bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unbalanced Effects of Dermatan Sulfates with Different Sulfation Patterns on Coagulation, Thrombosis and Bleeding
Authors: Vicente C. P. , Zancan P. , Peixoto L. L. , Alves-Sá R. , Araújo F. S. , Mourão P. A. S. , Pavão M. S. G. 
Published: March 2018

SummaryWe compared the anticoagulant, antithrombotic and bleeding effects of highly sulfated dermatan sulfates from invertebrates and their mammalian counterpart. An invertebrate dermatan sulfate containing 2-O-sulfated α-L-iduronic acid and 4-O-sulfated N-acetyl-β-D-galactosamine residues is a potent anticoagulant due to a high heparin cofactor II activity. It inhibits thrombin due to the formation of a covalent complex with heparin cofactor II, as in the case of mammalian dermatan sulfate, but the effect occurs at lower concentrations for the invertebrate polysaccharide. Surprisingly, the invertebrate dermatan sulfate has a lower potency to prevent thrombus formation on an experimental model and a lower bleeding effect in rats than the mammalian dermatan sulfate. In contrast, another invertebrate dermatan sulfate, also enriched in 2-O-sulfated α-L-iduronic acid, but in this case sulfated at O-6 position of the N-acetyl-β-D-galactosamine units, has no in vitro or in vivo anticoagulant activity, does not prevent thrombus formation but shows a bleeding effect similar to the mammalian glycosaminoglycan. Overall, these results demonstrate unbalanced effects of dermatan sulfates with different sulfation patterns on coagulation, thrombosis and bleeding, and raise interesting questions concerning the relationship among these three biological actions of sulfated polysaccharides.
Thiosulfinates Inhibit Platelet Aggregation and Microparticle Shedding at a Calpain-dependent Step
Authors: Brohard-Bohn Brigitte , Pain Sabine , Bachelot-Loza Christilla , Auger Jacques , Rendu Francine 
Published: March 2018

SummaryThiosulfinates (TSs) are sulfur compounds generated through the processing of different Allium species with antiplatelet property. To further define this platelet inhibitory effect we studied diallyl-TS (Al2TS), dipropyl-TS (Pr2TS), and dimethyl-TS (Me2TS) on platelet responses. The three TSs inhibited dose-dependent platelet aggregation, with IC50 values of 15 ± 2, 19 ± 2, and 9 ± 1 μM for Al2TS, Pr2TS and Me2TS, respectively. TSs had no effect on the expression of a platelet procoagulant surface, measured by flow cytometry as the binding of annexin V-FITC. They inhibited the microparticle shedding and clot retraction. Since the microparticle shedding is a calpain-activation dependent step, we assessed calpain activation by analysis of autoproteolysis in shorter active forms and by talin proteolysis in the presence of TSs. Calpain activation was inhibited by TSs independently of fibrinogen binding. Thus, TSs represent a new category of platelet inhibitors, acting on cal-pain-induced events.
Moderate Wine and Alcohol Consumption: Beneficial Effects on Cardiovascular Disease
Authors: Parks Dale , Booyse Francois 
Published: March 2018

SummaryCardiovascular disease, in particular coronary heart disease (CHD) and associated myocardial infarction (MI), is the leading cause of death among adults in the Western world (1). Although CHD is a complex multi-factorial disease, major insights have been gained in our understanding of the etiology underlying the initiation and progression of CHD. The pathogenesis of CHD and the ensuing atherothrombotic complications resulting in MI, involves the complex and often synergistic interplay between multiple dysfunctional cellular and molecular mechanisms that have been altered through interactions with various environmental and/or systemic factors (i. e. CHD risk factors). Typically, these deleterious effects are exerted at the level of the heart muscle, blood vessels and blood components and result in dysfunction in endothelial cells (ECs), smooth muscle cells, cardiac myocytes, blood cells (platelets and monocytes) and plasma components (lipoproteins, fibrinogen, clotting factors, etc.). These combined effects will then contribute further to the initiation and progression of CHD and eventual MI. Consequently, any systemic factors (such as alcohol or wine components) that will reduce, minimize or inhibit these induced dysfunctions will be expected to reduce the overall risk for cardiovascular disease and CHD-related mortality.
Enhanced Fibrinolytic Potential in Mice with Combined Homozygous Deficiency of α2-antiplasmin and PAI-1
Authors: Collen D. , Lijnen H. R. , Dewerchin M. 
Published: March 2018

