bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Fraction of Circulating Activated Platelets in Acute and Previous Cerebrovascular Ischemia
Authors: Ruf Andreas , Vogt Axel , Lichy Christoph , Buggle Florian , Patscheke Heinrich , Hacke Werner , Grau Armin 
Published: March 2018

SummaryDetermination of circulating activated platelets may be helpful to estimate the prognosis and to stratify therapies in arterial vascular disorders including stroke. We used flow cytometry and phase contrast microscopy to study whether the fraction of platelets expressing p-selectin and CD63 and the fraction of platelets with shape change are increased in patients with acute and previous cerebrovascular ischemia.The proportion of platelets expressing activation dependent antigens was higher in patients with acute (n = 24; p-selectin: 8.23 ± 4.21%; CD63: 3.53 ± 2.53%) and with previous cerebrovascular ischemia (n = 46; 3.86 ± 1.98%; 2.80 ± 1.79%) as compared to age- and sex-matched control subjects (n = 35; 2.17 ± 0.96%; 1.79 ± 0.75%; p ≤0.005, respectively). In patients with previous ischemia, there was no difference between treatment with aspirin (n = 25) or phenprocoumon (n = 21). Hypertension, diabetes mellitus and smoking were not associated with increased antigen expression (analysis of variance). The fraction of discoid platelets and platelet counts were not significantly different between groups.Our results indicate increased expression of platelet neoantigens in acute and to a less degree in previous cerebrovascular ischemia. Ongoing platelet activation after cerebrovascular ischemia despite therapy with aspirin or phenprocoumon indicates that new anti-platelet drugs may be of benefit for these patients. Flow cytometry appears to be a useful tool to assess platelet function in cerebrovascular ischemia.
Coronary Artery Disease and Fibrinolysis: From the Blood to the Vessel Wall
Authors: Sobel Burton E. 
Published: March 2018

SummaryThis review addresses a continuum of the role of derangements in the fibrinolytic system from the blood to the vessel wall in the pathogenesis of acute coronary events and the underlying vasculopathy. Pharmacologic modification of fibrinolysis has become a primary therapy for acute myocardial infarction caused by thrombotic occlusion of infarct-related coronary arteries. Patients with type 2 diabetes and other insulin resistant states exhibit impaired fibrinolysis in blood, implicated in the pathogenesis of macroangiopathy. An altered balance of activity of proteins involved in the fibrinolytic system within vessel walls (the proteo[fibrino]lytic system) has been recognized as well and appears likely to contribute to the acceleration of macroangiopathy. Accordingly, normalization of the proteo(fibrino)lytic system in blood and in vessel walls is a particularly attractive target for retardation of the progression of macrovascular disease associated with insulin resistant states.
Oxidative Stress and Atherosclerosis: Its Relationship to Growth Factors, Thrombus Formation and Therapeutic Approaches
Authors: Peter Karlheinz , Kübler Wolfgang , Ruef Johannes , Nordt Thomas K. , Runge Marschall S. , Bode Christoph 
Published: March 2018

SummaryThe initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.
Angiogenesis in Ischemic Disease
Authors: Risau Werner , Marti Hugo H. 
Published: March 2018

SummaryAngiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.5 and 12.5. In addition, VEGF and its receptors are also critically involved in the regulation of pathological blood vessel growth in the adult during various angiogenesis-dependent diseases that are associated with tissue hypoxia, such as solid tumor growth and ischemic diseases. It is now well established that therapeutic angiogenesis can be achieved in animal models of hind limb and myocardial ischemia by exogenously adding VEGF and/or other angiogenic growth factors. Available clinical data from human trials also suggests that patients with severe cardiovascular diseases could potentially benefit from such therapies. However, much more work needs to be done to compare the potency of different angiogenic factors or the combination thereof, as well as the best way of delivery, either as recombinant proteins, as naked DNA or via adenoviral vectors. Nevertheless, the therapeutic efficacy of simply injecting naked plasmid DNA or proteins into ischemic tissue to deliver secreted angiogenic factors is an encouraging finding. Time will show whether the adverse side effects of therapeutic angiogenesis, mainly vascular permeability and edema formation, can be minimized and angiogenic factors can be used as an effective therapy in patients for the treatment of ischemic diseases such as arterial occlusive disease, myocardial infarction, and, eventually, also stroke.
Unstable Angina in 1998
Authors: Lichtlen P. R. 
Published: March 2018

