bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role of Plasminogen in Atherosclerosis and Restenosis Models in Mice
Authors: Ploplis Victoria A. , Busuttil Steven , Carmeliet Peter , Collen Desire , Plow Edward F. 
Published: March 2018

SummaryIn addition to its preeminent role in fibrinolysis, the plasminogen system is believed to play a key role in mediating cell migration. Leukocyte migration into the vessel wall is a key and early event in the development of the lesions of atherosclerosis and restenosis, pathologies which may be viewed as specific examples of vascular inflammatory responses. The development of mice in which the plasminogen gene has been inactivated affords an opportunity to test the contribution of plasminogen in leukocyte migration during in vivo. This article summarizes recent studies conducted in murine models of the inflammatory repsonse, restenosis and atherosclerosis in which leukocyte migration, and in particular monocyte/macrophage migration, has been evaluated in plasminogen-deficient mice. Recruitment of these cells through the vessel wall in inflammatory response models and into the vessel wall in restenosis and transplant atherosclerosis models is substantially blunted. These data implicate plasminogen in the migration of leukocytes in these murine models. With the numerous correlations between components and/or activation of the plasminogen system in restenosis and atherosclerosis, these results also support a role of plasminogen in the corresponding human pathologies.
Plasminogen Activator Inhibitor Type-1 (PAI-1) and its Role in Cardiovascular Disease
Authors: Peter Karlheinz , Ruef Johannes , Kübler Wolfgang , Bode Christoph , Nordt Thomas K. 
Published: March 2018

SummaryCardiovascular disease is responsible for approximately 50% of total mortality in Europe, the USA and Japan (1). Established risk factors including smoking, hypercholesterolemia, and hypertension explain about half of the incidence of cardiovascular disease only (2). Reduced endogenous fibrinolytic activity secondary to increased plasma activity of plasminogen activator inhibitor type-1 (PAI-1) is now considered as a new cardiovascular risk factor. In this review, evidence is gathered for the notion that PAI-1 constitutes a predictor of cardiovascular disease and also contributes to the development of cardiovascular disease as a pathogenetic factor. The review will focus on experimental studies modulating PAI-1 activity and clinical studies addressing coronary heart disease, myocardial infarction, restenosis after coronary angioplasty, and graft occlusion after coronary artery bypass grafting.
Structure and Function of the Urokinase Receptor
Authors: Resnati Massimo , Mondino Anna , Blasi Francesco 
Published: March 2018

SummaryThe binding of the urokinase plasminogen activator (uPA) to its receptor (uPAR) regulates cell adhesion, surface proteolysis, chemotaxis and cell extravasation in a number of experimental systems. Recent evidences have suggested that uPAR can by itself mediate chemotaxis of human monocytes and cause profound changes in cytoskeletal organization indicating that this receptor has the properties of a cell-surface regulated chemokine. Indeed, it is likely that upon binding to uPA, uPAR undergoes a conformational change that uncovers a new epitope located in the linker region between domain 1 and 2 of the receptor and is endowed with a potent chemotactic activity. This conformational change can be mimicked in vitro by enzymatic processing of a recombinant receptor. We have shown that chymotrypsin cleaves uPAR between domain 1 and 2 in an area that can be also cleaved by uPA at high efficiency and generate a receptor that can mediate monocytes migration independently of uPA binding. This mechanism is pertussis-toxin sensitive and involves activation of tyrosine kinases and cytoskeletal reorganization events in vitro. These studies indicate that in addition to its receptor function, upon binding to uPA, uPAR becomes a pleiotropic ligand for other still to be identified surface molecules.
Treatment of Ischaemic Stroke
Authors: Einhäupl K. , Masuhr F. 
Published: March 2018

SummaryStroke is a neurological emergency that requires rapid diagnostic workup and immediate treatment. Basic medical management such as maintenance of a high level of systemic blood pressure, provision of an optimal supply of oxygen, and correction of hyperthermia, hyperglycaemia and hypovolemia can contribute to a more favourable clinical outcome of stroke patients. Neuroprotective drugs have shown to be effective in reducing cerebral infarct size in several animal species but their clinical benefit in stroke patients remains to be proven. Neither heparin nor aspirin can improve neurological outcome or significantly reduce death or dependency several months after the ischaemic event, but aspirin is clearly effective in reducing early death or stroke recurrence within the first few weeks. Early anticoagulation should be used for patients at high risk for recurrent cardioembolic stroke and with carotid or vertebral artery dissection, although this recommendation is not based on the results of randomised controlled trials.
Pharmacokinetics and Pharmacodynamics of Lanoteplase (n-PA)
Authors: Moser Martin , Kohler Benedikt , Kübler Wolfgang , Bode Christoph , Nordt Thomas K. 
Published: March 2018

