bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemostatic Risk Factors and Arterial Thrombotic Disease
Authors: Siscovick David , Rosendaal Frits , Reiner Alexander
Published: March 2018

The pathogenesis of arterial thrombotic disease involves multiple genetic and environmental factors related to atherosclerosis and thrombosis. Acute thrombosis at the site of a ruptured, lipid-rich atherosclerotic plaque is the usual precipitating event in the transition from stable or subclinical atherosclerotic disease to acute myocardial infarction (MI), stroke, or peripheral arterial occlusion (1). Pathologic studies of coronary arteries in acute MI suggest that the acute thrombosis likely involves activation of both platelets and the coagulation system.
Fc-receptor Dependent Platelet Aggregation Induced by Monoclonal Antibodies against Platelet Glycoprotein Ib or von Willebrand Factor
Authors: Cauwenberghs Nancy , Schlammadinger Agotha , Vauterin Stephan , Cooper Susan , Descheemaeker Gretel , Tornai Istvan , Deckmyn Hans
Published: March 2018

In this paper we describe two pathways leading to platelet activation by crosslinking glycoprotein (GP) Ib to the platelet Fc-receptor (FcγRII). First the monoclonal antibody (MoAb) 9C8, raised against human platelet GPIbα, dose-dependently induced platelet aggregation of citrate-anticoagulated platelet-rich plasma, an effect that can be inhibited by several activation inhibitors. The FcγRII-inhibitory MoAb IV.3 was able to prevent the aggregatory effects of MoAb 9C8, indicating that crosslinking of the antigen GPIbαto the FcγII-receptor is necessary for the activating effect. Secondly we observed a synergistic activating effect of two anti-von Willebrand factor (vWF) MoAbs 1C1E7 and B724, both known to enhance vWF binding to GPIbαin the presence of shear or ristocetin. When these antibodies are added together to PRP, platelet aggregation is induced without further need for an additional modulator. This effect can be blocked by either MoAb IV.3 or an inhibitory anti-GPIbαMoAb, indicating that again the platelet activation results from signaling through FcγRII crosslinked to vWF bound to GPIbα. In addition, both the anti-GPIbαMoAb 9C8, or the two anti-vWF MoAbs 1C1E7 and B724 induce genuine platelet activation, as evidenced by the secretion of ATP and protein tyrosine phosphorylation. These findings with both anti-GPIbαand anti-vWF MoAbs add further proof to recent reports demonstrating an interaction between the platelet receptors GPIbαand FcγRII, suggesting a role for the FcγII-receptor in GPIb-related signaling.
High Density Lipoproteins Induce Cell Cycle Entry in Vascular Smooth Muscle Cells Via Mitogen Activated Protein Kinase-dependent Pathway
Authors: Junker Ralf , Pulawski Ewa , Fobker Manfred , Levkau Bodo , Eckardstein Arnold von , Seedorf Udo , Assmann Gerd , Walter Michael , Nofer Jerzy-Roch
Published: March 2018

In this study we found that HDL acts as a potent and specific mitogen in vascular smooth muscle cells (VSMC) by stimulating entry into S-phase and DNA synthesis in a time- and concentration-dependent manner, induction of cyclins D1, E, and A, as well as activation of cyclin D-dependent kinases as inferred from phosphorylation of the retinoblastoma protein (pRb). Moreover, HDL induced activation of the mitogen-activated protein kinase pathway including Raf-, MEK-1, and ERK1/2, as well as the expression of proto-oncogen c-fos, which is controlled by ERK1/2. PD98059, an inhibitor of MEK-1 blocked the mitogenic activity of HDL and cyclin D1 expression. HDL-induced VSMC proliferation, cell cycle progression, cyclin D1 expression, and activation of the Raf-1/MEK-1/ERK1/2 cascade were blocked by pre-incubation of cells with pertussis toxin indicating involvement of trimeric G-protein. By contrast, none of these responses was inhibited by the protein kinase C inhibitor, GF109203X. The mitogenic effects of native HDL were not mimicked by apo A-I, reconstituted HDL containing apo A-I, or cholesterol-containing liposomes. In conclusion, HDL possesses an intrinsic property to induce G-protein- and MAP-kinase-dependent proliferation and cell cycle progression in VSMC. The strong and specific mitogenic effect of HDL should be taken into account, when therapeutic strategies to elevate the plasma level of these lipoproteins are developed.
Symptomatic Onset of Severe Hemophilia A in Childhood is Dependent on the Presence of Prothrombotic Risk Factors
Authors: Halimeh S. , Kurnik K. , Schobess R. , Wermes C. , Junker R. , Kreuz W. , Pollmann H. , Nowak-Göttl U. , Escuriola Ettingshausen C.
Published: March 2018

It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and anti-thrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.
Beneficial Effect of the Active Form of Vitamin D3 against LPS-induced DIC but not against Tissue-factor-induced DIC in Rat Models
Authors: Aoshima Keiji , Suga Yukio , Yamazaki Masahide , Morishita Eriko , Saito Masanori , Miyamoto Ken-ichi , Nakao Shinji , Asakura Hidesaku
Published: March 2018

