bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Inhibition of Activated Fibrinolysis Predicts Microbial Infection, Shock and Mortality in Febrile Medical Patients
Authors: Raaphorst Joost , Bossink Ailko , Hack C. Erik , Groeneveld A. B. Johan 
Published: March 2018

SummaryTo evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0° C axillary or 38.3° C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin- 2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to febrile illness within 28 days after inclusion. The peak plasma levels of TAT complexes were elevated in 44% and the PAP complexes in all patients. The t-PA and PAI-1 levels were elevated in 74 and 94% of patients, respectively. Values for TAT and PAP did not differ among subgroups, while peak t-PA and IL-6 levels were higher in patients with positive microbiological results, developing shock or ultimately dying than in those without the complications (p <0.005). Peak PAI-1 levels were elevated in patients developing shock and ultimate death versus those with an uncomplicated course (p <0.05). Peak IL-6 related to PAI-1 and t-PA levels, which interrelated. Patients with elevated TAT levels had increased plasma levels of IL-6, PAP, PAI-1 and t-PA versus those with normal TAT (p <0.05). Our data indicate that inhibition of activated fibrinolysis, which may partly depend on both cytokinemia and activation of coagulation, predicts microbial infection, septic shock and mortality of febrile medical patients. This suggests an early pathogenic role of inhibition of activated fibrinolysis in the downhill course of serious microbial infection.
Complementary Roles for Fibrin(ogen), Thrombospondin and vWF in Mediating Shear-dependent Aggregation of Platelets Stimulated at Threshold Thrombin Concentrations
Authors: Kasirer-Friede Ana , Legrand Chantal , Frojmovic Mony 
Published: March 2018

SummaryWe have evaluated the relative contribution of the adhesive ligands, von Willebrand factor (vWF), fibrinogen (Fg) and thrombospondin (TSP), all surface-expressed on washed platelets (WP) activated with a threshold thrombin concentration (~ 0.04 U/ml), to platelet micro-aggregation (PA) at shear rates (G) from 300-2000 s-1. In suspensions of thrombin-activated WP sheared immediately (τ0), all three ligands were required for optimal aggregation at all G, as shown by a 50-70% inhibition of capture efficiencies of PA (measured from initial rates of PA), by antibodies (Abs) directed against each protein. This aggregation involved both GPIb and GPIIbIIIa, as indicated by ~ 80% and 100% inhibition by Ab 6D1 and Ab 10E5, respectively. For WP preexposed to thrombin for 10 min to ensure maximal surface expression of secreted ligands and activated GPIIbIIIa (τ10), vWF was predominantly required at all G (63-75% inhibition by anti-vWF Ab), together with TSP (35-50% inhibition by anti-TSP Ab). Under these conditions, Fg was extensively converted to fibrin, so that fibrin, rather than Fg, could participate in microaggregation, with GPIb less required than GPIIbIIIa as indicated by a 30-60% inhibition by Ab 6D1 as compared to 100% inhibition by Ab 10E5. Our results show that interactions between multiple ligands and receptors favour microaggregation depending on shear and thrombin activation conditions.
The Conformational Basis of Thrombosis
Authors: Huntington James , Mushunje Alec , Zhou Aiwu , Robin Carrell 
Published: March 2018

SummaryAntithrombin readily undergoes a spontaneous transition from its active five-stranded form to a six-stranded inactive latent form. The recognition of this change in plasma has been obscured by the immediate linkage of newly formed latent antithrombin to a molecule of active antithrombin to give a dimer with an electrophoretic mobility readily confused with that of native active antithrombin. A new micromethod now allows unequivocal identification of latent antithrombin in whole plasma. This shows that at 37° C some 10% of plasma antithrombin is converted to the latent form in 24 h. The rate of conversion is greatly accelerated at increased temperatures, as occurs in the pasteurisation of plasma concentrates that should now be checked for efficacy. But increased transition also occurs in the plasma at the slightly increased temperatures that accompany incidental infections. This is of particular significance if there is a conformationally unstable variant of antithrombin; here fever can provoke a sudden transition with the onset of a characteristically severe episode of thromboembolism. Such variants are not rare and include those previously classified as pleiotropic. The precise structural pathway, now known with antithrombin, provides a model of the changes occurring in other conformational diseases, including Alzheimer’s and the prion dementias.
Tissue Factor: An Enzyme Cofactor and a True Receptor
Authors: Morrissey James 
Published: March 2018

