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Increasing D-dimer (DD) levels after discontinuation of vitamin K antagonist (VKA) therapy indicate an increased risk of recurrence of venous thromboembolism (VTE). However, after discontinuation of d irect-acting n on-VKA o ral a nti c oagulants (DOACs or NOACs) the extent of coagulation activation and its clinical impact is unknown. Blood samples were collected from consenting patients with proximal VTE at the end of anticoagulation treatment with apixaban (n = 37), dabigatran (n = 17), rivaroxaban (n = 9) or VKA (n = 184) and 4 weeks later. DD, prothrombin fragments F1 + 2 (F1 + 2) and thrombin–antithrombin complexes (TAT) were measured. All patients underwent follow-up at 12 months to establish recurrent VTE or death from any cause. Irrespective of the treatment, DD and F1 + 2 but not TAT demonstrated a similar increase between baseline and week 4. At 12 months, 18 patients (7.3%) had recurrent VTE and two (0.8%) had died. For all patients and subgroups of VKA and DOAC, positive likelihood ratios were numerically higher for baseline values but only TAT values at 4 weeks were found to be related to a small increase of outcome event likelihood (2.6; 95%CI 1.23-5.50), which was driven by VKA patients (3.1; 95%CI 1.32-7.30) and not by DOAC patients (2.27; 95%CI 0.52-9.95). For all parameters, negative likelihood ratios were not predictive. In logistic regression analysis, only ΔTAT (optimal cut-off > 178% from baseline demonstrated a significant risk increase for VTE/death (odds ratio 3.76; 95% confidence interval 1.46-9.68; p = 0.006). In conclusion, the concept of testing coagulation activation parameters may also be transferred to VTE patients at the end of DOAC therapy. For patients with an increase of TAT levels within 4 weeks after treatment discontinuation (> 178% from baseline) is associated with an increased risk for VTE recurrence or death at 12 months.

Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM).Inclusion criteria were a) serum ferritin100 μg/L or b) serum ferritin300 μg/L and transferrin saturation20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients.80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p0.0001) and by 13% (p0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred.Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.

Rivaroxaban is increasingly used to treat patients with acute venous thromboembolism (VTE), a potentially life-threatening condition. Because absorption of rivaroxaban decreases from nearly 100% to 66% under fasting conditions, it is recommended that VTE patients take rivaroxaban with a meal. However, this recommendation is based on preclinical pharmacokinetic (PK) studies in healthy volunteers. So far, no clinical evidence is available to support this recommendation. We describe a case of a compliant young patient who developed recurrent pulmonary embolism during rivaroxaban treatment. PK studies provided evidence that malabsorption of rivaroxaban 20 mg due to irregular intake of meals during shift work was the leading cause of recurrent pulmonary embolism. When the patient was instructed to take rivaroxaban with a regular meal, peak plasma concentrations increased from 115 to 318 ng mL(-1) (+ 176%). Consequently, the importance of taking rivaroxaban with food may have a greater clinical relevance than data from preclinical PK studies suggest.

Economic news may not only report about the economy but also impact the development of an economy by affecting economic expectations. This study explores the impact of economic news on the economic expectations of experts. A content analysis of economic news tone and volume of two German and one Swiss public service news shows is combined with survey data on macroeconomic expectations of experts on the topics of general economy, capital expenditures, and private consumption. Results confirm that past news tone explains economic expectations on private consumption up to 70 per cent. This effect varies among news shows and the overall economic situation. The authors hold media dependency and an asymmetric third-person effect responsible for these variations.

Objective and methods Acute modification of plasma lipidomic profile was assessed by top-down shotgun profiling on a LTQ Orbitrap hybrid mass spectrometer in 14 patients treated with two different apheresis techniques: plasma lipidfiltration (LF) and whole blood dextran sulfate adsorption (DSA). Results Patients treated with DSA revealed a significantly more pronounced reduction of LDL-cholesterol (LDL-C), a diminished decrease of HDL-cholesterol (HDL-C) and triglycerides (TG), and a similar reduction in lipoprotein (a) (Lp(a)) level. Against the overall tendency of reduction of lipid metabolites of all lipid classes in post-apheresis plasma, independent of apheresis technology applied, a highly significant increase of phosphatidylethanolamines (PE) in response to DSA was observed. Conclusion These data indicate that DSA technology may be associated with an activation or damage of blood cells at contact surface which subsequently leads to a massive liberation of cellular and membrane PE's. Pathophysiological consequences, especially with respect to coagulation system and oxidative stress, have to be further elucidated.