1 α,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; I. V.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug’s efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.
Tissue Factor Pathway Inhibitor (TFPI) Levels in the Plasma and Urine of Children with Meningococcal Disease
Authors: Eling M. , Stephens A. C. , Oragui E. E. , Rivers R. P. A. , Levin M.
Published: March 2018

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the TF-dependent coagulation system. In meningococcal disease, up-regulation of tissue factor expression on blood monocytes and possibly on endothelial cells has the potential to trigger the activation of the TF-dependent pathway of coagulation. Intravascular coagulation is considered to be a major pathogenic factor in meningococcal disease. We postulated that imbalance between TF expression and TFPI concentration might lead to uncontrolled coagulation in meningococcal disease. The aim of this study was to assess the levels of total TFPI in the plasma of patients with meningococcal disease and assess whether increased leaking of the TFPI was occurring. TFPI antigen levels and activity were measured in the plasma of 54 patients with meningococcal disease, and 13 healthy control children. TFPI antigen level were also determined in the urines of 14 of the 54 and 9 healthy control children. Plasma TFPI activity was reduced in the meningococcal diseased patients (mean of 0.503 ± 0.341 U/ml; control, 1.010 ± 0.199 U/ml; p <0.0001), as was the TFPI antigen levels (mean of 54.85 ± 35.05 ng/ ml; Control, 94.51 ± 11.44 ng/ml; p <0.0001). In contrast, TFPI antigen levels were increased in the urine of these patients when compared to the levels found in the urine of the healthy control children (mean of 12.96 ± 5.392 ng/mmol creatinine; Control, 0.239 ± 0.191 ng/mmol creatinine; p <0.035). A lack of correlation between TFPI-activity and TFPI-antigen plasma levels was observed (r = 0.002, p = 0.85). This data is consistent with the hypothesis that in meningococcal disease there is increased inactivation of plasma TFPI by the up regulation of tissue factor expression but in addition increased clearance of TFPI in urine is occurring.
Genetic Variation of the Extra-large Stimulatory G Protein α-Subunit Leads to Gs Hyperfunction in Platelets and Is a Risk Factor for Bleeding
Authors: Freson Kathleen , Hoylaerts Marc , Jaeken Jaak , Eyssen Marijke , Arnout Jozef , Vermylen Jos , Geet Chris Van
Published: March 2018

Alternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimulatory G-protein α-subunit (Gsα) and the extra-large stimulatory G-protein α-subunit (XLsα), are located on the imprinted chromosomal region 20q13.12-13. We presently report a functional polymorphism in the imprinted XL-GNAS1 gene. In three patients, a 36 bp insertion and two basepair substitutions flanking this insertion were found in the paternally inherited XL-GNAS1 exon 1. They clinically manifest an enhanced trauma-related bleeding tendency and a variable degree of mental retardation. A platelet aggregation inhibition test to evaluate Gs function was developed. Their platelets display Gs hyperfunction and an enhanced cAMP generation upon stimulation of Gs-coupled receptors. The prevalence of the XLsα insertion in a normal control group was 2.2%. Normal controls, inheriting the insertion maternally, had a normal platelet Gs activity, whereas controls inheriting the insertion paternally had increased inducible platelet Gs activity, defining the insertion as a functional polymorphism. This paternally inherited XLsα insertion represents a new genetic cause of an inherited bleeding tendency, although to a variable degree.
Plasmin Induces Local Thrombolysis without Causing Hemorrhage: A Comparison with Tissue Plasminogen Activator in the Rabbit
Authors: Landskroner Kyle , Novokhatny Valery , Zimmerman Thomas , Kong Mansze , Kanouse Joel , Jesmok Gary , Marder Victor
Published: March 2018

The direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites.

These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.
Thrombophilic Risk Factors in Patients with Central Retinal Vein Occlusion
Authors: Marcucci Rossella , Bertini Laura , Giusti Betti , Brunelli Tamara , Fedi Sandra , Cellai Anna Paola , Poli Daniela , Pepe Guglielmina , Abbate Rosanna , Prisco Domenico
Published: March 2018

Few and contrasting data are available on the prevalence of hemostatic risk factors in patients with central retinal vein occlusion (CRVO). Aim of this study was to investigate the metabolic and inherited risk factors for venous thrombosis in 100 CRVO patients (age: 59 yrs; range 18-77) and in 100 controls (age: 56 yrs; range 18-84). In patients homocysteine (Hcy) levels were significantly higher than in controls and were affected by the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (p <0.001). The prevalences of activated protein C resistance (APCR), factor V Leiden positivity, elevated PAI-1 and Lp(a) levels were significantly higher in patients with respect to controls. At multivariate analysis, only hyperhomocysteinemia (OR 11, 95% CI 3.6-36.2; p <0.0001) and elevated PAI-1 levels (OR 8.9, 95% CI 3.5-41.3; p <0.01), in addition to hypertension (OR 40.5, 95% CI 8.6-188.8; p <0.00001) and hypercholesterolemia (OR 3.1, 95% CI 1.6-20.5; p <0.05), were independent risk factors for CRVO. These data demonstrate a potential role of hemostatic risk factors in the pathophysiology of CRVO.
Phenotypic APC Resistance in Carriers of the A20210 Prothrombin Mutation Is Associated with an Increased Risk of Venous Thrombosis
Authors: Tosetto Alberto , Simioni Monica , Ruggeri Marco , Madeo Domenico , Rodeghiero Francesco , Castaman Giancarlo
Published: March 2018

We hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 ± 0.12 vs. 0.95 ± 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 ± 0.08 vs. 1.05 ± 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.
Incidence, Natural History and Risk Factors of Deep Vein Thrombosis in Elective Knee Arthroscopy
Authors: Hunt N. , Strachan R. K. , Nicolaides A. N. , Delis K. T.
Published: March 2018

Aims: to determine the incidence, anatomical distribution and extent of deep vein thrombosis (DVT) in limbs undergoing elective unilateral knee arthroscopy without active prophylaxis, to evaluate its effect on venous function following early diagnosis, and to quantify the impact of risk factors on its incidence. Methods: 102 consecutive patients undergoing unilateral knee arthroscopy without prophylaxis were studied. A history was obtained with emphasis on the risk factors for thromboembolism, and physical examination and colour duplex were performed prior to and within a week after surgery. Patients who developed calf DVT were given aspirin (150 mg) and compression stockings; those with proximal DVT were admitted for anticoagulation (heparin followed by warfarin). Follow-up (mean 118 [range 84-168] days) entailed weekly physical and duplex examinations during the first month and monthly thereafter. Results: 8 patients developed calf DVT in the operated leg (incidence 7.84% [95% Cl: 2.7%-13.2%]); thrombosis was asymptomatic in 4 of those (50%), caused calf tenderness in 4 (50%) and a positive Homan’s sign in one (12.5%). DVT occurred in the following veins: peroneal 4 subjects (50%), soleal 4 (50%), gastrocnemial 2 (25%) and tibial 2 (25%). Propagation of a calf DVT to the popliteal vein was identified in 1 patient (12.5%). After a median period of 118 days, total clot lysis was found in 50% of DVTs, with partial thrombus resorption in the rest; reflux in the thrombosed veins was present in 75% of limbs with DVT. 43% of patients had 1 risk factor for DVT and 20% had ≥2. The incidence of DVT was higher amongst those with two or more risk factors for thromboembolism (p <.05) or those with previous thrombosis alone (p <.005). Symptoms or signs of pulmonary embolism were not documented. Conclusions: Elective unilateral knee arthroscopy performed without prophylaxis is complicated by ipsilateral calf DVT in 7.8% (95% CI: 2.7%-13.2%) of cases. The risk is higher in the presence of previous thrombosis (relative risk: 8.2) and two or more risk factors for DVT (relative risk: 2.94). Thrombosis may propagate to the proximal veins, despite early diagnosis. 50% of calf clots totally lyse in 4 months, yet reflux develops in at least 75% of limbs with DVT. Further studies to determine optimal prophylaxis are warranted.
Fibrin D-dimer, Markers of Coagulation Activation and the Risk of Major Ischaemic Heart Disease in the Caerphilly Study
Authors: Rumley Ann , Sweetnam Peter , Yarnell John , Rumley Joseph , Lowe Gordon
Published: March 2018

We have previously reported that plasma fibrin D-dimer (a marker of turnover of cross-linked fibrin) showed a strong and independent association with incident ischaemic heart disease (IHD) in the Caerphilly Study cohort of 1,998 men aged 49-65. To establish the specificity of this finding, we assayed plasma samples from this cohort with a more specific assay for fibrin D-dimer: this showed an association with incident IHD which was at least as strong and independent as that for the original assay (odds ratio, OR for top fifth compared to bottom fifth 3.79; 95% CI 1.77-8.10; p < 0.0001). To establish potential causes of the increased fibrin turnover, we also assayed several potential markers of coagulation activation or thrombotic tendency (prothrombin fragment F1+2, thrombin-antithrombin complexes, factor VIIc, activated partial thromboplastin time [APTT] and activated protein C resistance): none of these variables were associated with incident IHD in this cohort. We suggest that further studies are required to establish the causes of increased cross-linked fibrin turnover, which is associated with incident IHD in the general population when measured by a specific assay.
Ser968Thr Mutation within the A3 Domain of Von Willebrand Factor (VWF) in Two Related Patients Leads to a Defective Binding of VWF to Collagen
Authors: Lavergne Jean-Maurice , Juhan-Vague Irène , Obert Bernadette , Cherel Ghislaine , Meyer Dominique , Girma Jean-Pierre , Ribba Anne-Sophie , Loisel Irmine
Published: March 2018

