bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling Through Platelet Integrin αIIbβ3: Inside-out, Outside-in, and Sideways
Authors: Shattil Sanford 
Published: March 2018

IntroductionCell adhesion, which plays a major role in the response of tissues to injury, involves a wide variety of cells, adhesion receptors, and ligands. Prominent among the cells responding to injury are platelets, the first line of defense against hemorrhage and an early player in the overall process of wound-healing.1 Prominent among the adhesion receptors is αIIbβ3, a platelet-specific integrin essential for hemostasis by virtue of its role in mediating platelet aggregation and platelet spreading on vascular matrices. Prominent among the ligands for αIIbβ3 are the multivalent adhesive proteins, fibrinogen and von Willebrand factor (vWF), which in soluble form, mediate platelet aggregation and, in solid phase, mediate adhesive spreading.2
In addition to the adhesive functions of αIIbβ3, this integrin serves as a bidirectional conduit for biochemical and mechanical information flow across the platelet plasma membrane.3 For example, intracellular signals modulate the ligand-binding function of αIIbβ3 (inside-out signaling), and signals generated by ligation and clustering of αIIbβ3 regulate the extent of platelet aggregation and spreading (outside-in signaling). The relationships between αIIbβ3 and intracellular signaling pathways have been the subject of intense study in human platelets, model cell systems, and more recently, in genetically-modified mice. Although model cells and mouse platelets have become indispensable tools to dissect mechanisms of αIIbβ3 signaling, conclusions drawn from their use must always be validated in human platelets. Despite this caveat, a broad, but still incomplete, picture of integrin signaling in platelets is beginning to emerge. This update will highlight selected recent developments in this area and discuss potential clinical implications.
Treatment of Patients with Factor VIII and Factor IX Inhibitors with Special Focus on the Use of Recombinant Factor VIIa
Authors: Hedner Ulla 
Published: March 2018

IntroductionIn caring for patients with hemophilia, the development of inhibitors against the missing coagulation protein remains a significant problem. Such inhibitors occur in about 15% of patients with severe hemophilia1 and are directed against the procoagulant part of the factor VIII or factor IX molecules. The goal in the treatment of patients with hemophilia is to achieve high enough levels of the missing factor to induce hemostasis in case of bleeding or to prevent bleeding during surgery. Patients with a low inhibitor titer, and especially those with a low anamnestic response, can be given high doses of the coagulation factor concentrate to induce hemostasis. However, for patients with high inhibitor levels, or high-responders, other treatments must be used, including procedures to decrease the antibody titers. To minimize the booster effect of high doses of antigen, immunosuppressive treatment may be added. Because such treatment procedures are complicated and associated with a number of potential side effects, they are not often used to treat mild-to-moderate bleeding episodes or to cover elective, less urgent surgery for inhibitor patients. As a result, a great deal of effort has been devoted to finding more convenient treatment modalities and to inducing immunologic tolerance to permanently eradicate the inhibitors.
Regulation of the Procoagulant Response to Arterial Injury
Authors: Giesen Peter , Schecter Alison , Nemerson Yale , Taubman Mark 
Published: March 2018