SummaryUnstable angina (UA) and non-Q-wave myocardial infarction (NQWMI) are acute coronary syndromes with repeated, severe ischemic events of short duration. These events are mainly due to a rapid decrease
in coronary blood flow, and to a rapid, reversible reduction of the arterial lumen in localized areas. Episodes often are a mixture of thrombus formation due to platelet aggregation and localized spasm, leading to vasoconstriction. Due to the short interval (minutes) of ischemic events, usually no or minimal irreversible myocardial damage takes place.The main goal of treatment is to prevent progression of this unstable situtation into a myocardial infarction. In the majority of cases, this is possible with adequate treatment of vasodilatory substances like nitrates, long-acting dihydropyridines like amlodipine and betablockers. In addition heparin and particular antiaggregatory drugs inhibiting platelet activation by blocking the GPIIb/IIIa receptor, the common pathway for platelet aggregation, are applied to prevent thrombus formation. This, in the majority of cases allows a passivation of the acute situtation, leaving time to undertake possible further steps as coronary angiography, eventually followed by PTCA of the culprit lesion or, in advanced cases of CAD, by CABG with complete revascularization.
Acute Myocardial Infarction: Selection of Reperfusion Strategies in the Individual Patient
Authors: Senges Jochen , Schiele Rudolf 
Published: March 2018

SummaryThe selection of the reperfusion therapy (thrombolysis, PTCA, or no reperfusion) in acute myocardial infarction should depend on the riskbenefit ratio, the availability, and the costs. Thrombolysis is available everywhere and is the standard of reperfusion therapy, but carries the risk of intracranial haemorrhage. PTCA is more effective with less risk, but it is also more expensive and available only in specialised centres. In current clinical practise in Germany, the only important determinant for using PTCA as a reperfusion strategy is the availability of a catheter laboratory. Besides availabilty, the selection of reperfusion therapy should be made more on clinical relevance: (i) PTCA especially in patients with a large benefit, the presence of contraindications to thrombolysis, or in cardiogenic shock, and (ii) thrombolysis, if PTCA is not immediately available.
Vectorcardiography: A Tool for Non-invasive Detection of Reperfusion and Reocclusion?
Authors: Eriksson Sven V. 
Published: March 2018

SummaryIn acute myocardial infarction, the perfusion status frequently fluctuates with rapid occurrences of coronary occlusion followed by myocardial ischemia. In patients with unstable angina, most episodes of ischemia are not accompanied by chest pain. In these patients it is important to be able to monitor the results of medical treatment non-invasively to establish the need for further intervention. It is not feasible to perform coronary angiography in all patients with acute myocardial infarction to evaluate patency of the infarct-related artery. Furthermore, even in a patent artery, no reflow may be present in the myocardial tissue. Angiography is therefore not the perfect golden standard to compare noninvasive ischemia monitoring with. Prognosis seems to be a better standard for comparison. This review indicates that vectorcardiography monitoring may identify myocardial reperfusion at an early
stage and gives valuable prognostic information both in patients with unstable angina and acute myocardial infarction with low interobserver variability.
Ventricular Remodeling after Acute Myocardial Infarction
Authors: Osterziel K. J. , Willenbrock R. , Gulba D. C. , Harsdorf R. v. , Dietz R. 
Published: March 2018

SummaryThe term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts.We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue – probably due to metalloproteinase activation – could be the initial event.As a consequence, wall stress is increased triggering deleterious adaptation processes, such as– intracardiac angiotensin II generation– cardiac endothelin formation and release– pro-apoptotic signals for cardiomyocytes– hypertrophic signals for fibroblasts and cardiomyocytesThis cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure.Therapeutic principles therefore are similar in both conditions:– reduction of wall stress (pharmacological or mechanical unloading of the heart)– blockade of angiotensin II generation or of AT1-receptors (ACEinhibitors or AT1 antagonists)– blockade of endothelin receptors (ETA-blockers)– blockade of adrenergic receptors (preferably β1-adrenergic receptor blockers).Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.
Activation Markers of Coagulation and Fibrinolysis: Alterations and Predictive Value in Acute Coronary Syndromes
Authors: Heller Wolfgang , Seipel Ludger , Hoffmeister Hans Martin 
Published: March 2018

SummarySeveral alterations of the coagulation, of the fibrinolysis and of inflammation are known in patients with acute coronary syndromes. To extent current knowledge of the pathopysiology and to optimize therapeutical strategies, the new molecular markers can be used in clinical studies. Furthermore, several studies were undertaken to assess the prognostic value of activation markers of these systems for patients with unstable angina pectoris and acute myocardial infarction with or without thrombolytic therapy. The majority of studies focussed on markers of thrombin activation, fibrinogen, fibrin degradation products and t-PA and its main inhibitor PAI-1. While there are stimulating results from larger studies, the value for prognosis for the individual patient still is limited by the overlap of patients with good versus a poor outcome.
Oral Anticoagulation after a First Episode of Venous Thromboembolism: How Long? How Strong?
Authors: Watzke H. H. 
Published: March 2018