We report the identification of a new mutation of von Willebrand Factor (VWF) gene within exon 30 occurring in two related patients (mother and daughter) with a hemorrhagic syndrome. A T A transvertion at nucleotide 5441 was found changing the serine 968 to threonine of the mature VWF subunit (S1731T of the preproVWF). The Ser968Thr mutation is located within the VWF A3 domain which interacts with type I and III collagens. Both patients were found to be heterozygous for the mutation. The propositus (daughter) exhibited a slightly prolonged bleeding time, levels of VWF:Ag and VWF:RCo at the lower limit of normal, contrasting with normal levels of VIII:C. Her mother exhibited borderline bleeding time and moderately decreased levels of VWF and VIII:C. In both patients multimeric structure of VWF and ristocetin- as well as botrocetin-induced binding of VWF to GPIb were normal; however both patients repeatedly showed decreased binding of VWF to collagen. The Ser968Thr substitution was reproduced by site-directed mutagenesis on the full-length cDNA of VWF. The mutated recombinant VWF (rVWF), T968rVWF, and the hybrid S/T968rVWF were transiently expressed by COS-7 cells. Both rVWF exhibited normal multimeric pattern and normal ristocetin- as well as botrocetin-induced binding to GPIb. T968rVWF showed significantly decreased binding to collagen while the hybrid S/T968rVWF bound to collagen in a similar way to that of the patients’ plasma VWF. Thus, our data demonstrate that the Ser968Thr mutation of the VWF A3 domain is clearly responsible for the abnormal binding of VWF to collagen observed in both patients. The Ser968Thr substitution of the VWF is the first mutation identified in two patients leading to a decreased affinity of VWF for collagen and a normal multimeric structure.
A Barbourin-albumin Fusion Protein that Is Slowly Cleared In Vivo Retains the Ability to Inhibit Platelet Aggregation In Vitro
Authors: Marques Janey , George Jacob , Smith Ian , Bhakta Varsha , Sheffield William
Published: March 2018

Barbourin is a 73 amino acid venom protein that inhibits platelet aggregation. Recombinant barbourin (BARH6), rabbit serum albumin (RSAH6), and a barbourin-RSA fusion protein (barbourin-linker-albumin; BLAH6) were secreted from Pichia pastoris yeast, and purified by nickel-chelate affinity chromatography via their C-terminal hexahisti-dine (H6) tags. BARH6 and BLAH6 did not differ in their IC50s for inhibition of platelet aggregation using either human platelets stimulated with thrombin or ADP, or rabbit platelets stimulated with ADP. BARH6 and BLAH6 were also effective in inhibiting platelet aggregation in whole blood, and formed complexes with platelet integrin αIIbβ3. The terminal catabolic half-life of BLAH6 approached that of RSAH6[3.4 ± 0.2 versus 4.0 ± 0.1 days (n = 4 ± SD)], but was substantially increased relative to that of BARH6 [0.15 ± 0.03 days (n = 3 ± SD)]. Our results suggest that fusion to albumin slows the clearance of barbourin in vivo, while preserving its ability to inhibit platelet aggregation.
Adenovirus-mediated Expression of a Truncated PDGFβ Receptor Inhibits Thrombosis and Neointima Formation in an Avian Arterial Injury Model
Authors: Ding Hongliu , Wang Rongqing , Marcel Robin , Fisher Daniel
Published: March 2018

Platelet-derived growth factor (PDGF) is a major mediator of neointima formation after arterial injury. We constructed a recombinant adenovirus, Ad/PDGFtr, that expresses the soluble extracellular domain of the murine PDGFβ receptor (PDGFtr). The expressed PDGFtr was appropriately glycosylated and secreted by chicken vascular smooth muscle cells (SMCs) in vitro. The expressed PDGFtr inhibited human PDGF-BB induced receptor autophosphorylation, and also inhibited PDGF-BB induced cell proliferation without affecting PDGF-AA induced mitogenesis. In vivo transduction of balloon-injured rooster femoral arteries with Ad/PDGFtr resulted in expression and secretion of the glycosylated PDGFtr. The expressed PDGFtr significantly inhibited neointima formation compared with controls. Neointima-associated thrombus was significantly reduced in Ad/PDGFtr transduced arteries compared with controls. Thus, in addition to impacting on SMC proliferation and migration, PDGF-BB plays a role in thrombus formation in response to arterial injury. Growth factor inhibition by localized gene delivery constitutes a powerful approach to intervene in the molecular pathways involved in vascular disease.
Temperamentskonzepte in der Psychopathologie
Authors: Jäger M.
Published: March 2018

Die Temperamentsforschung hat in der Psychopathologie eine lange Tradition. Hier sind beispielsweise die Beiträge von Ernst Kretschmer und Gottfried Ewald zu nennen, welche beide fließende Übergänge zwischen Temperaments- bzw. Persönlichkeitseigenschaften und manifesten psychischen Erkrankungen beschreiben. Allerdings wird von Kretschmer der Temperamentsbegriff deutlich weiter gefasst als dies bei Ewald der Fall ist. Karl Leonhard führte die Konzepte seines Lehrers Ewald weiter aus und bemühte sich, die Zusammenhänge zwischen akzentuierten Temperamentszügen, Persönlichkeitsstörungen und affektiven Psychosen weiter herauszuarbeiten. Demgegenüber konnte beispielsweise Kurt Schneider keine solchen Beziehungen bzw. Übergänge finden. Die hier diskutierten Fragen haben heute nicht an Aktualität verloren und sollten weiterhin Gegenstand empirischer Forschung sein. Hierzu stehen inzwischen standardisierte Instrumente zur Verfügung wie beispielsweise die von Hagop Akiskal entwickelte TEMPS-Skala.
Die klinische Relevanz von Temperament
Authors: Brieger P.
Published: March 2018