IntroductionThrombosis is commonly associated with arterial injury. Clinically, this is seen with all interventional procedures designed to treat coronary artery stenosis, such as percutaneous transluminal coronary angioplasty (PTCA),1 directional coronary, 1 atherectomy (DCA)2 and coronary artery stenting.3 Acute thrombosis occasionally results in total occlusion of the vessel lumen. However, more typical is the deposition of smaller nonocclusive mural thrombi.Thrombosis is also a common feature of many animal models of arterial injury.4-8 These models have provided considerable information about the molecular events associated with injury-induced thrombus formation. Platelet adherence to the injured arterial wall occurs within minutes in all models of arterial injury. In some models, platelet deposition is followed by fibrin deposition, a consequence of activation of the coagulation cascade. The presence and extent of fibrin deposition varies with the degree of injury (superficial or deep), the type of vessel (carotid, femoral, aorta, or coronary), the state of the vessel prior to injury (normal, cholesterol fed, previously injured), and the species. In the pig carotid balloon injury model, endothelial denudation in the absence of medial injury is associated with platelet deposition but no fibrin generation. More severe injury, defined by the presence of a medial tear, results in marked platelet accumulation and fibrin generation, even in the presence of high doses of heparin.4,9 Unlike the porcine model, balloon injury to normal rodent arteries is associated with rapid platelet deposition but does not result in significant fibrin deposition, even in the presence of medial injury.5-8
In contrast to that found using normal arteries, fibrin deposition is seen when previously injured rabbit arteries, possessing a neointima, are subjected to a second injury.5,7,8,10 As determined by scanning and transmission electron microscopy, abundant fibrin formation is detected within 30 minutes of the reinjury. Platelet deposition is also more dense after the second injury and associated with fibrin-platelet microthrombi. We have recently found a similar difference between single and double injury in rat aorta and carotid arteries. These studies suggest that, in contrast to the deposition of platelets, which accompanies any injury to the arterial wall, the deposition of fibrin and the formation of large thrombi are more dependent on the type of injury produced and may be regulated by specific processes occurring in the arterial wall.
Matrix Metalloproteinase System Deficiencies and Matrix Degradation
Authors: Collen D. , Lijnen H.R. 
Published: March 2018

IntroductionMatrix metalloproteinases (MMPs) constitute a tightly regulated family of enzymes that degrade most components of the extracellular matrix. They are classified based on substrate specificity. Collagenases (MMP-1, interstitial collagenase, EC 3.4.24.7; MMP-8, neutrophil collagenase, EC 3.4.24.34; MMP-13, collagenase-3) degrade connective tissue collagens. Gelatinases (MMP-2, gelatinase A, EC 3.4.24.24; MMP-9, gelatinase B, EC 3.4.24.35) degrade collagen types IV, V, VII and X, elastin, and denatured collagens. Stromelysins (MMP-3, stromelysin-1, EC 3.4.24.17; MMP-10, stromelysin-2, EC 3.4.24.22) and matrilysin (MMP-7, EC 3.4.24.23) degrade the proteoglycan core proteins, laminin, fibronectin, elastin, gelatin, and nonhelical collagen, whereas stromelysin-3 (MMP-11) does not degrade any of the major extracellular matrix components. Macrophage metalloelastase (MMP-12, EC 3.4.24.65) degrades insoluble elastin, collagen IV, fibronectin, laminin, entactin, and proteoglycans.1-7 About 20 members of the MMP family have been identified, including at least four membrane-type (MT) MMPs.8-13
MMPs are generally secreted as zymogens that are extracellularly activated by organomercurial compounds, several proteinases (including plasmin, trypsin, chymotrypsin, kallikrein, cathepsin G, or neutrophil elastase), oxygen free radicals, or by association with the cell surface.1,5,6 Active MMPs are inhibited by specific tissue inhibitors of MMPs (TIMPs) via formation of a noncovalent stoichiometric complex.5,6 Four members of the TIMP family have been identified, of which TIMP-1, synthesized by most types of connective tissue cells and by macrophages, acts against all members of the collagenase, stromelysin, and gelatinase classes.2,14,15
MMPs are mainly involved in the degradation of extracellular matrix components, but may also play a role in activation and processing of cytokines or growth factors,16 in shedding of membrane-bound receptors,17 in liberation of Fas ligand,18 or in activation of tumor necrosis factor-α.19 Degradation of extracellular matrix is required to allow cell migration and tissue remodeling, which play essential roles in many (patho)physiological processes. The role of the plasminogen/plasmin (fibrinolytic) and MMP systems in neointima formation after vascular injury, atherosclerosis, graft arterial disease, myocardial ischemia, angiogenesis, tumor growth and dissemination, infection, and chronic inflammatory disorders of the kidney, lung, gastrointestinal tract, skin, joints, or cornea has recently been reviewed.20 We will discuss some recent data on interactions between the MMP and plasminogen/plasmin systems and their role in neointima formation and atherosclerotic aneurysm formation.
Hemostatic Factors and Inflammatory Disease
Authors: Degen Jay 
Published: March 2018

