bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that Adenosine Diphosphate Can Activate Adenylate Cyclase via Conversion to Adenosine in Platelet-rich Plasma Containing Magnesium
Authors: Heptinstall S. , Glenn J. R. 
Published: March 2018

SummaryWhen adenosine diphosphate (ADP) is added to hirudinized platelet-rich plasma (PRP) in which the level of platelet cAMP has been pharmacologically elevated, there is an initial rapid fall in the level of cAMP brought about by inhibition of adenylate cyclase. This may be followed by a subsequent activation of adenylate cyclase that does not occur when citrated PRP is used in place of hirudinized PRP, and is more pronounced in the presence of added Mg2+. Here we provide evidence that a) the Mg2+-dependent activation of adenylate cyclase seen in hirudinized PRP is mediated by adenosine, b) the adenosine produced synergizes with forskolin and with DN9693 to raise the level of cAMP in platelets, but not with iloprost, c) Mg2+ does not influence directly the rate or extent of cAMP production and so is more likely to influence the rate of adenosine production, and d) activation of adenylate cyclase by adenosine can lead to inhibition of platelet aggregation. ARL 66096, a P2T purinoceptor antagonist which inhibits ADP-induced platelet aggregation, prevented inhibition of adenylate cyclase by ADP. Conversely, ARL 66096 did not appear to inhibit conversion of ADP to adenosine and subsequent activation of adenylate cyclase.
Heterogeneity and Immunochemical Properties of Anti-β2-glycoprotein I Autoantibodies
Authors: Regnault V. , Hachulla E. , Darnige L. , Roussel B. , Bensa J. C. , Arvieux J. 
Published: March 2018

SummaryMost anticardiolipin antibodies (ACA) associated with antiphospholipid syndrome (APS) are directed against epitopes expressed on β2-glycoprotein I (β2GPI). Despite a good correlation between standard ACA assays and those using purified human β2GPI as the sole antigen, some sera from APS patients only react in the latter. This is indicative of heterogeneity in anti-β2GPI antibodies. To characterize their reactivity profiles, human and bovine β2GPI were immobilized on γ-irradiated plates (β2GPI-ELISA), plain polystyrene precoated with increasing cardiolipin concentrations (CL/β2GPI-ELISA), and affinity columns. Fluid-phase inhibition experiments were also carried out with both proteins. Of 56 selected sera, restricted recognition of bovine or human β2GPI occurred respectively in 10/29 IgA-positive and 9/22 IgM-positive samples, and most of the latter (8/9) were missed by the standard ACA assay, as expected from a previous study. Based on species specificity and ACA results, IgG-positive samples (53/56) were categorized into three groups: antibodies reactive to bovine β2GPI only (group I) or to bovine and human β2GPI, group II being ACA-negative, and group III being ACA-positive. The most important group, group III (n = 33) was characterized by (i) binding when β2GPI was immobilized on γ-irradiated polystyrene or cardiolipin at sufficient concentration (regardless of β2GPI density, as assessed using 125I-β2GPI); (ii) and low avidity binding to fluid-phase β2GPI (Kd in the range 10–5 M). In contrast, all six group II samples showed (i) ability to bind human and bovine β2GPI immobilized on non-irradiated plates; (ii) concentration-dependent blockade of binding by cardiolipin, suggesting epitope location in the vicinity of the phospholipid binding site on native β2GPI; (iii) and relative avidities approximately 100-fold higher than in group III. Group I patients were heterogeneous with respect to CL/β2GPI-ELISA and ACA results (6/14 scored negative), possibly reflecting antibody differences in terms of avidity and epitope specificity. Affinity fractionation of 23 sera showed the existence, in individual patients, of various combinations of antibody subsets solely reactive to human or bovine β2GPI, together with cross-species reactive subsets present in all samples with dual reactivity namely groups III and II, although the latter antibodies were poorly purified on either column. Therefore, the mode of presentation of β2GPI greatly influences its recognition by anti-β2GPI antibodies with marked inter-individual heterogeneity, in relation to ACA quantitation and, possibly, disease presentation and pathogenesis.
Abnormal Tyrosine Phosphorylation Linked to a Defective Interaction between ADP and Its Receptor on Platelets
Authors: Maclouf Jacques , Rosa Jean-Philippe , Gallet Carole , Vallès Géraldine , Nurden Paquita , Nurden Alan , Lévy-Toledano Sylviane 
Published: March 2018