SummaryTissue factor is considered to be the physiologic trigger of the blood clotting system in normal hemostasis and in many – perhaps most – thrombotic diseases. A wealth of new knowledge is available regarding the structure and assembly of the TF:VIIa complex and the role of factor VIIa and tissue factor in hypercoagulable states. The exciting recent finding that tissue factor can function as a signaling receptor, and suggestions that tissue factor may have important, non-hemostatic roles, will be the subject of much additional study in the near future.
Thrombophilia, Thrombosis and Pregnancy
Authors: Eldor Amiram 
Published: March 2018

SummaryThe risk of venous thromboembolism (VTE) in pregnancy is 0.05-1.8%, six times greater than in the non-pregnant state, and pulmonary embolism remains the most common cause of maternal death. Maternal age, previous history of VTE, Caesarean section and the presence of thrombophilia, significantly increase the risk of VTE. Acquired or hereditary thrombophilia occur in almost two-thirds of women presenting with recurrent miscarriages, pre-eclampsia, intrauterine growth restriction, abruptio placentae, or stillbirth, which are associated with microvascular thrombosis in placental blood vessels. Women with VTE during pregnancy and especially those with thrombophilia require individualized management, based on the type of defect, the family history and the presence of additional risk factors. These factors are important in determining the dose and duration of antithrombotic therapy during pregnancy and the puerperium, and the thromboprophylactic strategy for future pregnancies. Oral anticoagulants are now seldom used during pregnancy because of their significant side effects. Low-molecular-weight heparins (LMWHs) are increasingly replacing unfractionated heparin in the prevention and treatment of VTE during pregnancy. LMWHs have also been shown to be effective in improving the outcome of pregnancy in women with previous obstetric complications.
Integrin Activation
Authors: Woodside D. G. , Liu S. , Ginsberg M. H. 
Published: March 2018

SummaryIntegrins are cell surface adhesion receptors that participate in a variety of important processes throughout the vasculature. Here we summarize some recent findings on the regulation of integrin mediated cellular adhesion. Particular emphasis is placed on the regulation of integrin affinity for ligand (activation), although this is just one mechanism by which regulation of integrin-dependent cell adhesion can occur. Also discussed are recent observations on the structural basis of integrin activation, the role of the cytoplasmic domain in integrin affinity regulation, and potential mechanisms by which activation signals are propagated from integrin cytoplasmic domains to the extracellular ligand binding domain.
Thrombolysis in Deep Vein Thrombosis: Is there still an Indication?
Authors: Forster Alan , Wells Philip 
Published: March 2018

SummaryThe most accepted therapy for DVT consists of anticoagulation with unfractionated heparin or low molecular weight heparin, followed by variable duration oral anticoagulation but thrombolytic therapy has been proposed in addition to standard anticoagulation. This paper reviews the literature on post thrombotic syndrome, the natural history of vein patency after therapy, and we perform a systematic review, using accepted standards for meta-analysis, to determine the outcomes when thrombolytic therapy is used to treat DVT. We demonstrate that thrombolytic therapy for DVT results in a significant increase in the risk of major hemorrhage and a significant increase in the rate of vein patency. However, although thrombolytic therapy is advantageous over anticoagulation as measured by early vein patency, a benefit in terms of a reduction in PTS risk, is unproven. Our review also shows that there is no evidence that there is a difference in efficacy between thrombolytic agents or that local therapy differs from systemic therapy. Finally, the potential role of catheter directed therapy is unknown since appropriate trials have not been performed but it is reasonable to use catheter directed therapy in patients with phlegmasia cerulea dolens. We conclude that more work is needed to define the role of thrombolytic therapy but it is too early to abandon this therapeutic modality.
Nichtalkoholische Fettleber bei Kindern und Jugendlichen
Authors: Zöhrer E. , Baumann U. , Jahnel J. 
Published: March 2018

