bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibrin Deposition in Squamous Cell Carcinomas of the Larynx and Hypopharynx
Authors: Bárdos Helga , Juhász Attila , Répássy Gábor , Ádány Róza
Published: March 2018

Extravascular fibrin deposition is frequently observed within and around neoplastic tissue and has been implicated in various aspects of tumor growth. The distribution of fibrin deposits was investigated in squamous cell carcinomas representing different stages of tumor progression of the larynx (n = 25) and hypopharynx (n = 9) by immunofluorescent techniques. Double and treble labelings were used to detect fibrinogen and fibrin in combination with marker antigens for tumor cells (cytokeratin), endothelial cells (von Willebrand factor), macrophages (recognized by KiM7), as well as factor XIII subunit A (FXIIIA) and tenascin (an embryonic extracellular matrix protein newly expressed during tumorigenesis). All tissue samples showed specific staining for fibrinogen/fibrin. Fibrin deposition was localized almost exclusively in the connective tissue compartment of tumors with characteristic accumulation at the interface of connective tissue and the tumorous parenchyma. In certain tumor samples showing highly invasive characteristics, fibrin deposits were observed in close association with tumor blood vessels in the tumor cell nodules. The overlapping reactions with polyclonal antibody to fibrinogen/fibrin and monoclonal antibody to fibrin indicate the activation of the coagulation cascade resulting in in situ thrombin activation and fibrin formation. Fibrin was crosslinked and stabilized by FXIIIA as revealed by urea insolubility test. Accumulation of phagocytozing macrophages detected by Ki M7 monoclonal antibody could be seen in areas of fibrin deposition. The blood coagulation factor XIIIA was detected in and around the cells labeled with Ki M7 antibody. Tenascin and fibrin deposits were found in the same localization in the tumor stroma and in association with tumor blood vessels within the tumor cell nodules. Neither fibrin nor tenascin were detected in the histologically normal tissue adjacent to tumors. The close association between fibrin deposits and macrophage accumulation strongly suggests the active participation of tumor-associated macrophages in the formation of stabilized intratumoral fibrin that facilitates tumor matrix generation and tumor angiogenesis.
Recombinant Antitrypsin Pittsburgh Undergoes Proteolytic Cleavage during E. coli Sepsis and Fails to Prevent the Associated Coagulopathy in a Primate Model
Authors: Taylor F. B. , Cadena R. A. DeLa , Courtney M. , Colman R. W. , Carrell R. W. , Harper P. L.
Published: March 2018

During severe sepsis there is dramatic activation of both contact pro-teases and the coagulation pathway. These processes contribute to the development of shock and disseminated intravascular coagulation (DIC) respectively. The Pittsburgh mutant of antitrypsin (358Met-Arg) is a novel protease inhibitor with activity against both thrombin and the contact proteases and should therefore prove beneficial as a therapeutic agent in the management of septic shock. This hypothesis was supported by an earlier study in a pig model where recombinant antitrypsin Pittsburgh (rAT Pittsburgh) at a concentration of 1 μM alleviated some of the features of shock, but did not improve survival. In order to reduce the lethal effects of E. coli sepsis we postulated that a higher concentration of antitrypsin Pittsburgh would be necessary. To test this hypothesis we used rAT Pittsburgh in a primate model. This was chosen in preference to another species as E. coli sepsis in the primate has been well characterised and closely resembles the changes seen in man.

Surprisingly this treatment did not alleviate the features of shock and unexpectedly appeared to exacerbate the associated coagulopathy. We propose two possible mechanisms for this unforeseen outcome. The first results from the broad spectrum of activity of antitrypsin Pittsburgh. As well as inhibiting thrombin and the contact proteases, the Pittsburgh mutant also inhibits activated protein C. Inhibition of the protein C system is known to exacerbate septic shock. Secondly, a significant quantity of inactive antitrypsin Pittsburgh, cleaved at the reactive centre, was detected in the plasma of the treated animals. Proteolytically altered serpins, including antitrypsin, have been shown to enhance the inflammatory process. Therefore the accumulation of cleaved rAT Pittsburgh might be expected to exacerbate septic shock.
Plasminogen Activator Inhibitor 1 Contains a Cryptic High Affinity Receptor Binding Site that Is Exposed upon Complex Formation with Tissue-type Plasminogen Activator
,
Authors: Horn Ivo , van den Berg Birgit , Moestrup Søren , Pannekoek Hans , Zonneveld Anton-Jan van
Published: March 2018

The low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic receptor, mediates the cellular internalization of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator and their complexes with plasminogen activator inhibitor type 1 (PAI-1). LRP preferentially binds the complexed forms, exemplified by equilibrium dissociation constants (KD) that are at least an order of magnitude lower than those of the free components. To understand the molecular interactions, underlying the preference of the receptor for complexes rather than for the free components, we have performed a detailed analysis of the affinity and kinetics of the binding of PAI-1 and t-PA:PAI-1 complexes to the receptor, using surface plasmon resonance. To assess the involvement of the heparin-binding domain of PAI-1 for the interaction with LRP, we determined the equilibrium dissociation constants for the binding to LRP of a panel of PAI-1 mutants with single- and multiple amino-acid substitutions of the basic residues that constitute the heparin binding site of PAI-1 (K65, K69, R76, K80 and K88). The binding of these PAI-1 mutants was partially reduced with a 2 to 4 fold increase in KD values for single (K80, K88) and combined (K80, 88) substitution mutant proteins respectively. LRP binding of complexes, composed of t-PA with either wild type PAI-1 or any one of the single PAI-1 mutants indicated a major role of lysine 69 (K69) for the binding of t-PA:PAI-1 complexes to LRP (KD values of 6.1, 3.7, 75.4, 5.4, 12.5 and 8.1 nM for wild type, K65A, K69A, R76A, K80A and K88A complexes, respectively). Since the KD for the binding of free t-PA to LRP is 158 nM, we conclude that the PAI-1 moiety harbors the major determinant for t-PA:PAI-1 complex binding to LRP. The in vitro binding studies were extended by binding and clearance studies with COS-1 cells. Degradation of both 125I-t-PA:PAI-1 K69A and 125I-t-PA:PAI-1 K69A K80A K88A complexes after 2 h of incubation was reduced compared to the degradation of 125I-t-PA:PAI-1 complexes. We conclude that PAI-1 contains a cryptic binding site (lysine 69) for LRP, that is specifically expressed upon t-PA:PAI-1 complex formation.
Plasma TAFI Levels Influence the Clot Lysis Time in Healthy Individuals in the Presence of an Intact Intrinsic Pathway of Coagulation
Authors: von dem Borne Peter , Meijers Joost , Bouma Bonno , Mosnier Laurent
Published: March 2018