Nach Akiskal gibt es fünf Temperamente: hyperthym, zyklothym, reizbar, depressiv und ängstlich. Mittels TEMPS-A-Skala können diese bestimmt werden. Anhand eines Fallbeispiels wird die Komplexität dieses Ansatzes dargestellt. Methodische Grenzen dieses Temperamentsbegriffs werden erklärt sowie Ergebnisse aus Genetik, Verlaufsforschung und Forschung zu Komorbidität, die das Konzept unterstützen. Temperament hilft, affektive Störungen besser zu verstehen.
Stellenwert der Disulfiramtherapie heute?
Authors: Grosshans M. , Mutschler J.
Published: March 2018

Disulfiram nimmt in der Suchtmedizin eine besondere, oftmals kontroverse, Rolle ein. Das Medikament ist inzwischen über 60 Jahre für die Behandlung der Alkoholabhängigkeit in vielen Ländern zugelassen. Seit 2011 ist Disulfiram in Deutschland formal allerdings nicht mehr zugelassen, kann aber weiterhin als „Off-lable“-Medikament eingesetzt und über Auslandsapotheken bezogen werden. Dieser Umstand und eine mögliche Ausweitung der Einsatzgebiete machen neben dem Wissen um die therapeutischen Effekte auch fundierte Kenntnisse um Wirkung, Wechselwirkungen, Kontraindikationen und Nebenwirkungen von Disulfiram erforderlich. In der folgenden Übersicht soll eine aktuelle Überblick gegeben werden.
The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling?
Authors: Peppelenbosch Maikel , Spek Arnold , Versteeg Henri
Published: March 2018

Tissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.
Thromboprophylaxis following Caesarean Section
Authors: Thomson A. J. , Conkie J. A. , McCall F. , Walker I. D. , Greer I. A. , Ellison J.
Published: March 2018

Pharmacological thromboprophylaxis is increasingly being used after caesarean section to prevent venous thromboembolism. Although a variety of low molecular weight heparins (LMWH) have been used no comparative study exists on their effects on the haemostatic system in this situation. Furthermore, their antithrombotic effect may be mediated through effects other than their inhibitory effect on activated factor X. We compared the plasma anti-factor Xa activity, plasma concentration of tissue factor pathway inhibitor (TFPI) and the reduction in plasma thrombin-antithrombin (TAT) complex concentration in 30 women randomised to receive either dalteparin 5,000 IU anti-Xa once daily (n = 10), enoxaparin 4,000 IU anti-Xa once daily (n = 10) or tinzaparin 50 IU/kg anti-Xa (average dose 3,650 anti-Xa units) once daily (n = 10) following caesarean section. Sampling occurred at 0, 1, 3, 6, 12 and 24 h relative to time of dosing. All preparations produced an increase in mean anti-Xa assay (p <0.0001), a reduction in mean TAT (p <0.05) and an increase in mean TFPI concentration (p <0.05). Analysis of variance (ANOVA) revealed a significant difference between the LMWHs in terms of mean anti-factor Xa activity (p <0.005) and reduction in plasma TAT concentration (p <0.005). Post hoc analysis indicated that the anti-Xa values of the groups receiving enoxaparin and dalteparin were significantly higher than those of the group receiving tinzaparin (p <0.05), but not significantly different from each other. Post hoc analysis of the reduction in plasma TAT concentration showed the reduction to be significantly less in the group receiving enoxaparin compared to the dalteparin and tinzaparin groups (p <0.05), which did not differ significantly from each other. There was no significant difference between treatment groups with regard to plasma concentration of TFPI. These findings demonstrate that LMWHs differ in their effects on haemostatic parameters including thrombin generation as assessed by TAT. The increase in TFPI may be an additional mediator of LMWH’s antithrombotic effects. Although these findings demonstrate that LMWHs differ in their haemostatic effects, this does not necessarily infer a clinical difference between these agents.
Identification and Characterization of Two Novel Mutations (Q421K and R123P) in Congenital Factor XII Deficiency
Authors: Kanaji Sachiko , Osaki Koichi , Kuroiwa Mika , Sakaguchi Masao , Mihara Katsuyoshi , Niho Yoshiyuki , Okamura Takashi , Kanaji Taisuke
Published: March 2018