ZusammenfassungDie nichtalkoholische Fettleber ist die häufigste chronische Lebererkrankung im Kindes- und Jugendalter und ist oft mit Adipositas und Diabetes mellitus Typ 2 assoziiert. Der Begriff „Nichtalkoholische Fettleber-Erkrankung“, kurz NAFLD („nonalcoholic fatty liver disease“), beinhaltet ein Erkrankungsspektrum reichend von Fettleber mit fehlender Progression bis hin zur nichtalkoholischen Steatohepatitis (NASH). Bildgebende Verfahren und laborchemische Parameter helfen bei der primären Beurteilung und zur Verlaufsbegutachtung – für die Prognose ausschlagegebend ist die Histologie der Leberbiopsie. Die Therapie von NAFLD beschränkt sich primär auf Änderungen des Lebensstils und der Ernährung, die bariatrische Therapie wird zunehmend angewendet.
Update Epilepsie
Authors: Steinhoff B. J. 
Published: March 2018

ZusammenfassungIn der Epileptologie hat sich eine intensive Diskussion zur Klassifikation epileptischer Anfälle und Syndrome entwickelt, die noch nicht abgeschlossen ist. Sie reflektiert die erheblichen Fortschritte, die im Verständnis der Ätiologie und Pathophysiologie gewonnen wurden, aber auch den lange noch nicht abgeschlossenen Erkenntniszugewinn. Weitere Modifikationen sind daher zwingend zu erwarten. Die diagnostischen Möglichkeiten haben sich weiter verbessert. Hauptproblem ist, dass sie nicht angemessen angewendet werden. Die Grundsätze der Epilepsietherapie haben sich in letzter Zeit nicht verändert. Es hat sich gezeigt, dass Lamotrigin und Levetiracetam zu den Standardantikonvulsiva werden. Neueste Antikonvulsiva haben zum Teil überzeugt. Leider wird ihre nachhaltige Anwendung in Deutschland im Gegensatz zum Rest der Welt durch die Auswirkungen des Arzneimittelmarktneuordnungsgesetzes praktisch verhindert. Neurostimulationsverfahren bieten interessante Perspektiven, aber nicht mehr.
Tissue-Faktor im akuten Koronarsyndrom
Authors: Steppich B. A. , Ott I. 
Published: March 2018

ZusammenfassungDie Ruptur einer arteriosklerotischen Plaque mit nachfolgender Thrombusbildung und Gewebsischämie stellt das führende pathophysiologische Korrelat des akuten Koronarsyndroms dar. Gewebsthromboplastin oder Tissue-Faktor (TF) als wichtigster physiologischer Initiator der extrinsischen Gerinnungskaskade nimmt eine zentrale Rolle in der Pathogenese des akuten Koronarsyndroms ein. Das Ausmaß des thrombotischen Prozesses wird zum einen durch den Gehalt an lokalem, vaskulären TF des rupturierten Plaques zum anderen durch zirkulierenden TF moduliert. Neben seiner gut charakterisierten Bedeutung bei der Atherothrombose ist TF darüber hinaus über eine Aktivierung von Signaltransduktionskaskaden an entzündlichen Prozessen sowie am vaskulären Remodeling beteiligt. Der vorliegende Artikel zeigt die gegenwärtige Vorstellung über die Beteiligung von TF beim akuten Koronarsyndrom auf und diskutiert mögliche Konsequenzen und therapeutische Ansatzpunkte.
New locations of intravascular tissue factor
Authors: Reinhardt C. 
Published: March 2018

SummaryTissue factor (TF) is the major initiator of blood coagulation, and a mediator of inflammation, angiogenesis, and carcinogenesis. According to recent evidence, preformed TF and inducible expression of the protein is observed in several blood components. TF is apparently constitutively expressed on circulating microparticles, and can be exposed within minutes on the cell membrane of activated eosinophils and platelets, and, potentially, on neutrophils. Expression in monocytes and neutrophils largely requires transcriptional activation of the TF gene. Eosinophils appear to harbour the highest concentration of preformed TF among all blood components under resting conditions. TF expression in eosinophil progenitor cells is substantially higher than in precursors of other granulocyte fractions. Eosinophil TF promotes transendothelial migration, which documents that presynthesized TF in blood supports functions apart from coagulation. It is still an open question how the intravascular TF is activated to trigger initiation of coagulation. TF activation in different blood components is likely to be differentially regulated according to the (patho)physiologic context.
Blood coagulation dynamics in haemostasis
Authors: Orfeo T. , Butenas S. , Undas A. , Brummel-Ziedins K. , Mann K. G. 
Published: March 2018