SummaryADP, a primary stimulus of platelets, binds to one or more populations of receptors on the platelet surface. These receptors are linked to discrete activation pathways. Both G proteins and tyrosine kinases have been implicated in the cellular responses to this agonist. We have studied a patient with a congenital abnormality of ADP-induced platelet aggregation in an effort to gain information on the signalling pathways used by ADP. Immunoblotting with a broadly reactive rabbit antibody recognizing the GTP-binding domain of G protein α-subunits, and with rabbit antibodies specific for Giαl-3, and Gα12 all showed normal reactivity when tested against the patient‘s platelets. The phosphorylation of proteins was studied using an anti-phosphotyrosine MoAb (4G10) and platelets stimulated in a platelet aggregometer with ADP, a thromboxane A2 mimetic (IBOP), TRAP-14-mer peptide and α-thrombin. With normal platelets, a time-dependent phosphorylation of several bands in the 60 to 130 kDa mol. wt. range was observed with all agonists. For the patient, minimal aggregation and little or no phosphorylation of proteins of 80-85 kDa (cortactin), 100-105 kDa and 125-130 kDa were seen in response to ADP. The aggregation and phosphorylation responses were slightly modified in the presence of low doses of thrombin but were normal with high doses. Aggregation and tyrosine phosphorylation were virtually absent with IBOP, a finding reproduced when normal platelets were incubated with IBOP and the CP/CPK ADP scavenging system, thereby underlining the role of ADP in the response to IBOP. Our results show that the ADP receptor pathway deficient in the patient is linked to a selective tyrosine phosphorylation response.
The Antiaggregating and Antithrombotic Activity of Clopidogrel Is Potentiated by Aspirin in Several Experimental Models in the Rabbit
Authors: Dol Frédérique , Bernat André , Falotico Robert , Lalé Alain , Savi Pierre , Herbert Jean-Marc 
Published: March 2018

SummaryIt is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1–20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1–10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP‘s effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.
Control of Smooth Muscle Cell Proliferation – The Role of the Basement Membrane
Authors: Roy Joy , Tran Phan Kiet , Lundmark Karin , Rahman Adnan , Hedin Ulf 
Published: March 2018

SummaryIn atherogenesis and in response to vessel injury, arterial smooth muscle cells (SMCs) are activated from a quiescent, differentiated state into an actively proliferating and synthetic phenotype which migrate into the intima where the cells participate in the formation of a fibrous plaque or intimal hyperplasia. The mechanisms involved in the control of SMC function are not clear and no preventive therapy against SMC activation is available. Interactions between SMCs and the extracellular matrix have been shown to influence SMC structure and function through integrin-mediated signaling processes. The SMC basement membrane is a specific form of extracellular matrix which seems to be crucial for the maintenance of SMC quiesence and the disruption of these interactions is part of cellular activation after atherogenic or traumatic stimuli. This concept of “negative growth control” may constitute a future target for the development of new strategies in the prevention of SMC activation in atherogenesis and restenosis formation.
Gene Regulation and Arteriosclerosis: Are Developmental Programs Reactivated in Vascular Disease?
Authors: Patterson Cam 
Published: March 2018