SummaryA number of studies have been published in the last years which shed light on the optimal intensity and the optimal duration of oral anticoagulation in patients with venous thrombosis.Based on these studies it is now generally recommended to treat patients with venous thromboembolism at an INR ranging from 2.0 to 3.0. The optimal duration of anticoagulation mainly depends on the nature of the thrombotic event. In patients with a temporary prothrombotic risk factor such as surgery, immobilization or trauma a relatively short duration of oral anticoagulation (3-6 months) is generally recommended. Patients with idiopathic venous thromboembolism require a considerably longer duration of anticoagulation (6 months at least).
Platelet Function Inhibitors in the Year 2000
Authors: Mousa Shaker , Bennett Joel 
Published: March 2018

SummaryPlatelet thrombi are responsible for much of the morbidity and mortality of arterial vascular disease (1). Because platelet inhibitors such as aspirin have proven to be of benefit to patients with these disorders, there has been a directed search for more potent anti-platelet agents. The following discussion addresses the mechanism of action and clinical utility of the currently available platelet function inhibitors. Although in theory these agents could impair platelet adhesion, aggregation, secretion, or platelet procoagulant activity, in practice they are focused almost exclusively on the biochemical events that proceed from platelet stimulation to ligand binding to the platelet fibrinogen receptor GPIIb-IIIa.
The Incidence of Deep Venous Thrombosis and Pulmonary Embolism among Patients with Inflammatory Bowel Disease: A Population-based Cohort Study
Authors: Blanchard James , Houston Donald , Wajda Andre , Bernstein Charles 
Published: March 2018

Summary
Background: There is an impression mostly from specialty clinics that patients with inflammatory bowel disease (IBD) have an increased risk of venous thromboembolic disorders. Our aim was to determine the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) from a population-based database of IBD patients and, to compare the incidence rates to that of an age, gender and geographically matched population control group.
Methods: IBD patients identified from the administrative claims data of the universal provincial insurance plan of Manitoba were matched 1:10 to randomly selected members of the general population without IBD by year, age, gender, and postal area of residence using Manitoba Health’s population registry. The incidence of hospitalization for DVT and PE was calculated from hospital discharge abstracts using ICD-9-CM codes 451.1, 453.x for DVT and 415.1x for PE. Rates were calculated based on person-years of follow-up for 1984-1997. Comparisons to the population cohort yielded age-adjusted incidence rate ratios (IRR). Rates were calculated based on person-years of follow-up (Crohn’s disease = 21,340, ulcerative colitis = 19,665) for 1984-1997.
Results: In Crohn’s disease the incidence rate of DVT was 31.4/10,000 person-years and of PE was 10.3/10,000 person-years. In ulcerative colitis the incidence rates were 30.0/10,000 person-years for DVT and 19.8/10,000 person-years for PE. The IRR was 4.7 (95% CI, 3.5-6.3) for DVT and 2.9 (1.8-4.7) for PE in Crohn’s disease and 2.8 (2.1-3.7) for DVT and 3.6 (2.5-5.2) for PE, in ulcerative colitis. There were no gender differences for IRR. The highest rates of DVT and PE were seen among patients over 60 years old; however the highest IRR for these events were among patients less than 40 years.
Conclusion: IBD patients have a threefold increased risk of developing DVT or PE.
Interpreting the International Normalized Ratio (INR) in Individuals Receiving Argatroban and Warfarin
Authors: DiCicco R.A. , Hursting M.J. , Montague T. , Jorkasky D.K. , Sheth S.B. 
Published: March 2018

SummaryThe effects of argatroban, a direct thrombin inhibitor, on the International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) and functional factor X during warfarin co-administration were established to provide means to interpret INRs during argatroban/warfarin co-therapy. Twenty-four subjects receiving warfarin (7.5 mg, day 1; 3-6 mg/day, days 2-10) and argatroban (1-4 μg/kg/min over 5 h, days 1-11) were assessed daily for these coagulation parameters prior to argatroban infusion (warfarin “monotherapy”) and at its conclusion (“co-therapy”). Argatroban increased aPTTs dose-dependently. Co-therapy INR increased linearly with monotherapy INR, with slope sensitive to argatroban dose and thromboplastin used. Prediction errors for monotherapy INRs were ≤± 0.4 for argatroban 1-2 μg/kg/min but ≥± 1.0 for higher doses. Despite co-therapy INRs >7, no major bleeding occurred. Factor X remained ≥37% of normal. Therefore, the predictable effect of argatroban (≤ 2 mg/kg/min only) on INRs during warfarin co-therapy allows for reliable prediction of the level of oral anticoagulation.
Rho-kinase Is Involved in the Sustained Phosphorylation of Myosin and the Irreversible Platelet Aggregation Induced by PAR1 Activating Peptide
Authors: Missy K. , Plantavid M. , Viala C. , Chap H. , Pacaud P. , Payrastre B. 
Published: March 2018