SummaryOur studies involve computational simulations, a reconstructed plasma/platelet proteome, whole blood in vitro and blood exuding from microvascular wounds. All studies indicate that in normal haemostasis, the binding of tissue factor (TF) with plasma factor (F) VIIa (extrinsic FXase complex) results in the initiation phase of the procoagulant response. This phase is negatively regulated by tissue factor pathway inhibitor (TFPI) in combination with antithrombin (AT) and the protein C (PC) pathway. The synergy between these inhibitors provides a threshold-limited reaction in which a stimulus of sufficient magnitude must be provided for continuation of the reaction. With sufficient stimulus, the FXa produced activates some prothrombin. This initial thrombin activates the procofactors and platelets required for presentation of the intrinsic FXase (FVIIIa- FIXa) and prothrombinase (FVa-FXa) complexes which drive the subsequent propagation phase; continuous downregulation of which is provided by AT and the thrombinthrombomodulin- PC complex. FXa generation during the propagation phase is largely (>90%) provided by the intrinsic FXase complex. TF is required for the initiation phase of the reaction but becomes non-essential once the propagation phase has been achieved. The propagation phase catalysts (FVIIIa-FIXa and FVa-FXa) continue to drive the reaction as blood is resupplied to the wound site by flow. Ultimately, the control of the reaction is governed by the pro- and anticoagulant dynamics and the supply of blood reactants to the site of a perforating injury. Our systems have been utilized to examine the qualities of hypothetical and novel antihaemorrhagic and anticoagulation agents and in epidemiologic studies of venous and arterial thrombosis and haemorrhagic pathology.
Key transcriptional regulators of the vasoprotective effects of shear stress
Authors: Boon R. A. , Horrevoets A. J. G. 
Published: March 2018

SummaryAtherosclerotic plaque rupture and subsequent thrombosis is the main cause of sudden coronary death. Remarkably, atherosclerosis only develops in certain predisposed areas of the vasculature. Endothelial cells in these predisposed areas experience low or oscillatory shear stress, which activates the proinflammatory and procoagulant transcription factors activator protein 1 (AP-1) and nuclear factor B (NFB), thus inducing a proinflammatory, procoagulant surface. In contrast, healthy endothelial cells that are exposed to prolonged high laminar shear stress, express antiinflammatory and anticoagulant genes. The key shear stress-induced transcription factors that govern the expression of these genes are Krüppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). Together KLF2 and Nrf2 govern ~70% of the shear stress-elicited gene sets. Nrf2 potently induces anti-inflammatory/antioxidant enzymes, while KLF2 induces anti-inflammatory and anticoagulant proteins, most specifically endothelial Nitric oxide synthase (eNOS) and thrombomodulin (TM). KLF2 also inhibits proinflammatory and antifibrinolytic genes through inhibition of the proinflammatory transcription factors AP-1 and NFB. The widespread beneficial effects of the key transcription factors KLF2 and Nrf2 on endothelial phenotype, holds the promise that their targeted modulation might lead to a new class of cardiovascular drugs.
Mikropartikel in der Frauenheilkunde
Authors: Toth B. 
Published: March 2018

ZusammenfassungMikropartikel (MP) werden bei Aktivierung oder Apoptose von zirkulierenden Blut- bzw. Endothelzellen sowie unter der Wirkung von Scherkräften freigesetzt. Sie nehmen u.a. Einfluss auf Gerinnung, Entzündungsprozesse und dienen als Transportmedium. Bislang gibt es wenige Untersuchungen zu zirkulierenden MP bei Patientinnen der Gynäkologie und Geburtshilfe. Erste Daten legen nahe, dass es zyklusabhängig Unterschiede in der Freisetzung von MP bei Frauen gibt und dass junge Frauen signifikant mehr Plättchen-MP und endotheliale MP aufweisen als altersentsprechende Männer. Pathologische Schwangerschaftsverläufe wie Abort und Präeklampsie gehen mit erhöhten MP-Konzentrationen einher. Inwieweit MP in die Pathophysiologie des Abortgeschehens bzw. der Präeklampsie eingreifen, ist Gegenstand weiterführender Untersuchungen. Studien an Mammakarzinom-Patientinnen legen nahe, dass die Konzentration zirkulierender MP mit dem Tumorstadium korreliert und MP ein ähnliches Sensitivitäts/Spezifitäts-Profil aufweisen wie etablierte Tumormarker.
Pathophysiologic significance of procoagulant microvesicles in cancer disease and progression
Authors: Castellana D. , Kunzelmann C. , Freyssinet J.-M. 
Published: March 2018