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a recently identified fibrinolysis inhibitor in plasma, that when converted to an enzyme potently attenuates fibrinolysis. It is activated by relatively high concentrations of thrombin that exceed the thrombin concentration required for fibrin formation. These high concentrations of thrombin are generated by the intrinsic pathway via activation of factor XI by thrombin. The down regulation of fibrinolysis by TAFI can be measured in a clot lysis assay. When the clot lysis times of healthy individuals were determined, large inter-individual differences were observed. To determine if differences in concentration of TAFI explain the variation in clot lysis between individuals, specific assays were developed for the measurement of TAFI antigen and activity in plasma. In normal plasma, there was a dose-dependent relationship between TAFI antigen and TAFI activity. There was also a correlation between clot lysis time and plasma TAFI antigen, indicating that the amount of TAFI that is activated during the clot lysis assay, is dependent on the concentration of TAFI. In the plasmas of 20 healthy individuals, clot lysis times, TAFI antigen and TAFI activity were determined. Both TAFI antigen and TAFI activity showed a significant correlation with the clot lysis time. No correlation between TAFI antigen and clot lysis time was found when the clot lysis time was determined in the presence of an antibody blocking the factor XI feedback loop. These results indicate that plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation.

Abbreviations: The abbreviations used are: TAFI, Thrombin Activatable Fibrinolysis Inhibitor; TAFIa, activated TAFI; CPI, carboxypeptidase inhibitor from potato tubers; CPN, carboxypeptidase N; tPA, tissue-type plasminogen activator.
In Vitro Platelet Binding Compared with In Vivo Thrombus Imaging Using αIIbβ3-Targeted Radioligands
Authors: Romano Jan , Maurer Alan , Knight Linda
Published: March 2018

Radioligands for the αIIbβ3 integrin on platelets are being studied for their ability to image venous thrombi and pulmonary emboli. One such radioligand, 123I-bitistatin, was previously shown to have higher thrombotic uptake in an animal model than other disintegrins, but the reason for this difference was not clear. The purpose of this study was to evaluate three labeled disintegrins, bitistatin, kistrin and barbourin, to look for in vitro differences in platelet binding which could explain the in vivo behavior.

Disintegrins labeled with 125I were compared in vitro for extent of binding to platelets and rates of binding and dissociation. These findings were related to organ distribution and image quality for imaging thrombotic lesions, following administration of 123I-disintegrins in an animal model. Fibrinogen at 8.8 μmol/l was able to displace 125Ibarbourin and 125I-kistrin more rapidly from ADP-stimulated platelets, with half-times of 3.5 and 10.7 min, compared with 125I-bitistatin (31.6 min). At equivalent concentrations in whole blood, a higher percentage of bitistatin bound to platelets compared with the other two. In vivo, kistrin and barbourin had significantly lower thrombus:muscle and pulmonary embolus:lung ratios in images compared with bitistatin. There was evidence of more metabolic deiodination of labeled kistrin and barbourin in vivo compared with bitistatin. A surprising finding was that conventional in vitro platelet binding studies did not predict the relative in vivo behavior of labeled disintegrins.

The results suggest that labeled bitistatin has improved targeting of thrombi because it is less easily displaced from stimulated platelets, permitting longer lesion retention. It also appears to have a greater association with resting platelets in the blood, which may increase bioavailability and delay metabolic breakdown.
Recombinant Tissue Factor Pathway Inhibitor Enhances the Binding of Factor Xa to Human Monocytes
Authors: Li Anguo , Chang Alvin , Peer Glenn , Wun Tze-Chen , Taylor Fletcher
Published: March 2018

Tissue factor pathway inhibitor (TFPI) is a kunitz-type inhibitor of activated factor X (Xa). TFPI was reported to mediate Xa binding to a few of carcinoma cell lines. In this study it was observed that the Xa activity associated with human peripheral blood mononuclear cells (PBMC) incubated with Xa in the presence of recombinant TFPI (rTFPI) was much higher than with Xa alone. Xa activity on PBMC was also observed after whole blood was incubated with pre-formed Xa/TFPI complex. Further studies with flow cytometric analysis demonstrate that rTFPI enhances the binding of Xa to human monocytes. Western blot analysis showed that rTFPI was cleaved into a few of fragments after its incubation with monocytes either in the presence or absence of Xa. Based on these results and the observations reported by others, we speculate that Xa/TFPI complex may bind to human monocytes by a yet unidentified mechanism. The recovery of Xa activity from Xa/TFPI complex on PBMC may be related to the cleavage of rTFPI by Xa and/or monocyte proteases. This observation suggests a new mechanism by which monocytes become procoagulant in some pathological conditions in addition of the well known tissue factor expression on proinflammatic monocytes.
Serotonin 5-HT1 Receptors Potentiate Histamine and Thrombin Stimulated Prostaglandin Synthesis in Endothelial Cells
Authors: Winneker Richard , Kilbourne Edward
Published: March 2018