SummaryIn acute myocardial infarction rapid, complete, and sustained reperfusion of the infarct-related coronary artery is the most important therapeutic principle. Lanoteplase or n-PA, a third-generation plasminogen activator consisting of a deletion and point mutant of tissue-type plasminogen activator (t-PA), is a promising agent to appraoch this therapeutic goal. The molecule exhibits an increased plasma half-life allowing single-bolus administration. In this article, after characterizing the n-PA molecule, the currently available pharmacokinetic and pharmacodynamic data including the results of the InTIME study are reviewed.
Anticoagulation after Artificial Valve Replacement with or without Atrial Fibrillation: How Much Is Really Needed?
Authors: Verheugt Freek W. A. 
Published: March 2018

SummaryInsertion of a mechanical artificial heart valve is an absolute indication for the use of lifelong oral anticoagulation, irrespective the presence or absence of atrial fibrillation. Depending on the type and position of the artificial valve the optimal International Normalized Ratio (INR) for these patients is between 2.5 and 4.5, although more prospective studies on the optimal range of oral anticoagulation are necessary. Addition of low dose antiplatelet therapy may further decrease the rate of thromboembolism, but also here more studies are needed. Patients with a bioprosthesis need only oral anticoagulation for the first three months following surgery in the absence of an indication for anticoagulation for other conditions.Atrial fibrillation is often seen in patients with artificial heart valves. Stroke prevention can be instituted by the mandatory oral anticoagulant therapy. The presence of atrial fibrillation and the use of oral anticoagulation prior to heart valve surgery support the indication for the insertion of a mechanical artificial heart valve. However, relative contraindications to oral anticoagulation and the presence of sinus rhythm may favor the use of a bioprosthesis.
Platelet Glycoprotein IIb/IIIa Receptor Blockade: Lessening the Risk of Coronary Interventions
Authors: Pitts William R. , Lange Richard A. 
Published: March 2018

SummaryFor the patient undergoing percutaneous coronary intervention, the administration of a platelet glycoprotein IIb/IIIa receptor blocker reduces the incidence of a periprocedural nonfatal myocardial infarction and the need for unplanned emergency stenting. In the diabetic patient undergoing intracoronary stenting, the use of a platelet glycoprotein IIb/IIIa receptor blocker appears to decrease the need for subsequent target vessel revascularization. There is considerable evidence in support of the use of glycoprotein IIb/IIIa receptor inhibitors in all categories of patients – “high-risk” patients, “low-risk” patients, and those undergoing primary angioplasty for acute myocardial infarction – and for the full armamentarium of percutaneous procedures (angioplasty, directional atherectomy, rotational atherectomy, and intracoronary stenting).
Low-molecular Weight Heparins in Venous and Arterial Thrombotic Disease
Authors: Hettiarachchi Rohan , Peters Ron , Prins Martin H. , Levi Marcel , Büller Harry R. , Bijsterveld Nick R. 
Published: March 2018

Summary
Introduction: Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolims, myocardial infarction, unstable coronary syndromes and ischemic stroke.
Methods: A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated.
Results: Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively.
Conclusion: Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.
Prevention of Restenosis after Percutaneous Coronary Interventions: The Medical Approach
Authors: Tocchi Monica , Patterson Cam , Rosanio Salvatore , Runge Marschall S. 
Published: March 2018