SummaryMicrovesicles (MV) are submicrometric membrane fragments (0.1 to 1 μm), released from the plasma membrane of activated or apoptotic cells. They are characterized by most of the antigenic profile of the cells they originate from, and by the presence of procoagulant phospholipids at their surface. MV are detectable in the peripheral blood of mammals and considered as efficient effectors in the haemostatic or thrombotic responses, able to remotely initiate or amplify beneficial or deleterious processes, depending on the circumstances. Variations in their level and pheno-type make them relevant pathogenic markers of thrombotic disorders and vascular damage. To date, MV are recognized as mediators of communication allowing cells to influence a target present in the local microenvironment as well as to at distant sites. The mechanisms by which MV interact with target cells are still unclear, but a number of studies suggest involvement of MV-cell fusion or ligand-receptor interactions. More importantly, MV have been shown implicated in horizontal transfer of genetic material. This review focuses on the role of MV in the context of cancer, and their possible part in cancer associated thrombosis.
Acute immune thrombocytopenic purpura
Authors: Bolton-Maggs P. 
Published: March 2018

SummaryImmune thrombocytopenia in children is usually a self-limiting illness, but in adults the disease is likely to be chronic, and may be associated with other pathology which predisposes to bleeding. Despite very low platelet counts serious bleeding is rare in both adults and children. More than 80% of children have mild clinical manifestations. Intracranial haemorrhage is rare at all ages, is unpredictable and can occur at any time when the count is very low. Currently recommended therapies for both adults and children are associated with significant side effects and occasional deaths. Treatment may interfere with quality of life more than the illness itself. Drugs can be withheld in the majority of children with appropriate advice to child and family. Treatment can be individualised, taking into account the person’s needs and lifestyle as well as bleeding. In chronic ITP many need no active therapy. The situation with adults is more complex but those with a platelet count above 30 x 109/l usually need no treatment as bleeding is rare, and those adults with refractory ITP unresponsive to treatment live with very low counts for years without significant bleeding suggesting the need to re-evaluate the balance of risks of treatment versus bleeding. It is notable that adults with ITP may die from infection, probably related to therapy.
Chronic immune thrombocytopenic purpura
Authors: Ruggeri M. , Rodeghiero F. 
Published: March 2018

SummaryFirst generation thrombopoietic growth factors (rhTPO and PEG-rHuMGDF), investigated in the early 2000s, proved effective in increasing platelet count in normal volunteers, in thrombocytopenia due to chemotherapy and also in a few cases of immune thrombocytopenic purpura (ITP). These agents did not complete their clinical development since one of them induced antibodies in the recipients that cross reacted with endogenous thrombopoietin (TPO), thus causing thrombocytopenia. This promoted the ingenious design of a new generation of thrombopoietic growth factors having no sequence homology with natural TPO. The two main agents are romiplostim, a peptibody already approved for clinical use in USA and eltrombopag, a non-peptide, orally active small molecule. In open label and placebo-controlled trials both agents proved to predictably increase platelet count in normal volunteers and in patients with ITP. With appropriate dosages (1–10 µg/kg weekly sub cutaneously for romiplostim; 50–75 mg/die per os for eltrombopag ) a platelet increase becomes significant after 7–10 days and peaks between 10–14 days. By dis -continuing treatment, platelet count returns to baseline level in 10–15 days. The response rate with both agents is above 70–80%, also in patients that had undergone several lines of treatment, or that have failed splenectomy. The response is maintained during the treatment, but is almost invariably lost even after several months of successful administration. Due to the lack of a curative potential and to the incomplete knowledge of long-term side effects, the place of these new drugs in the management of ITP is still unsettled and their use is best restricted to refractory patients or in preparation of splenectomy. It seems however that a new paradigm in the treatment of ITP has been established where the focus is not on reducing platelet consumption but on increasing platelet production.