The factor XII genes of two unrelated factor XII-deficient Japanese families were screened, and two novel mutations were identified. A heterozygous mutation (Q421K) was identified in the gene of a cross-reacting material (CRM)-negative patient with reduced FXII activity (entitled Case 1). No mutations were discovered in the other allele. Case 2 was a CRM-negative patient with severe FXII deficiency. In this case, a homozygous mutation (R123P) was discerned. Expression studies in Chinese Hamster Ovary (CHO) cells demonstrated accumulation of mutant Q421K factor XII in the cell, and insufficient secretion, while the R123P mutant showed lower levels of accumulation than wild-type, and no evidence of secretion in culture supernatant. In the presence of proteasome inhibitor, all types of FXII (wild-type, Q421K, R123P) accumulated in the cells. Protease protection experiments using the microsomal fraction of these cell lines demonstrated that while 20% wild-type FXII (total wild-type:100%) and 10% R123P mutant (total R123P-type: 40%) were resistant to treatment with trypsin, 50% Q421K-type FXII (total Q421K-type:130%) remained resistant to digestion. From these results, we conclude that Q421K is less susceptible to proteasome degradation than wild-type, but is unable to exit the ER efficiently, resulting in insufficient secretion phenotype. In contrast, R123P is susceptible to proteasome degradation and is not secreted.
Localization of Blood Coagulation Factors In Situ in Pancreatic Carcinoma
Authors: Rucinska Monika , Zacharski Leo , Kozlowski Leszek , Zimnoch Lech , Piotrowski Zdzislaw , Kudryk Bohdan , Kisiel Walter , Wojtukiewicz Marek
Published: March 2018

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor; prothrombin; and factors VII, VIIIc, IX, X, XII, and subunit “a” of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.
Hepatic Thrombopoietin mRNA Is Increased in Acute Inflammation
Authors: Fandrey Joachim , Frackowski Urszula , Jelkmann Wolfgang , Wolber Eva-Maria
Published: March 2018

The plasma concentration of thrombopoietin (TPO) in general is inversely related to the mass of platelets and megakaryocytes. However, reactive thrombocytosis of inflammatory disease is accompanied by elevated TPO levels. To investigate whether the rate of TPO mRNA expression is altered during acute inflammation, rats were injected with bacterial lipopolysaccharide (LPS). After 6 h, total RNA from liver and kidney was reverse transcribed and analyzed by competitive PCR for TPO and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). LPS-treated rats showed a significant increase in hepatic TPO mRNA concentration. The ratio of TPO to GAPDH mRNA was 3.5 ± 0.6% in the livers of control rats and 8.3 ± 2.0% in the livers of LPS-treated rats (mean ± SD). Thus, reactive thrombocytosis of inflammatory disease might result from an increase in hepatic TPO production. Since platelets are involved in the immune reaction, reactive thrombocytosis may be a mechanism of host defense.
Identification of Critical Residues on Thrombin Mediating Its Interaction with Fibrin
Authors: Hall Scott , Gibbs Craig , Leung Lawrence
Published: March 2018

Thrombin binding to fibrin may be important in localizing thrombin to the site of vascular injury. However, fibrin-bound thrombin retains its catalytic activity toward fibrinogen, and may be prothrombotic under certain conditions. A collection of 52 purified thrombin mutants was used to identify those residues mediating the thrombin-fibrin interaction. Comparison of fibrinogen clotting activity with fibrin binding activity identified twenty residues involved in fibrinogen recognition with four of these residues important in fibrin binding (Lys65, His66, Tyr71, Arg73). No mutant was identified with normal clotting activity and deficient fibrin binding, suggesting that these two properties are not readily dissociable. A DNA thrombin aptamer that binds to these residues was able to inhibit the thrombin-fibrin interaction, and displace thrombin that was already bound. Mapping of these fibrin-binding residues on thrombin revealed that they are localized within exosite I, and comprise a subset of the residues important in fibrinogen recognition.
Comparison of the Responses of Global Tests of Coagulation with Molecular Markers of Neutrophil, Endothelial, and Hemostatic System Perturbation in the Baboon Model of E. coli Sepsis
Authors: Wada Hideo , Yamamuro Miho , Inoue Akiko , Shiku Hiroshi , Sakuragawa Nobuo , Redl Heinz , Peer Glenn , Taylor Fletcher
Published: March 2018

This study correlates changes in neutrophilic activity and endothelial injury with markers of hemostatic activity following the infusion of increasing concentrations of E. coli organisms. It focuses on the hemostatic response as a marker of microvascular injury and uses the response to increasing concentrations of E. coli to refine our definition of disseminated intravascular coagulation (DIC) and distinguish between a compensated (non-overt DIC) and uncompensated (overt DIC) response. We observed that the global coagulation tests reflected activation of the hemostatic system in a dose dependent manner (overt DIC) in the early phases (T+2 to 6 h) of the response to increasing concentrations of E. coli, but that they failed to do so in the late phases (T+ 24 to 48 h). We observed that molecular markers, soluble thrombomodulin and elastase, unlike thrombin/antithrombin and plasmin/antiplasmin complexes, remained elevated out to T+24 to 48 h indicating endothelial injury that persists beyond the initial inflammatory insult in compensated as well as uncompensated DIC.
A Novel Function of Extraerythrocytic Hemoglobin
Authors: Ohmura Sayuri , Sugiki Masahiko , Anai Keita , Maruyama Masugi , Yoshida Etsuo
Published: March 2018