IntroductionVascular integrity is preserved by a sophisticated system of circulating and cell-associated hemostatic factors that control local thrombin generation, platelet deposition, and the conversion of soluble fibrinogen to an insoluble fibrin matrix.1,2 However, there is considerable evidence that hemostatic factors play both a wider physiological role than simply controlling blood loss, and a wider pathological role than simply triggering inopportune thrombotic events, such as myocardial infarction and stroke. In tissue repair, a crucial physiological process, fibrin(ogen) is thought to provide a critical provisional matrix on which cells can proliferate, organize, and carry out specialized functions. A variety of cell types specifically bind to and migrate on fibrin(ogen) matrices. These include endothelial cells, macrophages, neutrophils, smooth muscle cells, fibroblasts, and keratinocytes.3-8 Direct binding to fibrin(ogen) through both integrin [e.g., αvβ3, α1β5, αMβ2 (CD11b/CD18, Mac-1)] and non-integrin receptors (e.g., intercellular adhesion molecule (ICAM-1)) appears to contribute to these cell-fibrin interactions.8-11 Fibrin(ogen) degradation products have also been reported to have an impressive array of biological activities, including mitogenic, angiogenic, chemotactic, and immunosuppressive activities.12-14 There are now substantial data indicating that fibrin(ogen) may plays an important role in the inflammatory response15,16 and that it may, in fact, direct leukocyte transendothelial cell migration.11 Similarly, through several G-protein coupled protease-activated receptors on fibroblasts, endothelial cells, leukocytes, smooth muscle cells, and other cell types, thrombin is thought to play an important role in inflammatory and fibroproliferative responses.17 Fibrinolytic factors, such as plasmin(ogen), also appear to be important modulators of inflammation.18 Finally, host fibrinogen, prothrombin, plasminogen, plasminogen activator, and other hemostatic factors appear to be crucial to the pathogenesis and virulence of many bacterial species.19-21 Unfortunately, despite a myriad of provocative observations made using in vitro systems, there is little direct in vivo evidence supporting an important role of fibrin(ogen) or other hemostatic factors in either the inflammatory response or disease progression. Direct and definitive analyses have been hampered by the lack of an experimental means to specifically manipulate the level or structure of selected hemostatic factors in vivo. Fortunately, this experimental roadblock has been effectively removed by the development of gene-targeting and gene transfer technologies in mice (see below).
Improvements in the Diagnostic Approach for Patients with Suspected Deep Vein Thrombosis or Pulmonary Embolism
Authors: Wells Philip , Anderson David 
Published: March 2018

IntroductionDeep vein thrombosis (DVT) and pulmonary embolism (PE), collectively known as venous thromboembolism (VTE), are common medical disorders that cause considerable morbidity and may result in fatalities if not promptly diagnosed and appropriately treated.1,2 In recent years there have been several important advances that have improved the diagnostic testing strategies for patients with suspected VTE. First, the accuracy and utility of the clinical diagnosis has been reevaluated and found to be a valuable adjunct to objective testing. Second, the fibrin degradation product, D-dimer, has been shown to be a sensitive and potentially useful test to exclude the diagnosis of VTE. Third, newer imaging modalities, such as spiral computerized tomographic angiography (spiral CT), have become available for the investigation of patients with suspected PE. Finally, diagnostic testing algorithms that rely primarily on non-invasive imaging procedures have been validated for the investigation of patients with suspected DVT and PE.The purpose of this chapter is to update the reader about recent advances and current strategies for the investigation of patients with suspected VTE. As a result of clinical trials, safe and feasible approaches for the management of patients with suspected VTE have been validated that minimize the need for invasive testing and are practical even for small centers with limited radiologic facilities.
Initial Treatment of Venous Thromboembolism
Authors: Kearon Clive 
Published: March 2018

