Subscribe: pubmed: Thromb Haemost[jour]
http://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=0vRu_d0bpxUnGUrBWsFKzyVbC2pmlEJfowY_EGcPO_o
Preview: pubmed: Thromb Haemost[jour]

pubmed: Thromb Haemost[jour]



NCBI: db=pubmed; Term=Thromb Haemost[jour]



 



The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.
Related Articles

The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.

Thromb Haemost. 2016 Dec 01;

Authors: Sulzgruber P, Koller L, Winter MP, Richter B, Blum S, Korpak M, Hülsmann M, Goliasch G, Wojta J, Niessner A

Abstract
Atrial fibrillation (AF) represents the most common cardiac arrhythmia. Especially in patients with chronic heart failure (CHF) the development of AF represents a severe complication resulting in haemodynamic deterioration. While pro-inflammatory cytokines proved to have a pivotal role in the development and progression of both AF and CHF, less attention has been paid to the cellular immunity. Therefore we prospectively enrolled 112 patients with CHF and performed fluorescein-activated cell sorting (FACS). Patients were stratified in two subgroups according to patients presenting with AF (n=56) and patients free of AF (n=56). Comparing AF to non-AF patients we found a significantly lower fraction of regulatory T cells (p<0.001) in patients presenting with AF. However there was a higher fraction of CD4(+) cells (p=0.007) and more specifically a significantly higher number of cytotoxic T cells characterised by the loss of CD28 within CD4 T cells (CD4(+)CD28(null); p=0.035) in individuals with AF. After a mean follow-up time of 4.5 years 32 (28.6 %) patients died due to cardiovascular causes. CD4(+)CD28(null) cells were significantly associated with cardiovascular mortality in patients presenting with AF, with an adjusted HR per one standard deviation (1-SD) of 1.59 (95 % CI 1.13-2.24; p=0.008), but not in patients free of AF with an adjusted HR per 1-SD of 1.27 (95 % CI 0.86-1.87; p=0.216). We found that the fraction of CD4(+)CD28(null) cells proved to be predictive on outcome in CHF-patients presenting with AF. Our results might indicate a potential role of CD4(+)CD28(null) cells in the pathogenesis of AF which needs to be confirmed in future studies.

PMID: 27904907 [PubMed - as supplied by publisher]




What ADAMTS13 does in the liver….
Related Articles

What ADAMTS13 does in the liver….

Thromb Haemost. 2016 Dec 01;

Authors: Wojta J

PMID: 27904906 [PubMed - as supplied by publisher]




Idarucizumab does not have procoagulant effects: Assessment of thrombosis biomarkers in healthy volunteers.
Related Articles

Idarucizumab does not have procoagulant effects: Assessment of thrombosis biomarkers in healthy volunteers.

Thromb Haemost. 2016 Dec 01;

Authors: Schmohl M, Glund S, Harada A, Imazu S, De Smet M, Moschetti V, Ramael S, Ikushima I, Grünenfelder F, Reilly P, Stangier J

Abstract
Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and 15 min after the end of infusion in Caucasian subjects, as well as pre-dose, 15 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and prothrombin fragment 1 + 2 (F1.2) were assessed over time in plasma samples up to 72 h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F1.2 levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F1.2 and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.

PMID: 27904905 [PubMed - as supplied by publisher]




Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A.
Related Articles

Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A.

Thromb Haemost. 2016 Dec 01;

Authors: Giangrande P, Andreeva T, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FW, Lentz SR, Nemes L, Poulsen LH, Santagostino E, You CW, Clausen WH, Jönsson PG, Oldenburg J, Pathfinder™2 Investigators

Abstract
Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

PMID: 27904904 [PubMed - as supplied by publisher]




Prediction of severe bleeding after coronary surgery: the WILL-BLEED Risk Score.
Related Articles

Prediction of severe bleeding after coronary surgery: the WILL-BLEED Risk Score.

Thromb Haemost. 2016 Dec 01;

Authors: Biancari F, Brascia D, Onorati F, Reichart D, Perrotti A, Ruggieri VG, Santarpino G, Maselli D, Mariscalco G, Gherli R, Rubino AS, De Feo M, Gatti G, Santini F, Dalén M, Saccocci M, Kinnunen EM, Airaksinen JK, D'Errigo P, Rosato S, Nicolini F