Following wounding, the surrounding fibroblasts migrate towards the clotted blood in the wounded space to form granulation tissue resulting in wound repair. One of the most abundant proteins in the wound is hemoglobin (Hb). The aim of the present study was to examine the effect of Hb on fibroblasts in producing components of the plasminogen-plasmin system which play an important role in wound healing. Human Hb Ao added to cultures of human fibroblasts elicited a dose-dependent increase in fibrinolytic activity. ELISA demonstrated an increased fibrinolytic activity due to increased urokinase-type plasminogen activator (uPA). An increase in tissue-type PA was also detected, while the type-1 PA inhibitor level remained unaffected. Globin showed a similar effect, while hemin and protoporphyrin IX exerted no effect. The influence of Hb was quenched when haptoglobin was added. Although northern blot analysis revealed no difference in uPA transcripts between stimulated and non-stimulated cells, immunopretipitation experiments confirmed an increased uPA synthesis in Hb- and globin-treated cells, suggesting that enhanced expression is achieved through translational regulation. These findings suggest a potential role for globin in modulating cellular functions during the process of wound healing.
Inactivation of Plasminogen Activator Inhibitor-1 Accelerates Thrombolysis of a Platelet-rich Thrombus in Rat Mesenteric Arterioles
Authors: Rupin Alain , Martin Frédéric , Vallez Marie-Odile , Bonhomme Edith , Verbeuren Tony
Published: March 2018

To investigate the role of active plasminogen activator inhibitor 1 (PAI-1) in the evolution of a microthrombus generated in the arteriolar microcirculation, the monoclonal antibody, 33H1F7, which transforms active PAI-1 to a tissue type plasminogen activator (t-PA) substrate, was evaluated in an arteriolar thrombosis model in the rat mesentery. Arterioles (200-300 μm) were stimulated electrically to create an endothelial lesion; ADP was then perfused for 2 min to induce the formation of a platelet-rich thrombus which lysed spontaneously in 140 ± 24 s. Two successive ADP superfusions produced comparable thrombi which lysed in comparable times. Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 μg/kg/min) was selected to be tested on the thrombosis model. Infusion of 33H1F7 beginning 10 min before the ADP application significantly reduced the lysis time in comparison to the control (123 ± 30 s versus 169 ± 33 s, P < 0.05, paired Student’s t-test) and the cumulative thrombus area during the lysis period was decreased by 56 ± 7%. These results demonstrate that inactivation of PAI-1 is able to accelerate lysis of a platelet-rich clot in a mesenteric arteriole of the rat. Thus active PAI-1 most likely participates to the resistance to thrombolysis in the arteriolar microcirculation and its inactivation may shorten ischemic periods after microvascular obstruction such as e.g. during cerebral stroke.
Lokale rt-PA-Lyse bei Paget-von-Schroetter-Syndrom
Authors: Hebgen A. , Daum K. H. , Fervers J. , Ludwig N.
Published: March 2018

Eine 39jährige, bislang gesunde Patientin stellte sich mit einer 2 Tage alten lividen und schmerzhaften Schwellung des rechten Armes im Sinne eines Paget-von-Schroetter-Syndroms vor. Nach duplexsonographischer und phlebographischer Diagnosebestätigung führten wir in Anbetracht der ausgeprägten klinischen Symptomatik eine lokale Lysetherapie mit insgesamt 30 mg rt-PA durch und konnten eine vollständige Rekanalisation der Vena axillaris und Vena subclavia erreichen.
Akuttherapie des Schlaganfalls
Authors: Eschenfelder Ch. C. , Zeller J. , Stingele R.
Published: March 2018

Die aktuellen Konzepte zur Behandlung der akuten zerebralen Ischämie sowie der Hirnblutung werden dargestellt. Die Indikationsstellung zur Thrombolyse im Standardfall und in besonderen Situationen, die Anwendung moderner MRT-Diagnostik und differenzialtherapeutische Überlegungen werden dargelegt. Bei der Therapie der Hirnblutung wird auf die Indikationsstellung zur neurochirurgischen Hämatomevakuation eingegangen und die akute hämostatische Therapie besprochen.
Direkte Thrombininhibition in der interventionellen Kardiologie
Authors: Heinze H. , Darius H.
Published: March 2018

Der direkte Thrombininhibitor Bivalirudin wurde im Rahmen der ACUITY-Studie bei 13 819 Patienten mit akutem Nicht-ST-Elevations-Koronarsyndrom prospektiv randomisiert untersucht. Dabei wurden drei antithrombotische Therapieregime im Rahmen eines frühinvasiven Vorgehens verglichen: Heparin plus Glykoprotein-IIb/IIIaRezerptorinhibitor (GPI), Bivalirudin plus GPI und Bivalirudin als Montherapie. Bezogen auf den Endpunkt der ischämischen Ereignisse war Bivalirudin allein vergleichbar mit Heparin plus GPI bei signifikant verringerter Rate von Blutungskomplikationen.
Antikörper als Helfer
Authors: Hagemeyer C. E. , Peter K. , Bode C. , Schwarz M.
Published: March 2018