SummaryThe molecular mechanisms regulating the development of vascular diseases such as atherosclerosis remain poorly understood at present. Similarities between genetic programs observed during the course of vascular disease with those observed during vascular development suggest that developmental processes are recapitulated in vascular disease. The earliest event in vascular development is the differentiation of endothelial cells from their mesodermally-derived hamangioblastic precursors. The receptor for vascular endothelial growth factor, KDR/flk-1, plays a critical role in these earliest stages of vascular development. During development and in the adult, expression of this receptor is restricted to vascular endothelial cells and their immediate precursors. We have therefore endeavored to determine the transcriptional events regulating KDR/flk-1 expression, with the hope of gaining insight into processes of vascular development that might also be important in vascular diseases of the adult.
Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) as Potential Marker of Atherosclerosis
Authors: Weirich Uta , Nordt Thomas K. , Ruef Johannes , Bode Christoph , Peter Karlheinz 
Published: March 2018

SummaryAn increasing number of descriptive reports on soluble adhesion molecules and association with various diseases are published. Throughout these reports soluble adhesion molecules are identified as markers of inflammation. Since atherosclerosis demonstrates features of a chronic inflammatory disease, a potential association of soluble adhesion molecules with atherosclerosis has been postulated. However, conflicting results have been reported. One reason for this might be the differing definitions of atherosclerosis and patient groups. Besides the definition of atherosclerosis based on clinical symptoms, few reports use a direct quantification of atherosclerosis in their search for a marker of atherosclerosis. In those reports that quantify atherosclerosis, sVCAM-1 seems to be more specific for atherosclerosis than other markers. The serum level of sVCAM-1 appears to correlate with the extent of atherosclerosis and might allow for the detection of early stages of atherosclerosis. Large scale prospective studies will have to prove that sVCAM-1 can be used as a diagnostic tool for the detection of early stages of asymptomatic atherosclerosis and whether an early therapeutic intervention based on this approach is able to prevent progression and manifestation of the clinical sequelae of atherosclerosis.
Lipid Lowering Therapy and Stabilization of Atherosclerotic Plaques
Authors: Müller-Wieland Dirk , Krone Wilhelm 
Published: March 2018

SummaryLipid-lowering therapy leads to a great reduction of cardiovascular complications, but has almost no effect on the degree of stenosis of coronary arteries. These and other studies have lead to a new paradigm of coronary artery disease, i. e. clinical prognosis is not only determined by the extent of a single stenosis, but mainly by the number and structure of atherosclerotic plaques. Rupture of an instable or vulnerable plaque, characterized by a large lipid-rich central core, inflammatory cells, and a thin fibrous cap, causes sudden thrombus formation and thereby acute coronary syndromes. There is accumulating evidence that cholesterol lowering can result in plaque stabilization and improvement of endothelial dysfunction.
Fibrinolytic Response to Venous Occlusion Compared to Physical Stress Test in Young Patients with Coronary Artery Disease
Authors: Graf Senta , Beckmann Renate , Hornykewycz Stephan , Koller-Strametz Jeanette , Binder Bernd R. , Nikfardjam Mariam , Huber Kurt 
Published: March 2018

Summary
Introduction: Venous occlusion (VO) and exercise stress (ES) are stimulators of the fibrinolytic system. Aim of this study was to answer which of both stimulation tests is more useful in patients with symptom-limited coronary artery disease (CAD) to evaluate possible defects in the fibrinolytic system.
Methods and results: We investigated 20 patients (M/F = 15/5; mean age = 36.7 years) with angiographically proven CAD for their plasma levels of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-type-1 (PAI-1) at basal conditions as well as after VO and at maximal ES (standardised bicycle stress test) and compared the data to those obtained from 12 sex- and age-matched healthy controls (M/F = 9/3; mean age = 40.4 years). At basal conditions mean t-PA activity and t-PA antigen plasma levels were within the normal range and comparable between the two study groups. After both VO and maximal ES, mean t-PA activity and t-PA antigen levels increased significantly more in the control group as compared to the CAD group. Mean PAI-1 activity plasma levels were significantly higher in the CAD group at basal conditions before VO (patients 7.0 ± 3.1; controls 3.9 ± 3.9; IU/ml; p = 0.025) as well as before ES (patients 8.1 ± 3.5; controls 4.3 ± 3.8; IU/ml; p = 0.009). PAI-1 activity plasma levels showed a significant decrease for patients and controls only after VO, while PAI-1 activity was not significantly decreased in both study groups at maximal ES.
Discussion: The significantly higher increase in mean plasma levels of t-PA activity and t-PA antigen after VO compared to ES in both groups might be explained by the fact that CAD induced symptoms in the patients during ES thus permitting only 80% of their age, sex, and body mass index related optimal work load.
Conclusion: VO and ES are applicable triggers of the endogenous fibrinolytic system in healthy subjects and patients who are not limited in their physical exercise. Standardised VO appears to be superior to ES as stimulation test of the endogenous fibrinolytic system in patients with symptomatic CAD.
Secondary Prevention of Stroke
Authors: MacWalter R. S. 
Published: March 2018