In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. In the present study a decreased TM expression in human prostate cancer cell lines, LNCaP, DU-145, and PC-3, in relation to normal prostate epithelial cells (PrEC) is shown. Sequencing and methylation-specific high resolution melting (MS-HRM) analyses of bisulphite-modified genomic DNA indicates a high degree of methylation in DU-145 cells and lesser degrees in PC-3 and LNCaP cells, whereas in PrEC the TM promoter is unmethylated. The expression of TM is negatively regulated by NF-κB- and GSK3-β-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. However, exposure of DU-145 cells to the demethylating agent, 5-aza-2′deoxycytidine, restores the TM expression and its control by retinoic acid, NF-κB- and GSK3-β-dependent signalling. In conclusion, the study establishes that in prostate cancer cell lines relative to PrEC the TM is down-regulated and that the TM promoter is hypermethylated, which seems to be responsible for the down-regulation and failed regulation of TM expression in DU-145 cells.

The level of thrombomodulin (TM) on cell surfaces reflects its biosynthesis, intracellular turnover, proteolytic cleavage, and release in soluble form (sTM). In the present study we examined the mechanisms mediating and regulating sTM release. Inducers of endothelial protein C receptor (EPCR) shedding, such as proinflammatory cytokines, phorbol ester, and ionomycin did not affect sTM release from human umbilical endothelial cells (HUVECs). In contrast, several natural and synthetic reducing compounds (i.e., glutathione, dihydrolipoic acid, homocysteine, N-acetyl-L-cysteine, dithiothreitol, and non-thiol cell-impermeable reductant, tris-(2-carboxyethyl)phosphine), but not oxidized glutathione or α-lipoic acid effectively up-regulated the release of sTM in endothelial cells. In addition, the direct activator of metalloproteases, 4-aminophenylmercuric acetate (APMA), was an effective inducer of TM shedding. Considerable inhibition of protein C activation was found with APMA, which is consistent with the effects of this agent on TM shedding. In addition to metalloproteases, serine proteases were shown by pharmacological inhibition studies to be involved in a similar degree in basal sTM release; however, serine proteases seem preferentially to be involved in thiol-induced TM proteolytic processing. From comparisons of non-thiol containing synthetic substrate with human recombinant TM it was demonstrated that disulfide bonds within TM are most likely modified by thiols making TM more susceptible to serine protease-mediated cleavage. In summary, the study shows that the extracellular redox state plays a crucial role in the regulation of TM shedding in HUVECs thereby offering new strategies to interfere with diminished activation of protein C during inflammatory diseases.

Upregulation of group IIA phospholipase A 2 (sPLA 2 -IIA) correlates with prostate tumor progression suggesting prooncogenic properties of this protein. Here, we report data on expression of three different sPLA 2 isozymes (groups IIA, V, and X) in normal (PrEC) and malignant (DU-145, PC-3, and LNCaP) human prostate cell lines. All studied cell lines constitutively expressed sPLA 2 -X, whereas sPLA 2 -V transcripts were identified only in malignant cells. In contrast, no expression of sPLA 2 -IIA was found in PrEC and DU-145 cells, but it was constitutively expressed by IFN-γ in LNCaP and PC-3 cells. Expression of sPLA 2 -IIA is upregulated in PC-3 and in PrEC cell in a signal transducer and activator of transcription-1-dependent manner, but not in LNCaP cell. Additional signaling pathways regulating sPLA 2 -IIA expression include cAMP/protein kinase A, p38 mitogen-activated protein kinase, protein kinase C, Rho-kinase, and mitogen-activated/extracellular response protein kinase / extracellular signal-regulated kinase. No deletions were revealed in the sPLA 2 -IIA gene from DU-145 cells lacking the expression of sPLA 2 -IIA. Reexpression of sPLA 2 -IIA was induced by 5-aza-2′-deoxycytidine demonstrating that DNA methylation is implicated in the regulation of sPLA 2 -II. Together, these data suggest that sPLA 2 -IIA and sPLA 2 -V, but not sPLA 2 -X, are differentially expressed in normal and malignant prostate cells under the control of proinflammatory cytokines; epigenetic mechanisms appear involved in the regulation of sPLA 2 -IIA expression, at least in DU-145 cells.

