opposite pattern, which suggests cellular events regulated at a different level within a common signal transduction pathway.
The Effect of Platelet PlA Polymorphism on Experimental Thrombus Formation in Man Depends on Blood Flow and Thrombogenic Substrate
Authors: Sakariassen Kjell , Grandjean Hélène , Thalamas Claire , Boneu Bernard , Sié Pierre , Cadroy Yves 
Published: March 2018

SummaryA number of studies have reported conflicting data on the association of the PlA1/PlA2 polymorphism of the GPIIIa gene and coronary syndromes. We have investigated the effect of this polymorphism on experimental platelet thrombus formation in man. Forty healthy male volunteers were genotyped for the PlA1/PlA2 polymorphism. Thrombus formation was induced ex vivo by exposing a tissue factor (TF) or a collagencoated coverslip in a parallel plate perfusion chamber to native blood for 2 and 4 min. The shear rates at these surfaces were 650 and 2,600 s–1. Platelet and fibrin deposition was quantified by immunoenzymatic methods. The frequencies of PlA1/PlA1 and PlA1/PlA2 genotypes were 52.5% and 47.5%, respectively. Ex vivo deposition of fibrin on TF was not affected by the PlA1/PlA2 polymorphism. However, the ex vivo platelet deposition at 650 s–1 was higher in blood from PlA1/PlA1 individuals than in PlA1/PlA2 individuals (P = 0.008 at 4 min). On collagen, neither fibrin nor platelet deposition was significantly affected by the PlA1/PlA2 polymorphism. Platelet thrombus formation is significantly influenced by genetic variations in the GPIIIa platelet receptor. This effect depends on the blood flow properties and the nature of the thrombogenic stimulus.
Regulated Secretion in Endothelial Cells: Biology and Clinical Implications
Authors: Ewenstein Bruce , Datta Yvonne 
Published: March 2018

SummaryRegulated secretion provides a means by which endothelial cells (EC) can rapidly and selectively alter the microenvironment of individual vascular beds, and modulate the interrelated processes of coagulation, fibrinolysis, and inflammation. The rapid release of high molecular weight multimers of von Willebrand factor (VWF) and surface expression of P-selectin in response to a wide variety of stimuli have been well documented, and are the result of exocytosis of Weibel-Palade bodies (WPB). The regulated release of other EC secretory proteins, including tissue plasminogen activator (tPA), interleukin-8, endothelin-1, and multimerin, has also been described. New light is being shed on how secretory proteins are selectively targeted to storage granules in EC, and on the molecular and cellular events that comprise regulated secretion. Knowledge of the mechanisms of sorting and secretion from EC storage granules may provide basis for new strategies for treating inflammatory and coagulation disorders.