The ability of serotonin 5-HT1 receptors to increase vascular tone was previously found to be activated by vasoconstrictiors such as hista-mine. In this study, treatment of cultured human aortic endothelial cells (HAEC) with the 5-HT1-selective agonist 5-carboxamidotryptamine (5-CT) alone had no effect on the levels of prostaglandin F2α (PGF2α) or 6-keto-prostaglandin F1α (6-keto PGFα1). However, 5-CT potentiated the histamine and thrombin stimulated increases in prostaglandins released by HAEC. In the presence of histamine, increasing doses of 5-CT caused a steep rise in PGF2α levels resulting in an increase in the ratio of PGF2α over 6-keto PGF1α . The ability of 5-CT to potentiate prostaglandin production was correlated with its ability to potentiate the histamine and thrombin mediated mobilization of arachidonic acid. These results demonstrate that the ability of 5-HT1 receptors to stimulate prostaglandin production in endothelial cells is activated by histamine and thrombin.
Infantile Hämangiome
Authors: Pleimes M.
Published: March 2018

Infantile Hämangiome sind mit einer Prävalenz von 2,6–4,5 % die häufigsten Tumoren des Säuglings- und Kleinkindesalters. Im Gegensatz zu vielen anderen Tumoren haben sie nach einer anfänglichen Proliferationsphase die Eigenschaft einer spontanen Remission durch Involution. Ein Großteil der Hämangiome kann diese Abfolge spontan durchlaufen, ohne dass therapeutisch interveniert werden muss. Bei einem kleinen Teil der Hämangiome kommt es jedoch schon frühzeitig zu Komplikationen, welche selten lebensbedrohlich sein können, aber oft bleibende funktionelle Schäden, Schmerzen oder dauerhaft entstellende Befunde hinterlassen. Die Herausforderung für den niedergelassenen Pädiater ist es, diese Fälle frühzeitig zu erkennen und einer entsprechenden Therapie zuzuführen. Dabei stehen je nach Lage und Art des Hämangioms sowie der Größe, welche auch vom Zeitpunkt der Erstpräsentation abhängt, unterschiedliche therapeutische Optionen zur Verfügung. Gerade in der sehr frühen Phase lassen sich manchmal sowohl Folgeschäden als auch Therapieintensität und -dauer positiv beeinflussen.

In diesem Artikel sollen Eigenschaften infantiler Hämangiome, Entwicklungsverlauf und therapeutische Modalitäten daher aktualisiert besprochen werden.
Kutane Lyme-Borreliose bei Kindern und Jugendlichen
Authors: Huppertz H.-I. , Hofmann H.
Published: March 2018

Die Lyme-Borreliose, übertragen durch die Zecke Ixodes ricinus und hervorgerufen durch die Spirochäte Borrelia burgdorferi, tritt in fast 90 % der Fälle mit Hauterscheinungen auf, dem Erythema migrans, manchmal auch multilokulär, dem Borrelien-Lymphozytom und der seltenen Acrodermatitis chronica atrophicans. Das typische Erythema migrans bedarf keiner Laborbestätigung, sondern wird sofort antibiotisch behandelt: bis 8 Jahre mit Amoxycillin, danach mit Doxycyclin. Die anderen Manifestationen bedürfen der serologischen Bestätigung. Die beste Prophylaxe ist die zügige Entfernung anheftender Zecken.
Effizienz neurolinguistischer Teletherapie
Authors: Scibor M. , Steidl S. , Noeth E. , Schölderle T. , Ziegler W. , Keidel M. , Hoffmann B.
Published: March 2018

Die dialogische Online-Telesprachtherapie bietet vor allem für den ländlichen Raum in Zukunft neue Chancen für eine bedarfsgerechte und wohnortnahe Versorgung der Patienten mit Sprach- und Sprechstörungen. Patient und Therapeut agieren in Echtzeit direkt über den Bildschirm miteinander, sodass dem Patienten aufwändige Wege in ein spezialisiertes sprachtherapeutisches Zentrum erspart werden können. Die Telesprachtherapie ermöglicht die Aufrechterhaltung einer sektorenübergreifenden Versorgungskette (supply chain) durch Überbrückung eventueller poststationärer Engpässe.
Schreibstörungen bei Morbus Parkinson
Authors: Renzi W.
Published: March 2018

Die Beeinträchtigung der Handschrift stellt ein häufig auftretendes Symptom im Krankheitsverlauf von Parkinson-Syndromen dar. Aufgrund der Basalgangliendegeneration sind automatische Schreibbewegungen erschwert, oftmals sind Mikrografie, Veränderungen der Schreibgeschwindigkeit und -beschleunigung sowie der Schreibflüssigkeit erkennbar. Zu den Einflussfaktoren auf schreibmotorische Leistungen zählen das Alter, gleichzeitige Dual-Task-Aufgaben sowie feinmotorische Leistungen. Einen alltagsrelevanten Effekt auf die Fähigkeit zu schreiben zeigen dopaminerge Medikamente sowie neurostimulative Verfahren wie die tiefe Hirnstimulation und repetitive transkranielle Magnetstimulation. Speziell auf eine Verbesserung schreibmotorischer Leistungen im klinischen Alltag zielt ergotherapeutisches Schreibtraining anhand Erprobung individueller Strategien. Computergestützte Bewegungsanalysen wie mit der Software CSWin ermöglichen dabei eine detaillierte Analyse von Schreibstörungen und deren gezielte Therapie. Ein positiver Effekt auf schreibmotorische Leistungen von Parkinson-Patienten konnte durch den Einsatz visueller Hinweisreize (Cues) sowie externen Feedbacks aufgezeigt werden.
Eskalationstherapien bei Morbus Parkinson
Authors: Ceballos-Baumann A. O.
Published: March 2018