SummaryWe have addressed the role of Rho-kinase in the different steps of thrombin receptor agonist peptide (TRAP) -induced platelet activation. Interestingly, under physiological conditions, incubation of platelets with increasing concentrations of the specific Rho-kinase inhibitor Y-27632 resulted in a dose-dependent reversion of the aggregation induced by 10 μM TRAP, without affecting serotonin secretion. Addition of Y-27632 after three minutes of TRAP stimulation, when the maximal aggregation was reached, resulted in a rapid disaggregation of platelets. Accordingly, the early peak of myosin light chain (MLC) phosphorylation induced by TRAP was not affected by Y-27632 but its sustained phosphorylation, observed during the irreversible phase of aggregation, was dependent of Rho-kinase activity. The rapid decrease in MLC phosphorylation upon Y-27632 treatment correlated well with the specific disappearance of myosin heavy chain from the cytoskeleton and preceded platelet disaggregation. Finally, we provide evidence that secreted ADP, known to play a key role in TRAP-induced irreversible phase of aggregation, was involved in the sustained MLC phosphorylation through Rho-kinase and could be replaced by epinephrine.
Regulation of Factor VIIIa in the Intrinsic Factor Xase
Authors: Fay Philip 
Published: March 2018

IntroductionHemophilia A, the most common of the severe, inherited bleeding disorders, results from a deficiency or defect in the plasma protein factor VIII. The activated form of the protein serves as an essential cofactor for factor IXa in the conversion of factor X to factor Xa. This surface-bound complex of enzyme and cofactor is referred to as the intrinsic factor Xase. Factor VIIIa dramatically increases the catalytic rate constant for substrate conversion by an unclear mechanism. The activity and stability of the factor Xase appears to be regulated by the integrity of the cofactor. Factor VIIIa possesses a labile structure, and subunit dissociation results in the decay of Xase activity. Furthermore, factor VIIIa is a substrate for proteolytic inactivation by several enzymes, including factor IXa, the enzyme for which it serves as a cofactor. Although interest in the structure, function, and metabolism of factor VIII is commensurate with its biochemical and clinical importance, the molecular basis for its role in coagulation and the regulation of function through complex intramolecular and intermolecular interactions remain poorly understood.
Mechanisms of Signaling through Urokinase Receptor and the Cellular Response
Authors: Koshelnick Yuri , Ehart Monika , Stockinger Hannes , Binder Bernd 
Published: March 2018

IntroductionThe urokinase-urokinase receptor (u-PA-u-PAR) system seems to play a crucial role in a number of biological processes, including local fibrinolysis, tumor invasion, angiogenesis, neointima and atherosclerotic plaque formation, inflammation, and matrix remodeling during wound healing and development.1-6 Binding of urokinase to its specific receptor provides cells with a localized proteolytic potential. It stimulates conversion of cell surface-bound plasminogen into active plasmin, which, in turn, is required for proteolytic degradation of basement membrane components, including fibronectin, collagen, laminin, and proteoglycan core proteins.7 Moreover, plasmin activates other matrix-degrading enzymes, such as matrix metalloproteinases.8 Overexpression of u-PA/u-PAR correlates with tumor invasion and metastasis formation,9-13 while reduction of cell-surface bound u-PA and inhibition of u-PAR expression leads to a significant decrease of invasive and metastatic activity.14 Specific antagonists that suppress binding of u-PA to u-PAR have been shown to inhibit cell-surface plasminogen activation, tumor growth, and angiogenesis both in vitro and in vivo models.15,16
Independently of its proteolytic activity, u-PA is implicated in many biological processes that seem to require u-PAR-mediated intracellular signal transduction, such as proliferation, chemotactic movement and adhesion, migration, and differentiation.17 Data obtained in the late 1980s indicated that u-PA not only provides cells with local proteolytic activity, but might also be capable of transducing signals to the cell.18-22 At that time, however, the u-PAR has just been isolated, cloned, and identified as a glycosylphosphatidylinositol (GPI)-linked protein and not a transmembrane protein. Signaling via the u-PAR was, therefore, regarded as being unlikely, and the effects of u-PA on cell proliferation18-22 were thought to be mediated by proteolytic activation of latent growth factors. The assumption of direct signaling via u-PAR was, in fact, considered controversial, until about 10 years later when a physical association between u-PAR and signaling proteins was found.23 From this report on, several proteins associated with u-PAR have been identified. Now, u-PAR seems to be part of a large “signalosome” associated and interacting with several proteins on both the outside and inside of the cell.