Introduction Pharmacological restriction of secretory group IIA phospholipase A2 (sPLA2-IIA) expression is thought to be beneficial in the treatment of inflammatory diseases such as sepsis and septic shock. In this study we investigated the effects of activated protein C (APC) on sPLA2-IIA expression, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and on DNA-binding activities of nuclear factor-κB (NF-κB) and CCAAT box enhancer binding protein-β (C/EBP-β) in human aortic smooth muscle cells (HASMC). Materials and methods To achieve elevated sPLA2-IIA production as occurring during inflammation, HASMC were stimulated with interferon-γ (IFN-γ) alone and in combination with other inductors, thus modeling the strong sPLA2-IIA elevation by inflammation. Results and conclusions APC inhibited the stimulated expression of sPLA2-IIA in HASMC dose-dependently (1–300 nM). At the same time, APC increased the phosphorylation of ERK 1/2 and decreased NF-κB and C/EBP-β DNA-binding activities in these cells, as compared with respective stimulated controls. Reverse transcriptase-polymerase chain reaction and cell-based ELISA reveal an endothelial protein C receptor (EPCR) expression in HASMC. Application of antibodies against EPCR and protease-activated receptor-1 (PAR-1) reduced the APC-induced ERK 1/2 activation and the treatment of cells with a PAR-1 antagonist diminished the sPLA2-IIA inhibition. The obtained results show that APC effectively suppresses the up-regulated sPLA2-IIA expression, which might contribute to the reported beneficial effects of APC in the treatment of severe inflammatory disorders.

The courses of 79 children (2 weeks to 19 years old) treated with two different low-molecular weight heparins (LMWHs)--nadroparin (n=66) and enoxaparin (n=13)--were retrospectively analysed. In 62 patients, LMWHs were given for short-term prophylaxis (1-2 weeks) during immobilization after surgery or trauma. Thirteen children with thromboembolic events received long-term prophylaxis with LMWHs for 2-18 months--six after thrombolytic therapy and seven after therapy with unfractionated heparin (UFH). Because of thromboembolic events, four patients were initially treated with LMWHs. In all patients with short-term prophylaxis, no thrombosis occurred. After thrombolytic therapy, three children had no reocclusion, two had no thrombus apposition and one had complete recanalization. In the seven patients treated with LMWHs after UFH, four had no reocclusion, two had recanalization and one had reocclusion. In all patients receiving LMWHs for initial treatment of thrombosis, no thrombus apposition, but also no recanalization, occurred. For short-term prophylaxis, nadroparin was used independent of the body weight and without determination of anti-factor Xa (anti-FXa) activity. Long-term prophylaxis was given mainly as doses of 45-100 anti-FXa U/kg resulting in anti-FXa activities between 0.2 and 0.4 U/ml. For treatment of thrombosis, doses of 200-300 anti-FXa U/kg corresponded to 0.5-1.0 anti-FXa U/ml. Side effects--slight gastrointestinal bleeding and temporary reversible hair loss--were seen in two patients. In conclusion, LMWHs proved to be efficacious and safe especially in prophylaxis of thromboembolic events in children.

Tissue injury following trauma and surgery may induce alterations in blood coagulation and fibrinolysis. Hypercoagulable state after surgery can be associated with the risk of postoperative thromboembolic complications. The contact of coagulation factors with TF after injury of vessel wall and organ tissues may contribute to the development of thrombosis after surgery (1). TF, the cell surface receptor and cofactor of factor VII/VIIa is normally not expressed by cells within the vasculature. Only monocytes and endothelial cells can be stimulated to express TF transiently by a variety of inflammatory and immunological reactions (for review see 2,3). Also surgical treatment was reported to induce TF synthesis in monocytes (4,5,6). TF is present in many extravascular tissues as vascular adventitia, organ capsules, epidermis, colonic mucosal epithelium, liver stroma, pancreas stroma and also on tumor cells (7-12). In this study, we investigated, whether we can detect the release of TF from the traumatized tissues and from activated monocytes into the circulation following abdominal surgery. To test the dependence of the extension of tissue injury during surgery we segregated the patients into group A with major abdominal operations and group B consisting of patients with appendectomy and cholecystectomy. No relationship could be established between changes of TF and postoperative thromboembolic complications.