IntroductionGoals of the initial treatment of venous thromboembolism (VTE) include the relief of symptoms and stabilization of the patient’s acute medical condition; reversal of vascular occlusion; and the prevention of recurrent VTE, including thrombus extension. The level of priority attached to achieving each of these goals depends on the severity of the patient’s presentation. For most episodes of VTE, all three goals are adequately achieved with anticoagulant therapy alone, which prevents progression of thrombosis while the patient’s endogenous fibrinolytic system gradually reverses vascular obstruction and collateral vessels develop. In a minority of patients, usually those with massive pulmonary embolism (PE) or absolute contraindications to anticoagulant therapy, additional pharmacological or mechanical measures are required to resuscitate the patient, accelerate the reversal of thrombotic occlusion, and/or prevent emboli from reaching the lungs. Anticoagulant therapy, therefore, remains the mainstay of treatment of VTE.The initial phase of anticoagulation with heparin or its derivatives serves two functions. First, it prevents recurrent VTE during the days that oral anticoagulation is being established. As the risk of recurrent VTE is highest acutely, a rapid onset of anticoagulation is a high priority.1-3 Second, this therapy functions to effectively “turn off” thrombosis acutely. Lack of, or inadequate, initial heparin therapy reduces the efficacy of the subsequent maintenance of anticoagulation with vitamin K antagonists.4-6
After providing a historical perspective, current approaches to the initial treatment of VTE will be reviewed, concentrating on recent developments and unresolved issues.
Do Interventions Provide Additional Benefit to Drug Treatment of Acute Coronary Syndromes? A Call for a Reserved, Watchful Approach
Authors: Gulba Dietrich 
Published: March 2018

IntroductionBalloon angioplasty has revolutionized clinical cardiology since its first use in coronary patients by Andreas Grünzig in 1977.1 Initially limited to single, concentric, and proximal lesions, its clinical applicability rapidly expanded to more complex stenoses and total occlusions. With equipment improvement and growing investigator experience, even the most vulnerable lesions found in patients with unstable angina or acute myocardial infarction, were soon recognized as potential targets for percutaneous interventions.2-6 The overwhelming and unquestioned success of coronary angioplasty is most prominently demonstrated by the estimated more than 1,000,000 procedures that will be performed worldwide during 1999.There is little doubt that, in patients with severe coronary lesions and exercise-induced angina, coronary angioplasty with minimal invasiveness can widen the vessel lumen and initiate coronary remodeling. This will lead, in many cases, to a durable relief from angina symptoms, as reviewed elsewhere.7 However, though vigorously advocated by interventional cardiologists, the benefit of percutaneous revascularization procedures in patients with acute coronary syndromes is less clear. This is even reflected in the AHCPR Clinical Practice Guidelines,
8 in which both conservative medical management and early invasive therapies are regarded as suitable alternatives in most patients. This chapter will address the question of whether and when coronary angioplasty will add to the benefits of conservative drug treatment.
Historical Perspectives on Thrombolytic Therapy
Authors: van de Loo Jürgen 
Published: March 2018

IntroductionRetrospectives may result in regret over missed opportunities, in grudging acknowledgment of the success of a scientific rival, anger or bemusement about one’s own mistakes, or just plain pride in achievement. Quite apart from these personal implications, it is fascinating to note how a particular medical field has developed, to identify which forces pushed it ahead or slowed it down, to recognize how political and economic influences affected the outcome, and to reflect on the roles that the personalities of responsible scientists played in the process.I would like to comment on the development of basic research on the fibrinolytic system as a prelude to its clinical application, the role of the pharmaceutical industry in producing acceptable drugs, the debate about the pathogenic role of coronary thrombosis in acute coronary syndromes, and finally, on the acceptance and nonacceptance among cardiologists during the infancy and adolescence of the discipline.
Heparin-induced Thrombocytopenia: Yet Another Treatment Paradox?
Authors: Warkentin Theodore 
Published: March 2018

SummaryFew topics in medicine rival heparin-induced thrombocytopenia (HIT) for the unexpected twists and turns enough to rival the plot of many a mystery novel. The underlying theme- anticoagulant-induced thrombosis- seems improbable, but is well-established: despite thrombocytopenia, patients rarely bleed spontaneously or even exhibit petechiae (1); rather, thrombosis develops in 30-75% of patients with HIT, depending upon the clinical situation, and in proportions far greater than expected based on the original reason for receiving heparin (2-4).But even beyond this fundamental contradiction, there exists for the unwary and uninformed practitioner several counterintuitive treatment paradoxes. One is the dichotomous nature of low-molecular-weight heparin (LMWH) respecting prevention and treatment of HIT. LMWH is far less likely to cause HIT than standard, unfractionated heparin (4, 5). Yet, for the patient with acute HIT caused by unfractionated heparin, LMWH is contraindicated (6, 7). The reason: LMWH preparations contain some heparin molecules with 12 or greater saccharide units, which are sufficiently long to bind platelet factor 4 (PF4), creating the multimolecular complexes bearing the HIT antigens. Consequently, ongoing platelet activation, thrombocytopenia, and thrombosis occur in many patients so treated (8).
A Novel Monoclonal Antibody against the Extracellular Domain of GPIbβ Modulates vWF Mediated Platelet Adhesion
Authors: Perrault Christelle , Moog Sylvie , Rubinstein Eric , Santer Martine , Baas Marie-Jeanne , de la Salle Corinne , Ravanat Catherine , Dambach Josiane , Freund Monique , Santoso Sentot , Cazenave Jean-Pierre , Lanza François 
Published: March 2018