SummaryRestenosis following successful percutaneous coronary revascularization continues to represent a major problem limiting the clinical efficacy of this procedure. The underlying mechanisms of restenosis are comprised of a combination of effects from vessel recoil, negative vascular remodeling, thrombus formation and neointimal hyperplasia. Indeed, there are important interactions among all of these mechanisms. For example, neointimal hyperplasia is stimulated by growth factors, which are released by local thrombi and the injured arterial segment itself, and act to enhance the expression of other growth-regulating proteins, in particular “second messengers“, proto-oncogenes and other cell cycle controlling proteins. This results in an inflammatory and myofibroproliferative response, which may worsen vessel narrowing caused by recoil and result in the formation of a clinically significant restenotic lesion.A multitude of pharmacologic trials have been conducted in an attempt to prevent restenosis, but most have demonstrated little benefit. Studies in smaller numbers of patients have suggested a potential benefit for several classes of agents, including: 1) the antiproliferatives, angiopeptin, trapidil and tranilast; 2) selective elimination or alteration of proliferating cells; 3) enhancement of natural growth inhibitors; and 4) signal transduction blockade or inhibition of the gene expression for various growth-stimulating proteins. Finally, there have been advances in related areas, including development of antithrombotic catheters, novel polymers, and more efficient methods for transferring genes into the vessel wall. All of these offer the possibility of delivering agents (drugs, genes, or antisense oligonucleotides) locally at the site of intervention in a way that may optimize antiproliferative effects while minimizing systemic effects – ultimately leading to a more specific inhibition of the restenosis process.
Stents for the Treatment of Aortic Aneurysms
Authors: Ebert D. , Langer M. , Uhrmeister P. 
Published: March 2018

SummaryThe endovascular treatment of abdominal aortic aneurysms has generated a great deal of interest since the early 1990s, and many different devices are currently available. The procedure of endovascular repair has been evaluated in many institutions and the different devices are compared. The first results were encouraging, but complications like endoleak, dislocation or thrombosis of the graft occurred. By the available devices the stent application is only promising, if the known exclusion criteria are strictly respected. Therefore a careful preinterventional assessment of the patient by different imaging modalities is necessary. As the available results up to now are preliminary and the durability of the devices has to be controlled, multicenter studies are required to improve the devices and observe their long- term success in the exclusion of abdominal aortic aneurysms.
Coagulation Factor XIII and Cardiovascular Disease in UK Asian Patients Undergoing Coronary Angiography
Authors: Mansfield Michael , Grant Peter , Warner Darren 
Published: March 2018

SummaryPossession of the coagulation factor XIII Val34Leu (FXIIIVal34Leu) polymorphism is associated with protection against myocardial infarction (MI) in Caucasians, in the absence of features of insulin resistance. The role of this polymorphism in the UK Asian population, with its high prevalence of insulin resistance and ischaemic heart disease, is unknown. We investigated the frequency of genotypes at this polymorphism, and measures of circulating FXIII in a group of UK Asians attending for coronary angiography. Genotype at the FXIIIVal34Leu polymorphism was not associated with MI. FXIII B-subunit levels correlated with waist: hip ratio (r = 0.19, p 0.005), HbA1c (r = 0.18, p 0.05), fasting triglycerides (r = 0.21, p 0.005), total cholesterol (r = 0.29, p 0.0005) and PAI-1 antigen (r = 0.24, p 0.005). An association between FXIIIVal34Leu and FXIII cross-linking activity was confirmed in these subjects (one-way ANOVA p 0.0005). This evidence does not support the hypothesis that FXIIIVal34Leu is protective against MI in the UK Asian population. FXIII B-subunit levels are strongly linked to risk factors for cardiovascular disease, suggesting an underlying association with insulin resistance.
Hypofibrinogenemia due to Novel 316 Asp → Tyr Substitution in the Fibrinogen Bβ Chain
Authors: Wyatt Jane , May Stephen , De Caigney Susan , George Peter , Brennan Stephen 
Published: March 2018

SummaryWe investigated the molecular basis of hypofibrinogenemia in a woman with a plasma fibrinogen of 1.0 mg/mL. After sequencing the coding region and intronic boundaries of all three fibrinogen genes a single heterozygous GACTAC mutation was identified at codon 316 of the B gene. This AspTyr substitution segregated with the hypofibrinogenemia in the only other affected family member. Examination by SDS-PAGE, isoelectric focussing, reverse phase chromatography and electrospray ionisation (ESI) mass spectrometery, failed to detect expression of the new B chain in purified plasma fibrinogen. The absence of the variant chain was confirmed by ESI tryptic mapping; while the [M + 1 H] and [M + 2 H] ions of the affected peptide (MGPTELLIEMEDWK) were clearly visible at 1,692 and 847 m/z, there were no new signals (1741 or 871 m/z) that would at indicate expression of the variant in plasma. Asp 316 and itschain homologue (Asp 252) are conserved in all known species and this is the first report of a mutation at either of these. The residue appears to be critical in maintaining the structure of the five stranded sheet that forms the dominant structural feature of the D domains.
The Role of Catalytic Cleft and Exosite Residues of Factor VIIa for Complex Formation with Tissue Factor Pathway Inhibitor
Authors: Iakhiaev Alexei , Ruf Wolfram , Rao Vijaya Mohan 
Published: March 2018