Medikamentenpumpen mit Apomorphin subkutan oder mit Levodopa/Carbidopa-Gel jejunal via perkutaner enteralen Gastrostomie (PEG) und die tiefe Hirnstimulation stellen die Eskalationstherapien bei Levodopa-Wirkfluktuationen und Dyskinesien dar, wenn die Optimierungsmöglichkeiten der oralen Medikation erschöpft sind. Bei unterschiedlicher Datenlage und Patientenpräferenzen dieser drei Eskalationstherapien ist die Beratung schwierig. Die Entscheidung muss in einem Abwägungsprozess zusammen mit dem Patienten und den Betreuungspersonen diskutiert werden. Ziel dieses CME-Artikels ist es, Indikationen sowie Vorteile und Nachteile dieser drei Eskalationstherapien bei der Parkinson-Krankheit vorzustellen.
Assoziation von aggressivem und impulsivem Verhalten mit klinischen Verlaufsparametern der Alkoholabhängigkeit
Authors: Soyka M. , Laqua C.
Published: March 2018

Ziele: Untersucht wurde die Assoziation von aggressivem und impulsivem Verhalten bei Alkoholabhängigen mit den klinischen Variablen Geschlecht, familiäre Belastung, Trinkmenge, Ersterkrankungsalter sowie psychiatrische Auffälligkeiten und Suizidversuche. Methoden: In die Arbeit eingeschlossen wurden 468 alkoholabhängige Patienten (364 Männer). Die Impulsivitäts- und Aggressionswerte wurden anhand der psychometrischen Selbstbeurteilungsskalen Barratt Impulsiveness Scale (BIS), Buss Durkee Hostility Inventory (BDHI), Temperament and Character Inventory (TCI) sowie NEO-Five-Factor-Inventory (NEO-FFI) ermittelt. Es wurde jeweils ein „median split“ der Summenwerte des BIS, Buss Durkee Physical Assault (tätlicher Angriff), Buss Durkee Irritability (Reizbarkeit), TCI und NEO-FFI durchgeführt. Ergebnisse: Es konnte kein Zusammenhang zwischen aggressivem Verhalten und dem Geschlecht sowie der familiären Belastung mit Alkoholstörungen festgestellt werden. Dagegen ergaben sich bei dem Ersterkrankungsalter, der täglichen Trinkmenge sowie den psychiatrischen Auffälligkeiten einschließlich der Suizidalität einige signifikante Zusammenhänge. Patienten mit höheren Werten bei den Unterpunkten Impulsivität, Reizbarkeit, tätlicher Angriff und Neugierverhalten wiesen ein statistisch jüngeres Ersterkrankungsalter auf. Auch tranken alkoholabhängige Personen mit höheren Werten bei Reizbarkeit, tätlichem Angriff und Neugierverhalten signifikant mehr als Personen mit niedrigeren Werten. Die Auftretenswahrscheinlichkeit von Suizidversuchen war assoziiert mit höheren Werten bei den Punkten Reizbarkeit, tätlicher Angriff und Neurotizismus sowie mit niedrigeren Werten bei der Extraversion. Unsere Ergebnisse entsprachen somit nur teilweise Cloningers Einteilung des Alkoholismus in zwei typische Verlaufsformen (Typ-I und II). Fazit: Die Ergebnisse zeigen eine Assoziation des aggressiven/impulsiven Verhaltens bei Alkoholabhängigen mit einigen klinischen Verlaufsparametern, jedoch nicht mit dem Geschlecht und der familiären Belastung. Es ist anzunehmen, dass Cloningers Prototypen lediglich zwei Extreme auf einer fortlaufenden Skala möglicher Ausprägungsformen des Alkoholabusus darstellen.
100 Jahre Kriegstraumata
Authors: Linden S.
Published: March 2018

Die psychologischen Reaktionen auf die traumatischen Fronterlebnisse des Ersten Weltkrieges erreichten epidemische Ausmaße, wie sie in keinem früheren Krieg beobachtet worden waren. Diese „Shell-shock“-Epidemie hatte einen profunden Einfluss auf das Leben der Soldaten in und hinter den Schützengräben und auf die Kampfmoral auf beiden Seiten der Front. Dieser Artikel analysiert auf der Grundlage von Krankenakten aus London und Berlin die unter den Begriffen „shell shock“ oder „Kriegsneurose“ zusammengefassten Krankheitsbilder. Die Dokumentation der klinischen Präsentationen zeigt die große Bandbreite der Symptome und Syndrome, aber auch klare Unterschiede zwischen den beiden Ländern, z. B. das gehäufte Auftreten psychogener nicht epileptischer Anfälle in Deutschland. Des Weiteren werden die damaligen und heutigen Erklärungsmodelle für derartige traumatische Reaktionen diskutiert. Wie damals schwingt auch heute das Pendel zwischen den beiden Polen der organischen und psychischen Genese. Schließlich werden die wesentlichen Therapieverfahren der Militärpsychiatrie und -neurologie des Ersten Weltkrieges dargestellt. Sowohl die Frage des Erklärungsmodells als auch die Suche nach der angemessenen Therapie für funktionelle neurologische Störungen haben heute wieder eine große Aktualität.
Behandlung psychisch belasteter und traumatisierter Asylsuchender und Flüchtlinge
Authors: Kluge U.
Published: March 2018