Summaryα2-antiplasmin (α2-AP) and plasminogen activator inhibitor-1 (PAI-1) are the main physiological inhibitors of the plasminogen/ plasmin system in mammalian plasma. In the present study, the relative importance of both inhibitors was evaluated with the use of mice with single or combined deficiency of α2-AP and PAI-1 in the same genetic background. Mice with combined deficiency (α2-AP–/–:PAI-1–/–) are viable, develop normally and are fertile. After amputation of the tail, bleeding times are prolonged (>15 min) in α2-AP–/–:PAI-1–/– mice, as compared to double wild-type or single deficient mice (4.6 to 10 min). Spontaneous lysis after 4 h of intravenously injected 125I-fibrin labeled plasma clots is significantly higher in mice with α2-AP deficiency both in the PAI-1+/+ background (89 ± 2% versus 42 ± 3%; p = 0.002) and in the PAI-1–/– background (83 ± 4% versus 53 ± 5%; p = 0.002). PAI-1 deletion in the α2-AP+/+ or α2-AP–/– background, however, has no significant effect (p = 0.13 or 0.18, respectively). Four hours after endotoxin injection, fibrin deposition in the kidneys is not significantly affected by PAI-1 deletion in mice with α2-AP+/+ or α2-AP–/– background (p = 0.07 and 0.19, respectively). In contrast, α2-AP deletion causes significantly reduced fibrin deposition in the PAI-1+/+ background (p = 0.01). Endotoxin injection causes a dramatic increase in PAI-1 antigen levels in kidney extracts of PAI-1+/+ animals, without effect on α2-AP levels.Taken together, these data indicate that the higher endogenous fibrinolytic capacity observed in mice with combined deficiency is mainly due to the lack of α2-AP and suggest a less important role for PAI-1.
Release of Soluble Urokinase Receptor from Vascular Cells*
Authors: Chavakis Triantafyllos , Willuweit Antje , Lupu Florea , Preissner Klaus , Kanse Sandip 
Published: March 2018

SummaryUrokinase-type plasminogen activator (uPA) and its cell surface-receptor (uPAR) regulate cellular functions linked to adhesion and migration and contribute to pericellular proteolysis in tissue remodelling processes. Soluble uPAR (suPAR) is present in the circulation, peritoneal and ascitic fluid and in the cystic fluid from ovarian cancer. We have investigated the origin and the vascular distribution of the soluble receptor, which accounts for 10-20% of the total receptor in vascular endothelial and smooth muscle cells. Phase separation analysis of the cell conditioned media with Triton X-114 indicated that suPAR associates with the aqueous phase, indicative of the absence of the glycolipid anchor. There was a polarized release of suPAR from cultured endothelial cells towards the basolateral direction, whereas the membrane-bound receptor was found preferentially on the apical surface. Both, uPAR and suPAR became upregulated 2-4 fold after activation of protein kinase C with phorbol ester, which required de-novo protein biosynthesis. Interleukin-1β (IL-1β), basic fibroblast growth factor (bFGF) or vascular endothelial growth factor increased suPAR release from endothelial cells, whereas platelet derived growth factor-BB, bFGF or IL-1β stimulated suPAR release from vascular smooth muscle cells. Immune electron microscopy indicated that in atherosclerotic vessels (s)uPAR was observed on cell membranes as well as in the extracellular matrix. These findings indicate that (s)uPAR from vascular cells is upregulated by proangiogenic as well as proatherogenic growth factors and cytokines, is preferentially released towards the basolateral side of endothelial cells and accumulates in the vessel wall.*Part of this work was supported by grants (Pr 327/1-4) from the Deutsche Forschungsgemeinschaft (Bonn, Germany) and the Novartis-Foundation (Nürnberg, Germany). This work is part of the MD/PhD-thesis of T.C. at the Institute for Biochemistry, Department of Medicine, Justus-Liebig-Universität, Giessen, Germany.
Abbreviations: bFGF: basic fibroblast growth factor, GPI: glycosyl-phosphatidylinositol, FCS: fetal calf serum, HUVEC: human umbilical vein endothelial cells, HVSMC: human vascular smooth muscle cells, IL-1β: interleukin-1β, mAb: monoclonal antibody, PBS: phosphate-buffered saline, PDGF-BB: platelet derived growth factor-BB, piPLC: phosphatidylinositol-specific phospholipase C, piPLD: phosphatidylinositol-specific phospholipase D, PMA: phorbol myristate acetate, scuPA: single chain uPA, suPAR: soluble urokinase receptor, uPA: urokinase- type plasminogen activator, uPAR: urokinase receptor, VN: vitronectin
Angiogenesis Research: Guidelines for Translation to Clinical Application
Authors: Browder Timothy , Palmblad Jan , Folkman Judah 
Published: March 2018

SummaryAngiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either “direct” or “indirect” and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.
Roles of Platelets and Factor XI in the Initiation of Blood Coagulation by Thrombin
Authors: Walsh Peter 
Published: March 2018

SummaryTo account for the variable hemostatic defect in patients with factor XI (FXI) deficiency, with normal hemostasis in contact factor deficiencies, a coagulation paradigm is presented whereby trace quantities of thrombin, generated transiently by exposure of tissue factor at sites of vascular injury, activates FXI bound to the platelet surface in the presence of prothrombin or high Mr kininogen (HK). Tissue factor pathway inhibitor (TFPI) limits the flux of thrombin generated by the tissue factor pathway, and protease nexin II (PNII), released from activated platelets, inhibits solution phase FXIa and localizes FIX activation to the platelet surface where FXIa is protected from inactivation by PNII. Either prothrombin or HK binds to the Apple 1 (A1) domain of FXI, thereby exposing a platelet-binding site in the FXI A3 domain. Dimeric FXI binds to activated platelets directly through the A3 domain of one monomer. After proteolytic activation of platelet-bound FXI by thrombin (or FXIIa), a substrate binding site for FIX is exposed in the opposite monomer that promotes FIX activation on the platelet surface resulting in the local explosive generation of thrombin and the formation of hemostatic thrombi at sites of vascular injury.
Genetic Approach to Thrombophilia
Authors: Bertina Rogier 
Published: March 2018

SummaryVenous thrombosis is a multifactorial disease. Multiple interactions between genetic and environmental factors contribute to the development of the disease. Presently, we know of six or seven genetic risk factors for venous thrombosis. However, together these defects can explain the clustering of thrombotic events in only a small subset of families with thrombophilia. As to the identification of new genetic risk factors for thrombosis, we seem to have arrived at the end of a practicable road with the classical approach of thrombophilia, which usually starts with the study of the association of hemostatic phenotypes and thrombotic risk. At the same time we have undertaken various genetic approaches aiming at identifying polymorphisms/ mutations causing thrombotic risk. This review summarizes what we have learnt so far, what to do and what not to do. The odds for finding remaining common genetic risk factors for venous thrombosis during the next ten years may be predicted to be fairly high.
Hermansky-Pudlak Syndrome and Chediak-Higashi Syndrome: Disorders of Vesicle Formation and Trafficking
Authors: Huizing Marjan , Anikster Yair , Gahl William 
Published: March 2018

SummaryThe rare autosomal recessive metabolic disorders Hermanky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) share the clinical findings of oculocutaneous albinism and a platelet storage pool deficiency. In addition, HPS exhibits ceroid lipofuscinosis and CHS is characterized by infections and an accelerated phase. The two disorders result from defects in vesicles of lysosomal lineage. Of the two known HPS-causing genes, HPS1 has no recognizable function, while ADTB3A codes for a subunit of an adaptor complex responsible for new vesicle formation from the trans-Golgi network. Other HPS-causing genes are likely to exist. The only known CHS-causing gene, LYST, codes for a large protein of unknown function. In general, HPS appears to be a disorder of vesicle formation and CHS a defect in vesicle trafficking. These diseases and their variants mirror a group of mouse hypopigmentation mutants. The gene products involved will reveal how the melanosome, platelet dense body, and lysosome are formed and trafficked within cells.
Unraveling the Mysteries of Phospholipid Scrambling
Authors: Wiedmer Therese , Sims Peter 
Published: March 2018

SummaryPlasma membrane phospholipid asymmetry is maintained by an aminophospholipid translocase that transports phosphatidylserine (PS) and phosphatidylethanolamine (PE) from outer to inner membrane leaflet. Cell activation or injury leads to redistribution of all major lipid classes within the plasma membrane, resulting in surface exposure of PS and PE. Cell surface-exposed PS can serve as receptor sites for coagulation enzyme complexes, and contributes to cell clearance by the reticuloendothelial system. The mechanism(s) by which this PL ”scrambling” occurs is poorly understood. A protein called phospholipid scramblase (PLSCR1) has been cloned that exhibits Ca2+-activated PL scrambling activity in vitro. PLSCR1 belongs to a new family of proteins with no apparent homology to other known proteins. PLSCR1 is palmitoylated and contains a potential protein kinase C phosphorylation site. It further contains multiple PxxP and PPxY motifs, representing potential binding motifs for SH3 and WW domains implicated in mediating protein-protein interactions. Although at least two proteins have been shown to associate with PLSCR1, the functional significance of such interaction remains to be elucidated. Evidence that PLSCR1 may serve functions other than its proposed activity as PL scramblase is also presented.
Plasmin and Matrix Metalloproteinases in Vascular Remodeling
Authors: Lijnen H. R. 
Published: March 2018

SummaryVascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.
Management des steroidsensiblen nephrotischen Syndroms im Kindes- und Jugendalter
Authors: Benz M. R. , Hackl A. , Weber L. T. , Ehren R. 
Published: March 2018

ZusammenfassungDas nephrotische Syndrom im Kindesalter erfüllt die Kriterien einer seltenen Erkrankung und doch ist es die häufigste Glomerulopathie in dieser Altersgruppe. Gleichzeitig ist es eine heterogene Erkrankung, die durch die Kategorien Alter bei Erstmanifestation, Ätiologie, Histologie und Ansprechen auf eine Standardtherapie mit Glukokortikoiden eingeteilt werden kann. Wichtigster Prognosefaktor ist das primäre Ansprechen auf eine Standardtherapie mit Glukokortikoiden und differenziert zwischen steroidsensiblem (SSNS) und steroidresistentem nephrotischem Syndrom (SRNS). Eine hohe kumulative Dosis an Glukokortikoiden oder die verlängerte Gabe bei Behandlung der Erstmanifestation scheinen das Rezidivrisiko nicht zu beeinflussen. Trotz der kurz- und langfristigen Nebenwirkungen der Glukokortikoide, die die primäre Therapiesäule des nephrotischen Syndroms darstellen, ist die Bewertung der medikamentösen Alternativen bei Patienten mit häufigen Rezidiven eines SSNS eine ständige differenzialtherapeutische Herausforderung. Dies gilt ebenso für die Therapie des SRNS. Beim SRNS ist eine molekulargenetische Abklärung dringend zu empfehlen. Der vorliegende Text gibt eine Übersicht zur Therapie des SSNS.
Polyneuropathie
Authors: Hermann W. 
Published: March 2018

ZusammenfassungAkute und chronische Störungen afferenter und efferenter Nervenfasern im peripheren Nervensystem können Schmerzen und Behinderungen verursachen sowie zu lebensbedrohlichen Situationen führen. Die Haut ist der Ausgangspunkt der sensiblen Afferenzen. Sie stellt mit ihren Sinnesmodalitäten für mechanische, thermische und Schmerzreize insgesamt das größte Rezeptororgan für die Kontaktaufnahme mit der Umwelt dar. Efferente somatomotorische Nervenfasern innervieren die Skelettmuskeln und viszeromotorische sympathische Nervenfasern versorgen als Effektoren glatte Muskelzellen der Blutgefäße und die Schweißdrüsen. Sie sind der Bedside-Diagnostik zugänglich. Die Polyneuropathie ist Ursache des Kommunikationsverlustes mit der Umwelt sowie verantwortlich für Defizite der Effektororgane. Durch die fachlich richtige Einordnung anamnestischer Angaben und klinischer Befunde allein auf der Basis der Bedside-Diagnostik ist eine pathophysiologisch-anatomisch fundierte Klassifikation des polyneuropathischen Syndroms möglich. Es integriert den speziellen Befundkomplex als Grundlage für die zielgerichtete ätiologische Diagnostik. Somit verdient das periphere Nervensystem im Hinblick auf seine komplexe Anatomie und Physiologie einen hohen Stellenwert in Anamnese und klinischer Untersuchung.
Hämostaseologische Globalteste
Authors: Moessmer G. , Spannagl M. 
Published: March 2018

ZusammenfassungHämostaseologische Globalteste messen eine Reihe von Reaktionsschritten im physiologischen Ablauf der Gerinnselbildung . Als Konsequenz stellt die ursprüngliche Plasma- oder Vollblutprobe einen beträchtlichen Volumenanteil im endgültigen Testansatz dar. Entsprechend hoch ist der Einfluss von Störfaktoren und anderen Faktoren (Medikation oder Komorbidität). Die genaue Beachtung der präanalytischen Bedingungen ist deswegen von außerordentlicher Bedeutung. Abgesehen von der standardisierten Ergebnismitteilung der Thromboplastinzeit in INR, sind die Messergebnisse zwischen verschiedenen Reagenzien wegen fehlender Standardisierung etwa der aPTT oder Thrombinzeit nicht vergleichbar. Bei der Interpretation der Ergebnisse müssen die vielfältigen Einfluss- und Störfaktoren berücksichtigt werden. Nur eine aus der klinischen Ausgangssituation präzise entwickelte Fragestellung wird zu relevanten Ergebnissen führen.
Quantification of coagulation factors and inhibitors
Authors: Marbet G. A. 
Published: March 2018