SummaryStroke is a common disorder and a leading cause of disability and death. Ischaemia is a more common cause than haemorrhage and radiological imaging is required to accurately differentiate these. Some specific risk factors for stroke are non-modifiable – these include age, gender, racial and hereditary factors. Certain risk factors for ischaemic stroke can be identified and modification of these can be used for secondary prevention – examples include hypertension, heart diseases, atrial fibrillation, diabetes mellitus, dyslipidaemia, smoking, excessive alcohol consumption and carotid stenosis. Carotid endarterectomy is valuable in selected patients. In ischaemic stroke and transient ischaemic attack antithrombotic therapy is an option used in secondary prevention. In atrial fibrillation, warfarin should be used where possible in secondary prevention. When warfarin is contraindicated aspirin should be used. In other patients, an antiplatelet regime is appropriate – aspirin is commonly used and is the least expensive regime. Other antiplatelet agents such as dipyridamole, ticlopidine and clopidogrel may have a place. Younger patients with ischaemic stroke may have a thrombophilia state and should be appropriately investigated.
Submassive and Massive Pulmonary Embolism: A Target for Thrombolytic Therapy?
Authors: Geibel Annette , Kasper Wolfgang , Konstantinides Stavros 
Published: March 2018

SummaryThrombolytic agents have been consistently demonstrated to dissolve pulmonary thrombi much more rapidly and effectively than heparin alone. Rapid resolution of pulmonary embolism (PE) is accompanied by a significant decrease in pulmonary artery pressure and an improvement in right ventricular function. However, it is no longer than 7 days until the findings of patients treated with heparin improve to a similar extent. Previous studies were not designed to determine whether this short-lasting difference in favor of thrombolysis can indeed affect the prognosis of patients with PE and thus justify the 1% (or even higher) risk of cerebral or fatal bleeding. Recently, two large registries demonstrated the importance of right ventricular dysfunction assessed by echocardiography as an independent predictor of mortality. Thrombolytic treatment was shown in one of these registries to be associated with a 50% reduction of death risk in clinically stable patients with right ventricular enlargement. It was thus possible to identify a group of patients with massive PE who are most likely to benefit from early thrombolysis. These findings now have to be confirmed by a prospective randomized trial which will compare thrombolysis with heparin alone in this high-risk patient population, focusing on clinical end points such as overall and event-free survival in the acute phase of PE.
Primary Stenting for Acute Myocardial Infarction
Authors: Yhip A. , Peter J. , Smalling Richard W. 
Published: March 2018

SummaryPrimary stenting for acute MI has been shown to be an improvement over PTCA alone. As with primary PTCA however there is an obligate delay in restoration of TIMI flow due to the time necessary for mobilization of the cath lab team. It is possible that a hybrid approach using partial thrombolysis plus early IIB/IIIA inhibitor administration followed by urgent angiography and stenting of the culprit lesion will be the ideal approach.
Fibrinolytic Variables in Patients with Recurrent Venous Thrombosis: a Prospective Cohort Study
Authors: Roberts Jeremy , Roberts Robin , Johnston Marilyn , Stevens Pamela , Skingley Peter , Patrassi G. M. , Sartori M. T. , Hirsh Jack , Prandoni Paolo , Weitz Jeffrey , Gent Michael , Ginsberg Jeffrey , Crowther Mark 
Published: March 2018