SummaryGPIb is disulfide-linked to GPIbα to form GPIb, a platelet receptor for von Willebrand factor (vWF). GPIb is in turn non covalently linked to GPIX and GPV to form the GPIb/V/IX complex. Apart from its contribution to controlling surface expression of the complex, the exact function of GPIbβ is not well established due to a lack of suitable ligands or antibodies. The present report describes a monoclonal antibody (RAM.1) that labeled the 26 kDa GPIbβ subunit on western blots and coprecipitated the three subunits of the GPIb/IX complex from lysates of platelets and transfected CHO and K562 cells. RAM.1 bound to GPIbβ deleted of its intracellular domain whereas Gi27, directed against intracellular GPIbβ, did not. Using synthetic peptides, the RAM.1 epitope was mapped to a putative cysteine loop within the COOH-terminal leucine-rich flanking region. In functional assays, RAM.1 had no effect on platelet aggregation induced by ADP, collagen or thrombin, but inhibited ristocetin induced platelet agglutination and botrocetin induced vWF binding. RAM.1 inhibited adhesion of GPIb/V/IX transfected K562 cells to a vWF matrix under flow, increased their rolling velocity and decreased the resistance of cells to detachment at high shear. This study suggests a role of GPIbβ in modulating the adhesive properties of GPIb/V/IX and describes a useful tool to analyze the exact functions of GPIbβ.
A Sensitive Immunochemical Assay for Measuring the Concentration of the Activated Protein C-protein C Inhibitor Complex in Plasma:
Authors: Knebel Richard , Lilja Hans , Strandberg Karin , Kjellberg Margareta , Stenflo Johan 
Published: March 2018

SummaryActivated protein C (APC) is a serine proteinase that regulates blood coagulation. In plasma it is inhibited mainly by the protein C inhibitor (PCI). The plasma concentrations of APC-PCI complex is increased in hypercoagulative states such as deep venous thrombosis. Formation of the APC-PCI complex induces a drastic conformational change in PCI that exposes new epitopes (neoepitopes) on the molecule. We have devised a simple immunofluorometric sandwich assay for measurements of the concentrations of APC-PCI complex, employing as the catcher, a monoclonal antibody that has a high affinity (KD ≈ 4 × 10-11M) for a complexation-specific neoepitope that is expressed on PCI. A monoclonal antibody against protein C is employed as the tracer. The method gives a linear dose-response curve (0.06-50 πg/l), has a low detection limit (0.06 πg/l) and no crossreactivity with native PCI at physiologic plasma concentrations. We have now determined the concentration of the APC-PCI complex in healthy individuals.
Apoptosis as a Determinant of Atherothrombosis
Authors: Mallat Ziad , Tedgui Alain 
Published: March 2018

SummaryClinical manifestations of atherosclerosis are the consequences of atherosclerotic plaque rupture that triggers thrombus formation. Tissue factor (TF) is a key element in the initiation of the coagulation cascade and is crucial in thrombus formation following plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), an anionic phospholipid that is redistributed on the cell surface during apoptotic death conferring a potent procoagulant activity to the apoptotic cell. Apoptosis occurs in the human atherosclerotic plaque and shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within the lipid core. These microparticles carry almost all TF activity and are responsible for the procoagulant activity of the plaque. Moreover, luminal endothelial cell apoptosis might be responsible for thrombus formation on eroded plaques without rupture. Apoptosis might also play a major role in blood thrombogenicity via circulating procoagulant microparticles that are found at high levels in patients with acute coronary syndromes.