Der Einsatz monoklonaler Antikörper hat einen enormen Fortschritt in der modernen Medizin ermöglicht. Der gezielte Ansatz an definierten molekularen Strukturen ermöglicht Therapiekonzepte, die zuvor undenkbar waren. Mittlerweile werden zahlreiche Antikörper klinisch eingesetzt, z. B. in der Onkologie, bei der Therapie chronisch-entzündlicher Krankheiten, Infektionskrankheiten und kardiovaskulärer Erkrankungen. Hierbei werden verschiedene Formate wie IgG-Moleküle, Fab-Fragmente und Einzelkettenantikörper eingesetzt. Einzelkettenantikörper stellen die kleinste funktionelle Form des Antikörpers dar und werden bevorzugt als rekombinate Antikörper verwendet. Fusion an radioaktive oder therapeutisch aktive Substanzen erweitern die therapeutischen Möglichkeiten der Antikörpertechnologie.

In dieser Übersichtsarbeit werden die Einsatzmöglichkeiten von Antikörpern als antithrombotisch und fibrinolytische Substanzen dargestellt. Hierbei erlaubt der Einsatz von Antikörpern einerseits die Entwicklung zielgerichteter antithrombotischer Substanzen, die z. B. eine konformationsabhängige Blockade des Thrombozytenaggregationsrezeptors GPIIb/IIIa ermöglichen. Andererseits kann durch Fusion von Antikoagulanzien an Antikörper, die dann die Funktion von Pilotmolekülen übernehmen, eine Anreicherung im Thrombus mit resultierender geringerer systemischer Blutungsneigung erreicht werden.
Nachbehandlung der pAVK nach Interventionen und Gefäßchirurgie mit Antikoagulanzien und Thrombozytenfunktionshemmern
Authors: Landgraf H.
Published: March 2018

Sowohl nach Gefäßoperationen als auch katheterinterventionellen Eingriffen bei pAVK erfolgt in der Regel eine medikamentöse Nachbehandlung mit Thrombozytenfunktionshemmern bzw. Antikoagulanzien. Nur in Teilbereichen sind diese Therapien in Hinblick auf Effektivität (Offenheitsrate, Mortalität) und Sicherheit (Blutungskomplikationen) entsprechend evaluiert.

Eine ausreichend sichere Datenbasis gibt es nur für die Nachbehandlung von Prothesenbypässen mit Azetylsalizylsäure, in den übrigen Indikationen ist weder der Einsatz von Thrombozytenfunktionshemmern noch von Antikoagulanzien sicher belegt.

Die Empfehlung, Azetylsalizylsäure bei allen infrainguinalen Bypässen wie auch nach endovaskulären Katheterinterventionen dauerhaft einzusetzen, erfolgt vor allem auch unter dem Gesichtspunkt der Sekundärprophylaxe bei manifester arterieller Gefäßerkrankung.
Gen- und autologe Stammzelltherapie bei pAVK mit chronischer Extremitätenischämie
Authors: Lawall H.
Published: March 2018

Die Behandlung mittels Gentransfer exprimierten Wachstumsfaktoren und die autologe Stammzelltransplantation stimulieren die Neovaskularisation. Dies könnte ein neuer Therapieansatz zur Verbesserung der Durchblutung bei der peripheren arteriellen Verschlusserkrankung (pAVK) sein. Vorläufige Ergebnisse der überwiegend unkontrollierten klinischen Untersuchungen deuten auf positive Effekte hin. In einer ersten doppelblinden, randomisierten Untersuchung bei Patienten mit kritischer Extremitätenischämie wurde nach Applikation von FGF (fibroblast growth factor) eine Reduktion der Amputationsrate beobachtet. Wie bei der autologen Stammzelltransplantation sind noch viele Fragen offen, denn die Bestätigung der ersten Ergebnisse durch große randomisierte Studien steht aus.
The coagulant response in sepsis and inflammation
Authors: Levi M.
Published: March 2018

Critically ill patients often have systemic activation of both inflammation and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an inter-leukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut-off by pro-inflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa and thrombin can bind to protease-activated receptors on various cells and the ensuing intracellular signaling leads to increased production of pro-inflammatory cytokines and chemo kines. Physiological anticoagulants can modulate inflammatory activity as well. Increasing knowledge on the various mechanisms underlying activation of inflammation and coagulation may lead to better (adjunctive) management strategies in critically ill patients.
Inflammation, innate immunity and blood coagulation
Authors: Xu J. , Lupu F. , Esmon C. T.
Published: March 2018

Inflammation drives arterial, venous and microvascular thrombosis. Chronic inflammation contributes to arterial thrombotic complications, whereas acute inflammation drives venous thrombosis and microvascular thrombosis. Mechanistically, inflammation modulates thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis. The inflammatory response can also result in cell apoptosis or necrosis. Products released from the dead cells, particularly histones, propagate further inflammation, tissue death and organ failure.

Inhibition of histone mediated cytotoxicity appears to be a new mechanism for protecting against this deadly cascade.