SummaryTo determine whether fibrinolytic testing predicts recurrent venous thrombosis, we have performed a prospective cohort study in which 303 patients with a first episode of venous thromboembolism underwent comprehensive fibrinolytic testing while receiving oral anticoagulants, and after anticoagulants had been discontinued. They were then followed for up to 3 years for recurrent venous thrombosis. No systematic differences in the levels or activity of type 1 plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (tPA) or euglobulin clot lysis times were detected between patients who did, or did not, suffer recurrent thrombosis. There were also no differences in these variables when patients whose initial thrombosis was idiopathic were compared to patients whose thrombosis occurred in the setting of a known thrombotic risk factor. Based on these results, neither measuring fibrinolytic parameters in patients with venous thromboembolism, nor modification of treatment based on the results of such testing, are justified. Our study also confirms that patients with idiopathic venous thromboembolism have a high risk of recurrence.
Like Fibrin, (DD)E, the Major Degradation Product of Crosslinked Fibrin, Protects Plasmin from Inhibition by α2-antiplasmin
Authors: Lee Agnes , Fredenburgh James , Stewart Ronald , Rischke Janice , Weitz Jeffrey 
Published: March 2018

SummaryPlasmin generation is localized to the fibrin surface because tissue-type plasminogen activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to fibrin is protected from inhibition by α2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting systemic activation of plasminogen. In this study we investigated whether (DD)E also protects plasmin from inhibition by α2-antiplasmin, facilitating degradation of this soluble t-PA effector. (DD)E and fibrin reduce the rate of plasmin inhibition by α2-antiplasmin by 5- and 10-fold, respectively. Kringle-dependent binding of plasmin to (DD)E and fibrin, with Kd values of 52 and 410 nM, respectively, contributes to the protective effect. When (DD)E is extensively degraded by plasmin, yielding uncomplexed fragment E and (DD), protection of plasmin from inhibition by α2-antiplasmin is attenuated. These studies indicate that (DD)E-bound plasmin, whose generation reflects the ability of (DD)E to stimulate plasminogen activation by t-PA, has the capacity to degrade (DD)E by virtue of its resistance to inhibition. This provides a mechanism to limit the concentration of (DD)E and maintain the fibrin-specificity of t-PA.
Platelets and Factor XI Bypass the Contact System of Blood Coagulation
Authors: Walsh Peter 
Published: March 2018

IntroductionFactor XI is a plasma glycoprotein (concentration ∼30 nM) that was first identified by Rosenthal et al1 as a plasma coagulation factor deficiency in patients with abnormal hemostasis, particularly common among Ashkenazi Jews.2,3 In spite of recent advances in our understanding of the structure of factor XI and its gene, the structure-function relationships of the protein, and the molecular genetics of factor XI deficiency, considerable confusion about the physiologic role and clinical relevance of factor XI has arisen from both clinical and biochemical observations. One problem arises from the fact that, until recently, the only known pathway for activation of factor XI involved proteolytic activation by factor XIIa and interactions with coagulation proteins of the contact phase of blood coagulation.4-7 The problem arose from the clinical observation that patients with deficiencies of factor XI are subject to bleeding complications, whereas patients with deficiencies of the contact proteins are not.2,3,8-13 A related unanswered question concerns the lack of correlation in many reported patients between plasma levels of factor XI and the severity of clinical bleeding manifestations.2,3,8,9,13-15 In addition, some patients with severe factor XI deficiency experience significant bleeding complications, whereas others appear to be hemostatically normal. These clinical and biochemical observations have motivated investigations focused on alternative mechanisms for activation of factor XI independent of contact phase protein.19-22 Additional studies have focused on the identification and characterization of platelet factor XI, which is postulated to be an alternative splicing product of the factor XI gene. Platelet factor XI is present in platelet membranes and might substitute for plasma factor XI in hemostasis and account for the absence of bleeding complications in some patients with severe plasma factor XI deficiency.14,16-18,23-26 Studies addressing these two important and related problems are presented and discussed in this chapter.