SummaryThe extrinsic coagulation pathway is initiated by the binding of plasma factor VIIa (VIIa) to the cell surface receptor tissue factor (TF). Formation of the TF-VIIa complex results in allosteric activation of VIIa as well as the creation of an extended macromolecular substrate binding exosite that greatly enhances proteolytic activation of substrate factor X. The catalytic function of the TF-VIIa complex is regulated by a specific Kunitz-type inhibitor, tissue factor pathway inhibitor (TFPI). TFPI inhibition of the TF-VIIa complex was enhanced by the presence of Xa. This study investigates the relative contribution of catalytic cleft and exosite residues in VIIa for inhibitory complex formation with TFPI. VIIa protease domain residues Q176, T239 and E296 are involved in the formation of stable inhibitor complex with free TFPI. Kinetic analysis further demonstrated a predominant role of the S2’ subsite residue Q176 for the initial complex formation with TFPI. In contrast, no significant reductions in inhibition by TFPI-Xa were found for each of the mutants in complex with phospholipid reconstituted TF. However, reduced rates of inhibition of the VIIa Gla-domain (R36) and Q176 mutant by TFPI-Xa were evident when TF was solubilized by detergent micelles. These data demonstrate docking of the TFPI-Xa complex with the macromolecular substrate exosite and the catalytic cleft, in particular the S2’ subsite. The masking of the mutational effect by the presence of phospholipid shows a critical importance of Xa Gla-domain interactions in stabilizing the quaternary TF-VIIa-Xa-TFPI complex.
Novel Design of Peptides to Reverse the Anticoagulant Activities of Heparin and other Glycosaminoglycans
Authors: Gradowski Joel , San Antonio James , Martinez Jose , Schick Barbara 
Published: March 2018

SummaryPatients undergoing anticoagulation with unfractionated heparin, low molecular weight heparin, or danaparoid may experience excess bleeding which requires reversal of the anticoagulant agent. Protamine is at present the only agent available for reversal of unfractionated heparin. Protamine is not effective in patients who have received low molecular weight heparin or danaparoid. We have developed a series of peptides based on consensus heparin binding sequences (Verrecchio et al., J Biol Chem 2000; 275: 7701-7707) that are capable of neutralizing the anti-thrombin activity of unfractionated heparin in vitro, the antifactor Xa activity of unfractionated heparin, Enoxaparin (Lovenox) and danaparoid (Orgaran) in vitro and the anti-Factor Xa activity of Enoxaparin in vivo in rats. These peptides may serve as alternatives for Protamine reversal of UFH and may be useful for neutralization of enoxaparin and danaparoid in humans.
Antithrombotic Effects of Ionic and Non-ionic Contrast Media in Nonhuman Primates
Authors: Markou Christos , Chronos Nicolas , Hanson Stephen 
Published: March 2018

SummaryThromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p <0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p <0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p <0.05). Thus the three agents evaluated – ioxaglate, iohexol, and iodixanol – all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.
Region of Factor IXa Protease Domain that Interacts with Factor VIIIa: Analysis of Select Hemophilia B Mutants
Authors: Bajaj S. Paul 
Published: March 2018

IntroductionThe identification of coagulation factor IX as a substance required for blood coagulation was first established by Pavlovsky, who reported that a mixture of blood from two hemophiliacs clotted normally.1 Based on this discovery and subsequent observations,2 hemophilia was divided into two conditions-hemophilia A or factor VIII deficiency, the most prevalent condition, and hemophilia B or factor IX deficiency, a less common condition. Since then, much has been learned about the molecular and structural biology of factor IX. It is a vitamin K-dependent protein that participates in the middle phase of the intrinsic as well as the extrinsic coagulation cascade.3 The gene for factor IX consists of eight exons and seven introns, is approximately 34 kb long, and located on the long arm of the X-chromosome at band Xq27.1.4,5 The positions of the introns in the factor IX gene are essentially identical to those of the other three homologous proteins, namely, factor VII, factor X, and protein C;3 the genes for the latter three proteins, however, are not located on the X-chromosome.