Der Beitrag gibt eine einführende Übersicht über Zahlen und Fakten, gesundheitsrechtliche Hintergründe und die aktuelle psychosoziale Situation von Geflüchteten und Asylsuchenden in Deutschland. Dargestellt werden die Herausforderungen für die psychiatrische, psychotherapeutische und psychosoziale Versorgung. Anhand eines erweiterten Traumabegriffes, welcher neben den medizinischen, psychologische, politische und soziale Zugänge berücksichtigt, werden Chancen und Schwierigkeiten in der Versorgung aufgezeigt. Abschließend wird anhand der Erfahrungen des Zentrums für Interkulturelle Psychiatrie und Psychotherapie (ZIPP) der Klinik für Psychiatrie und Psychotherapie der Charité Universitätsmedizin Berlin, Campus Mitte das Spannungsverhältnis zwischen therapeutischem und gesellschaftspolitischem Alltag dargestellt. Als Ausblick werden neuere Projekte und Initiativen an der Klinik für Psychiatrie vorgestellt.
Hans Fallada und der Neoanalytiker Dr. Harald Schultz-Hencke
Authors: Neumärker K.-J.
Published: March 2018

Das Leben des Hans Fallada (1893–1947), mit bürgerlichem Namen Rudolf Ditzen, ist gekennzeichnet durch Aufenthalte in psychiatrischen Kliniken, Heilstätten für Nerven- und Gemütskranke sowie Gefängnissen. Seine schriftstellerische Kreativität – mehr als 30 Bücher schrieb er – war von Abhängigkeit zu Nikotin, Morphium, Alkohol und Medikamenten begleitet. Ärztliche Interventionen waren vielfach, aber ohne nachhaltigen therapeutischen Erfolg. Bislang unbekannt ist die Tatsache, dass sich 1946 auch der Neoanalytiker Harald Schultz-Hencke und Annemarie Dührssen um Falladas Gesundheitszustand bemühten.
Elective Surgery on Factor VIII Inhibitor Patients Using Continuous Infusion of Recombinant Activated Factor VII
Authors: Ludlam Christopher , Collins Peter , Hay Charles , Wilde Jonathan , Grigeri Alessandro , Melsen Tina , Savidge Geoffrey , Smith Mark
Published: March 2018

We examined recombinant activated factor VII (rVIIa) administered by continuous infusion to eight patients with inhibitors to factor VIII, undergoing elective surgery. rVIIa was infused at a fixed rate of 16.5 μg/kg/h for a median of 13.5 days (range 1-26). There was effective haemostasis at this infusion rate in only one of two minor procedures and two of six major operations. Three patients experienced excessive bleeding despite plasma factor VII activity around 10 IU/ml. Serious bleeding occurred in two other patients caused by procedural errors unrelated to rVIIa and required re-operation. The median rVIIa clearance on day 1 was 57 ml/h/kg (range 18-100) and on day 3 was 100 ml/h/kg (range 61-200). Clearance on the final infusion day was not significantly different from day 3. The infusion did not induce pathological activation of the coagulation mechanism. The only thrombotic adverse events were two episodes of superficial thrombophlebitis of the infused vein in one subject. In conclusion, the 16.5 μg/kg/h infusion rate reliably achieves plasma factor VII activity levels of 10 IU/ml, but this level does not provide reliable haemostasis.
Relationship between Factor VII Activity and Clinical Efficacy of Recombinant Factor VIIa Given by Continuous Infusion to Patients with Factor VIII Inhibitors
Authors: Morfini M. , Rocino A. , Baudo F. , Scaraggi F. A. , Gringeri A. , Santagostino E.
Published: March 2018

A multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out.

Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 μg/kg (median: 100) were followed by CI given at median rates of 20 μg/kg/h for major surgery and of 17 and 16 μg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 μg/kg/h, respectively; median FVII:C: 14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.
Structure and Biology of Tissue Factor Pathway Inhibitor
Authors: Birktoft Jens , Steer Sarah , Bajaj S. Paul , Bajaj Madhu
Published: March 2018

Human tissue factor pathway inhibitor (TFPI) is a modular protein comprised of three Kunitz type domains flanked by peptide segments that are less structured. The sequential order of the elements are: an N-terminal acidic region followed by the first Kunitz domain (K1), a linker region, a second Kunitz domain (K2), a second linker region, the third Kunitz domain (K3), and the C-terminal basic region. The K1 domain inhibits factor VIIa complexed to tissue factor (TF) while the K2 domain inhibits factor Xa. No direct protease inhibiting functions have been demonstrated for the K3 domain. Importantly, the Xa-TFPI complex is a much more potent inhibitor of the VIIa-TF than TFPI by itself. Furthermore, the C-terminal basic region of TFPI is required for rapid physiologic inhibition of coagulation and is needed for the inhibition of smooth muscle cell proliferation. Although a number of additional targets for attachment have been reported, the C-terminal basic region appears to play an important role in binding of TFPI to cell surfaces. A primary site of TFPI synthesis is endothelium and the endothelium-bound TFPI contributes to the antithrombotic potential of the vascular endothelium. Further, increased levels of plasma TFPI under septic conditions may represent endothelial dysfunction. We have proposed that the extravascular cells that synthesize TF also synthesize TFPI providing dual components necessary for the regulation of clotting in their microenvironment. Like the TF synthesis in these cells is augmented by serum, so is the case with the TFPI gene expression. TFPI gene knock out mice reveal embryonic lethality suggesting a possible role of this protein in early development. Since TF-induced coagulation is thought to play a significant role in many disease states, including disseminated intravascular clotting, sepsis, acute lung injury and cancer, recombinant TFPI may be a beneficial therapeutic agent in these disease states to attenuate pathologic clotting. The purpose of this review is to outline recent developments in the field related to the structural specificity and biology of TFPI.
A New Blood Corpuscle
Authors: Gaetano Giovanni de
Published: March 2018

At the occasion of the first centennial anniversary of Giulio Bizzozero’s death (1901), an impossible interview is presented to honour this distinguished and creative investigator. The imaginary conversation between a reporter and Bizzozero – aged 36 years – takes place at the University of Turin in 1882, few months after Bizzozero’s announcement of the discovery of a new blood corpuscle with seemingly important function in thrombosis and blood coagulation. “An investigator who is not prepared in advance to look for other than the known elements – says Bizzozero – will be attracted only by the red and white corpuscles.”