Summary In the present family cohort study fibrinogen was determined using a functional as well as an immunochemical assay. The relationship of both fibrinogen values to other hemostatic variables, parameters of the metabolic syndrome and arteriosclerotic signs was tested. A strong similarity was obtained between values of both fibrinogen assays in the investigated group. Both fibrinogen values correlated with each other and showed the same correspondence on age and C-reactive protein. Both fibrinogens were significantly correlated with t-PA antigen, von Willebrand factor antigen and plasminogen. Both values increased with increasing tertiles of active PAI-1 antigen. Fibrinogen values were strongly correlated with BMI, WHR, area of insulin in oral glucose tolerance test, total cholesterol, LDL-cholesterol and apolipoprotein B. The positive association with other hemostatic risk factors such as t-PA antigen, PAI-1 and von Willebrand factor points to a common reaction of hemostatic factors. Even there good correspondence, higher values of functional fibrinogen in middle aged men with arteriosclerotic signs support a higher risk prediction of functional fibrinogen. The inclusion of fibrinogen in screening programmes requirs a standardisation of fibrinogen assays as a basis of uniform reference data and commercial controls in the region of interest. We conclude that a common increase of fibrinogen, and other hemostatic factors as well as established arteriosclerotic risk factors raises the risk for atherothrombosis in patients with metabolic syndrome.

Summary Risk prediction of arteriosclerotic vessel disease by hemostatic variables presupposes an association between the disease and hemostatic factors. In a family cohort study the relationship of t-PA antigen, t-PA activity, active PAI antigen and whole PAI antigen to metabolic variables and arteriosclerotic signs has been investigated. 260 members (135 males and 125 females) on indexpatients with hyperuricaemia and / or combined hyperlipidemia were included. t-PA activity was strongly correlated with PAI-1 (active PAI antigen > whole PAI antigen) and showed an inverse relation to t-PA antigen. t-PA antigen was stronger correlated with the active PAI-1 antigen than with whole PAI-1 antigen. An increase of t-PA antigen was associated with a proportional increase of PAI-1 antigen as a cause for the inverse relation between t-PA activity and t-PA antigen. The circulating t-PA activity is influenced predominantly by the active PAI-1 antigen. Although both PAI-1 antigens were positively correlated with t-PA antigen, the active PAI antigen was stronger associated with t-PA antigen. Possibly, a high ratio of whole PAI antigen / active PAI antigen is caused by an increase of latent PAI, the main form of PAI in the platelets. The circulating fibrinolytic activity is better characterised by the active PAI-1 antigen than by the whole PAI-1 antigen. The obtained results indicate to include t-PA and PAI-1 into the metabolic syndrome. The evaluation of the individual results give reason to suppose the existence of a common reaction of the hemostatic risk factors t-PA antigen, active PAI-1 antigen, fibrinogen and von Willebrand factor antigen. A high hemostatic state was predominantly found in patients with arteriosclerotic signs.

The relationship between PAT activity and t-PA antigen concentration and their dependence on age, sex, body mass index, lipoprotein metabolism parameters and life style was studied in a subpopulation of the DRECAN Study. PAT activity and t-PA concentration showed a similar dependence on age and sex. The ratio PAI activity/t-PA concentration correlated much better with PAT activity than with t-PA concentration. PAT activity and t-PA concentration were equally strong correlated with body mass index and triglyceride concentration. Both fibrinolytic variables showed no significant differences between smokers and non-smokers. PAT activity as well as t-PA concentration were lower in users of oral contraceptives than in non-users. This result was independent of the relationship between BMI as well as triglyceride concentration on PAT activity and t-PA concentration and not the only responsible factor for the higher PAT and t-PA values in men compared to women. The amount of alcohol and beer per day was a significantly influential factor on PAT activity in men. The high PAT activity in middle-aged men is possibly connected with the described higher prevalence of elevated PAT activity in young postinfarction patients compared with unselected patients.