Abstract
Severe perioperative bleeding after coronary artery bypass grafting (CABG) is associated with poor outcome. An additive score for prediction of severe bleeding was derived (n=2494) and validated (n=1250) in patients from the E-CABG registry. Severe bleeding was defined as E-CABG bleeding grades 2-3 (transfusion of >4 units of red blood cells or reoperation for bleeding). The overall incidence of severe bleeding was 6.4 %. Preoperative anaemia (3 points), female gender (2 points), eGFR <45 ml/min/1.73 m(2) (3 points), potent antiplatelet drugs discontinued less than five days (2 points), critical preoperative state (5 points), acute coronary syndrome (2 points), use of low-molecular-weight heparin/fondaparinux/unfractionated heparin (1 point) were independent predictors of severe bleeding. The WILL-BLEED score was associated with increasing rates of severe bleeding in both the derivation and validation cohorts (scores 0-3: 2.9 % vs 3.4 %; scores 4-6: 6.8 % vs 7.5 %; scores>6: 24.6 % vs 24.2 %, both p<0.0001). The WILL-BLEED score had a better discriminatory ability (AUC 0.725) for prediction of severe bleeding compared to the ACTION (AUC 0.671), CRUSADE (AUC 0.642), Papworth (AUC 0.605), TRUST (AUC 0.660) and TRACK (AUC 0.640) bleeding scores. The net reclassification index and integrated discrimination improvement using the WILL-BLEED score as opposed to the other bleeding scores were significant (p<0.0001). The decision curve analysis demonstrated a net benefit with the WILL-BLEED score compared to the other bleeding scores. In conclusion, the WILL-BLEED risk score is a simple risk stratification method which allows the identification of patients at high risk of severe bleeding after CABG.

PMID: 27904903 [PubMed - as supplied by publisher]




A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection.
Related Articles

A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection.

Thromb Haemost. 2016 Dec 01;

Authors: Zhao B, Zhang Y, Huang Y, Yu J, Li Y, Wang Q, Ma Y, Song HY, Yu M, Mo W

Abstract
Currently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro. When administered subcutaneously, DTIP showed potent and dose-dependent extension of aPTT, PT, TT and CT in rats (n=10 per group). The antithrombotic dose of DTIP induced significantly less bleeding than bivalirudin determined by transecting distal tail assay in rats. Furthermore, DTIP reached peak blood concentration in 0.5-1 hour and did not cause increased bleeding after five days of dosing compared to dabigatran etexilate. The antithrombotic effect of DTIP was evaluated in mice using lethal pulmonary thromboembolism model and FeCl3-induced mesenteric arteriole thrombus model. DTIP (1.0 mg/kg, sc) prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism from 30 % to 80 %. Intravital microscopy showed that DTIP (1.0 mg/kg, sc) decelerated mesenteric arteriole thrombosis caused by FeCl3 injury. These data establish that DTIP is a novel antithrombotic agent that could be used to prevent thrombosis without conferring an increased bleeding risk.

PMID: 27904902 [PubMed - as supplied by publisher]




Effect of ticagrelor on endothelial calcium signalling and barrier function.
Related Articles

Effect of ticagrelor on endothelial calcium signalling and barrier function.

Thromb Haemost. 2016 Dec 01;

Authors: Gündüz D, Tanislav C, Schlüter KD, Schulz R, Hamm C, Aslam M

Abstract
The P2Y12 receptor is a Gi-coupled receptor whose activation inhibits adenylyl cyclase and thereby reduces the concentration of intracellular cAMP. Here the hypothesis was tested whether AR-C 66096 or ticagrelor, two direct-acting and reversibly binding P2Y12 receptor antagonists, protect endothelial cell (EC) barrier function by raising intracellular cAMP in ECs. The study was carried out on primary human umbilical vein ECs (HUVECs) and human pulmonary microvascular ECs (hPMECs). AR-C66096 (10 µM) induced a 50 % increase in cAMP in ECs whereas ticagrelor (2-10 µM) had no effect. Likewise, AR-C666096 antagonised thrombin-induced hyperpermeability in both HUVECs and hPMECs, but ticagrelor had no effect on basal EC monolayer permeability. Ticagrelor, however, sensitised ECs for thrombin-induced hyperpermeability and potentiated the thrombin effect. Ticagrelor but not AR-C66096 caused an increase in cytosolic calcium ([Ca(2+)]i). This increase in [Ca(2+)]i was abrogated by LaCl3 (Ca(2+) influx inhibitor) but not by xestospongin C (IP3 receptor antagonist) or by depletion of intracellular stores with thapsigargin, suggesting a Ca(2+) influx from the extracellular space. Accordingly, ticagrelor caused an increase in myosin light chain (MLC) phosphorylation, an important regulator of EC contractile machinery and thus permeability, which was abrogated by LaCl3. The ability of ticagrelor to potentiate EC permeability was abrogated by a MLC kinase inhibitor (ML-7; 10 µM). Our data demonstrate that the P2Y12 receptor antagonist AR-C66096 exerts a protective effect on ECs in vitro, possibly by raising intracellular cAMP, whereas ticagrelor sensitises EC barrier function by inducing Ca(2+) influx and activating downstream EC contractile machinery.

PMID: 27904901 [PubMed - as supplied by publisher]