Having discovered blood platelets, Bizzozero, convinced that scientific and social progress should proceed hand in hand, will turn – as a scientist and a member of the Italian Kingdom’s Senate – to such social issues as the welfare of the poor.

He will die in Turin, aged 55 years, shortly after Giuseppe Verdi, few months before the conferment of the first Nobel Prize for Medicine (to E. von Behring).
Protein C Inhibitor Regulates the Thrombin-Thrombomodulin Complex in the Up- and Down Regulation of TAFI Activation
Authors: Mosnier Laurent , Elisen Marc , Meijers Joost , Bouma Bonno
Published: March 2018

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a carboxypeptidase B-like proenzyme that after activation by thrombin down regulates fibrinolysis. Thrombomodulin (TM) stimulates the activation of both TAFI and protein C whereas activated protein C (APC) inhibits the activation of TAFI by down regulating thrombin generation. Recently, protein C inhibitor (PCI) was identified as a potent inhibitor of thrombin bound to TM and it can thereby regulate the balance between TAFI activation, and inhibition of TAFI activation by APC. Both in a purified system and in plasma, activation of TAFI and protein C by IIa-TM could be inhibited by PCI. Previously we found in plasma that at low concentrations (~1 nM), TM predominantly stimulated the activation of TAFI whereas at higher concentrations of TM (~10 nM) the activation of protein C resulted in inhibition of the activation of TAFI. In agreement with this, PCI inhibited the activation of TAFI at 1 nM TM whereas at 10 nM TM PCI inhibited the activation of protein C resulting in an increase in the activation of TAFI. This suggests that PCI can up regulate TAFI activation by inhibiting the protein C activation. PCI may therefore be an important regulator in the balance between coagulation and fibrinolysis by differentially inhibiting the activation of TAFI and of protein C. The local TM concentration plays an important role in the outcome of this process.
Treatment of femoral and tibial fractures in puppies by elastic plate osteosynthesis
Authors: Meige F. , Autefage A. , Sarrau S.
Published: March 2018

Seventeen puppies, two to four months old, with a femoral (n=12) or tibial (n=5) diaphyseal fracture were treated by elastic plate osteosynthesis with a Veterinary Cuttable Plate (VCP) or straight plate. In one case of femoral fracture treated with a VCP, plate bending due to an excessive elasticity of the implant was observed three days after the osteosynthesis and surgical revision was required. Two cases of femoral overgrowth and one case of slight femoral head and neck retroversion were identified during the radiographic follow-up but without any clinical consequences. Bone healing was obtained for all fractures four to eight weeks (5.64±0.88 weeks) after the surgical procedure, and functional results were excellent in all cases. Our study confirms that elastic plate osteosynthesis with either a VCP or straight plate can be used to treat femoral diaphyseal fractures in medium and large breed puppies less than four months old, but that modification of implant elasticity or rigid osteosynthesis use is required when such puppies reach four months. The same technique can also be used successfully to treat tibial fractures in puppies younger than four months old.
Frequency and distribution of patellar luxation in dogs
Authors: Alam M. R. , Lee J. I. , Kang H. S. , Kim I. S. , Park S. Y. , Lee K. C. , Kim N. S.
Published: March 2018

This study investigated the frequency and distribution of patellar luxation in the dogs presented to the Chonbuk National University Animal Medical Centre during January 2000 to September 2005. Patellar luxations were classified as medial or lateral, and unilateral or bilateral, were graded I to IV, and were subdivided according to age, sex and size of the dogs. The incidence of medial patellar luxation (MPL) was greater than the incidence of lateral patellar luxation (LPL) in both small and large dogs. Small-breed dogs were admitted almost exclusively with MPL. LPL was found uncommon; however it was observed more often in larger-breed dogs. Surgical correction was performed primarily in the dogs (165 stifles in 111 dogs) with grade II, III and IV patellar luxations following different surgical techniques. The combination of the surgical techniques was found to be more effective for the management of the disease. The prognosis was found to be favourable, because when the grade was low, the dog was younger, without cruciate ligament rupture, and as the surgical correction was performed with combination of more techniques.
Chondrokalzinose des Hüftgelenks
Authors: Hubert J. , Rüther W. , Hawellek T.
Published: March 2018

Die Chondrokalzinose des Hüftgelenks ist gekennzeichnet durch Calcium-Phosphat-Kristall-Ablagerungen im hyalinen Knorpel der Hüfte und im Faserknorpel des Labrums acetabulare. Physikochemisch wie auch in ihrem pathogenetischen Potenzial werden zwei Gruppen von Calcium-Phosphat-Kristallen unterschieden: BCP-und CPPD-Kristalle. Bei der Chondrokalzinose lassen sich beide Minerale nachweisen. Es ist unklar, ob die beiden Kristallformen eine unterschiedliche Pathogenese und klinische Bedeutung haben. Calcium-Phosphat-Kristalle können das Hüftgelenk sowohl auf biomechanischer als auch auf biochemischer Ebene schädigen. Sie können eine kristallbedingte Synovialitis erzeugen. Möglicherweise tragen auch Nozizeptoren im Labrum actebulare zur Schmerzentstehung im Hüftgelenk bei. Die Prävalenz von Calcium-Phosphat-Kristallen im Hüftgelenk wird durch die schwierige Diagnostik vermutlich unterschätzt. Es steht aktuell nur eine symptomatische Therapie mit antiinflammatorischer Schmerzmedikation zur Verfügung, ein kausaler Therapieansatz fehlt weiterhin.
Neue Antikoagulanzien
Authors: Bauersachs R. M.
Published: March 2018

Dieser Übersichtsartikel referiert den aktuellen Stand der Entwicklungen auf dem Gebiet der neuen Antikoagulanzien. Erläutert werden unterschiedliche Angriffspunkte in der Gerinnungskaskade: Hemmung der Initiationsphase, Faktor-Xa- oder Thrombinhemmung. Der Schwerpunkt liegt bei den Substanzen in fortgeschrittener Entwicklung, die die Phase-II-Studien zur venösen Thromboembolie (VTE)-Prophylaxe als ˶proof of concept“ erfolgreich abgeschlossen haben.