ZusammenfassungDie kurze Übersicht richtet sich an Anfänger in der Gerinnungsdiagnostik. Für das systematische Studium wird auf ausgezeichnete Lehrbücher im deutschen Sprachraum verwiesen. Die funktionellen Methoden zur Bestimmung von Gerinnungsfaktoren und physiologischen Gerinnungshemmern / Regulatoren sind ursprünglich quantitative Parallel- Line oder Slope-Ratio-Assays. Auf den heutigen Automaten werden sie nach der Art der klinisch-chemischen Methoden abgearbeitet. Neben der üblichen internen und externen Qualitätskontrolle soll bei auffälligen Resultaten oder zur Diagnosesicherung bei Verdacht auf Hämophilie zusätzlich ein Ansatz mit drei unterschiedlichen Verdünnungen der Patientenprobe gefahren werden. Weichen die einzelnen Bestimmungen um mehr als 10-15% von ihrem errechneten Aktivitätsmittelwert ab, ist die Untersuchung nicht verwertbar und fordert weitere diagnostische Aktivitäten (z. B. Suche nach einem Inhibitor). Als Beispiel für besondere Probleme in der Diagnostik werden Diskrepanzen zwischen chromogener Methode und koagulometrischer Einstufenbestimmung des Faktors VIII besprochen.
Genomische Diagnostik thrombophiler Gerinnungsstörungen bei Frauen
Authors: Lindhoff-Last E. , Luxembourg B. 
Published: March 2018

ZusammenfassungDie Aufklärung der DNA-Sequenzen sowohl der Gerinnungsfaktoren als auch der Gerinnungsinhibitoren hat die Erforschung genetischer Ursachen einer venösen Thromboseneigung ermöglicht. Da die Entstehung venöser Thrombosen ein multifaktorielles Geschehen ist, weisen Frauen auf Grund frauenspezifischer Risikosituationen (z. B. hormonale Kontrazeption, Schwangerschaft, Wochenbett) in bestimmten Lebensphasen ein zusätzliches expositionelles Thromboserisiko auf. Von wesentlicher Bedeutung ist es, die thrombophilen Neigungen zu definieren, bei denen eine genetische Diagnostik von besonderer klinischer Relevanz ist, zumal auch eine habituelle Abortneigung, schwangerschaftsinduzierte hypertensive Erkrankungen und frustrane In-vitro-Fertilisationen in Zusammenhang mit einer Thrombophilie gebracht werden. Trotz der vielfältigen Möglichkeiten einer genomischen Diagnostik ist eine DNA-Analyse nur in wenigen Fällen klinisch notwendig: Sinnvoll ist eine Mutationsanalytik bezüglich einer Faktor- V-Leiden-Mutation, da die Risiken zwischen homo- und heterozygoter Ausprägung differieren und von klinischer Relevanz in der Schwangerschaft und bei Schwangerschaftskomplikationen sind. Ebenso bewiesen ist dies für die Prothrombinmutation G20210A, wobei die Datenlage für deren homozygote im Vergleich zur heterozygoten Form auf Grund der Seltenheit unzureichend ist.Die Analytik der homozygoten Form der MTHFR-Mutation C677T ist nicht zu empfehlen, da die klinische Relevanz für die meisten Indikationen nicht ausreichend belegt ist. Für angeborene Mangelzustände von Antithrombin, Protein C und Protein S ist die Datenlage auf Grund ihrer geringen Inzidenzen selbst in venösen Thrombosekollektiven sehr gering. Die Mutationsanalytik kommt hier nur in Frage, wenn die Aktivitätsuntersuchungen der Proteine trotz wiederholter Messungen keine eindeutige Beurteilung zulassen. Alle übrigen Mutationsanalysen (z. B. PAI-1-Polymorphismus, Faktor-XIII-Val34Leu-Polymorphismus) sind bei Frauen zurzeit ohne klinische Relevanz.