Bei den Faktor-Xa-Inhibitoren ist Fondaparinux als indirekter Hemmer bereits für die Prophylaxe und die Therapie thromboembolischer Erkrankungen sowie das akute Koronarsyndrom zugelassen (OASIS 5 und 6). Rivaroxaban ist der erste direkte Faktor-Xa-Hemmer, für den eine Zulassung für die Indikation VTE-Prophylaxe beantragt wurde. Die erste Studie aus dem RECORD 1–4-Programm wurde abgeschlossen, die Studien zur Therapie von VTE (EINSTEIN) und zur Schlaganfallprophylaxe bei Vorhofflimmern (ROCKET AF) befinden sich in Phase III, Der Einsatz bei akutem Koronarsyndrom wird ebenso wie bei Apixaban in Phase II untersucht. Die ADOPT-Studie mit Apixaban zur VTEPrävention bei internistischen Indikationen und die BOTTICELLI- Studie bei Vorhofflimmern haben Phase III erreicht. Nachdem Ximelagatran zurückgezogen werden musste, ist Dabigatran der am weitesten entwickelte direkte Thrombininhibitor, dessen umfangreiches Phase-III-Programm REVOLUTION vorgestellt wird und der sich für die Indikation VTE-Prophylaxe ebenfalls bereits im Zulassungsverfahren befindet.
Viral haemorrhagic fever and vascular alterations
Authors: Aleksandrowicz P. , Wolf K. , Falzarano D. , Feldmann H. , Seebach J. , Schnittler H.
Published: March 2018

Pathogenesis of viral haemorrhagic fever (VHF) is closely associated with alterations of the vascular system. Among the virus families causing VHF, filoviruses (Marburg and Ebola) are the most fatal, and will be focused on here. After entering the body, Ebola primarily targets monocytes/ macrophages and dendritic cells. Infected dendritic cells are largely impaired in their activation potency, likely contributing to the immune suppression that occurs during filovirus infection. Monocytes/macrophages, however, immediately activate after viral contact and release reasonable amounts of cytokines that target the vascular system, particularly the endothelial cells.

Some underlying molecular mechanisms such as alteration of the vascular endothelial cadherin/catenin complex, tyrosine phosphorylation, expression of cell adhesion molecules, tissue factor and the effect of soluble viral proteins released from infected cells to the blood stream will be discussed.
Die Bedeutung der Tumeszenz-Lokalanästhesie in der ambulanten Varizenchirurgie
Authors: Sommer B. , Hagedorn M. , Sattler G.
Published: March 2018

Die Tumeszenzlokalanästhesie (TLA) wurde vor zehn Jahren von dem amerikanischen Dermatologen und Pharmakologen J. Klein zur Erleichterung der kosmetischen Fettabsaugung eingeführt. Nachdem sich diese Form der großen Lokalanästhesie außerordentlich gut bewährt hatte, wurden ihre speziellen Vorteile nach und nach auch für andere Indikationen genutzt, so auch in der Phlebologie. In diesem Beitrag werden Vor- und Nachteil der Methode besprochen, soweit sie für die Phlebologie bedeutsam sind.
Toxische Reaktion oder Allergie vom Spättyp nach Sklerosierungstherapie?
Authors: Szliska Christiane , Freitag M. , Straube Myrjam , Fischer-Barth Wilma , Altmeyer P. , el Gammal S. , Seifarth Dagmar
Published: March 2018

Bei einer 39jährigen Patientin mit einer chronischen Veneninsuffizienz beidseits wurde eine Sklerosierungstherapie durchgeführt. Die Patientin reagierte an den mit Varigloban® verödeten Stellen sieben Wochen nach Verödungsbeginn mit Infiltraten, die von starkem Juckreiz begleitet waren, während die mit Aethoxysklerol® behandelten Bereiche reizlos blieben. Unter einer Therapie mit Prednison systemisch bildeten sich die Hautveränderungen vollständig zurück. Aufgrund der verzögerten Manifestation der Reaktion sowie der Mitreaktion aller mit Varigloban® behandelten Areale sollte an eine allergische Reaktion vom Spättyp gedacht werden. Wir konnten in der Intra- und Epikutantestung (nach 3wöchiger Steroidfreiheit) keine relevanten Typ-IV-Sensibilisierungen auf die Bestandteile und Varigloban® 4% selbst nachweisen, so daß hier möglicherweise ein anderer Mechanismus (z.B. toxische Genese) diskutiert werden muß.
Identification of a novel factor X deletion in combination with a missense mutation in the F10 gene
Authors: Oldenburg J. , Pavlova A. , Superti-Furga A. , Zieger B. , Hainmann I.
Published: March 2018

The genotype-phenotype relationship of compound heterozygous factor X deficiency in a young girl with severe factor X deficiency and bleeding symptoms is characterized. We identified a novel deletion of exon 6 and a missense mutation (c.856G>A, Val286Met) in exon 7 of the F10 gene leading to a compound heterozygous state and causing severe factor X deficiency. Therapeutic options for patients with symptomatic factor X deficiency are demonstrated.
Contraception and thrombophilia
Authors: Rott H. , Kruempel A. , Kappert G. , Nowak-Göttl U. , Halimeh S.
Published: March 2018

The risk of thromboembolic events (TE) is increased by acquired or inherited thrombo -philias (IT). We know that some hormonal contraceptives also increase the risk of thrombosis, thus, the use of such contraceptives are discussed as contraindications in women with IT. TEs are infrequent events in children and adolescents and in the majority of cases are associated with secondary complications from underlying chronic illness. Although adolescents are not typically considered to be at high-risk for TE, this cohort is frequently using hormonal contraception, leading to an increased risk in cases with unknown IT. The risk of TE with pregnancy alone is higher than associated with combined hormonal contra -ception. Progestin-only methods have not been found to increase the risk of TE with only moderate changes of coagulation proteins compared to normal reference values. Conclusion: Thrombophilic women are good candidates for progestin-only contraceptive methods.
Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare
Authors: Budde U. , Bentele K. , Christen H.-J. , Knapp R. , Mey A. , Schneppenheim R. , Eberl W.
Published: March 2018

To determine the frequency and clinical relevance of acquired von Willebrand syndrome (aVWS) due to antiepileptic therapy by valproic acid, we investigated 50 consecutive children in three neuropediatric institutions. Coagulation factors were determined in local laboratories before and three times after starting therapy with valproic acid. Parameters of von Willebrand factor (VWF) were additionally investigated in a reference laboratory including multimeric analysis. Significant changes in the coagulation system were found concerning fibrinogen (decreased from 287 ± 70 mg/dl to 222 ± 67 mg/dl; p < 0.001) and platelet count. Changes of VWF para -meters were also found but no patient developed laboratory defined aVWS. We conclude that the bleeding tendency observed in some children undergoing antiepileptic therapy with valproic acid is not due to aVWS.
Anticoagulants of primary haemostasis
Authors: Steigerwald U. , Walter U. , Kössler J.
Published: March 2018

Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases. Established antiplatelet agents use different pharmacological targets for this role. Acetylic salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of COX-1. Ticlopidin or clopidogrel are ADP-P2Y12 receptor antagonists. Tirofiban, abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb/IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation. The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase-5.

Efforts are made to improve antiplatetelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk. Current clinical studies focus on a new generation of ADP receptor antagonists (prasugrel, cangrelor and ticagrelor) as successors of ticlopidin and clopidogrel after coronary arterial interventions. Developments using platelet targets different from established drugs are thrombin receptor antagonists (like SCH530348) or thromboxane receptor antagonists (like S18886/terutroban) in patients with cerebrovascular events. Results from recent experimental studies could lead to new strategies for antiplatetelet therapy (like inhibition of GP Ib receptor, GP VI receptor, platelet-leukocyte interaction, factor XII and others) in the future.
The present state of aspirin and clopidogrel resistance
Authors: Guyer K. E.
Published: March 2018

Antiplatelet therapy has demonstrated significant clinical benefit in the treatment of acute coronary syndrome. However, as with any treatment strategy it has been unable to prevent all cardiovascular events. This is far from surprising when considering the complexity of arterial thrombosis and more specifically platelet physiology. This lack of treatment success has provoked the introduction of various diagnostic tests and testing platforms with the intent of guiding and optimizing clinical treatment. Such tests have resulted in the generation of clinical data that suggest suboptimal response to antiplatelet agents such as aspirin and clopidogrel.

In the case of both aspirin and clopidogrel, this suboptimal response has been termed resistance. Drug resistance would imply a lack of pharmacological response that has not been specifically investigated in many of the clinical studies performed to date. Rather, the term resistance has been used to describe various facets of platelet activation and aggregation relative to the testing method. Many of these measured parameters are not addressed in the therapeutic intent of the antiplatelet drug in question.
Monitoring anticoagulation of primary haemostasis
Authors: Calatzis A. , Leitner M. , Panzer S.
Published: March 2018

This article provides an overview on current commercially available methods to determine primary haemostasis as a target of drug-mediated anticoagulation. It focuses on whole blood methods only, and references the currently major achievements that have been reported with each method in respect to its clinical use. Advantages and disadvantages of the various methods are presented, based on considerations of platelet physiology, and on feasibility of the procedures.
Ulcus cruris bei einem 37jährigen Mann als Hinweis auf ein Klinefelter-Syndrom
Authors: Schilling S. , Kalodikis L. , Hermes B. , Kohl P. K. , Spreng A.
Published: March 2018

In der Ätiopathogenese des chronischen venösen Ulcus cruris spielen neben den vaskulären weitere hereditäre, hormonelle sowie stoffwechselbedingte Faktoren eine Rolle, welche differentialdiagnostisch berücksichtigt werden müssen. Bei einem 37jährigen Patienten mit Ulcus cruris auf dem Boden einer chronischen venösen Insuffizienz wurde aufgrund verkleinerter Hoden und einer Gynäkomastie, bei insgesamt eher weiblichem Körperbau, ein Klinefelter-Syndrom vermutet, das durch eine Chromosomenanalyse bestätigt wurde. In der Literatur finden sich Hinweise darauf, daß hypostatische Ulcera crurum bei Klinefelter-Patienten 20- bis 50mal häufiger auftreten als in der Normalbevölkerung. Nach Ausschluß einer postthrombotischen Genese des Ulkus ergaben weiterführende Laboruntersuchungen erhöhte Kardiolipin-IgG-Antikörper und einen ebenfalls erhöhten Wert für den Plasminogen-Aktivator-Inhibitor, dessen Aktivität ebenfalls eine Rolle in der Pathogenese der Ulzera bei Klinefelter-Patienten spielen soll.