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CD14(+)CD16(++) "nonclassical" monocytes are associated with endothelial dysfunction in patients with coronary artery disease.
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CD14(+)CD16(++) "nonclassical" monocytes are associated with endothelial dysfunction in patients with coronary artery disease.

Thromb Haemost. 2017 Feb 23;:

Authors: Urbanski K, Ludew D, Filip G, Filip M, Sagan A, Szczepaniak P, Grudzien G, Sadowski J, Jasiewicz-Honkisz B, Sliwa T, Kapelak B, McGinnigle E, Mikolajczyk T, Guzik TJ

Abstract
Endothelial dysfunction and inflammation are key mechanisms of vascular disease. We hypothesised that heterogeneity of monocyte subpopulations may be related to the development of vascular dysfunction in coronary artery disease (CAD). Therefore, we examined the relationships between monocyte subsets (CD14(++)CD16(-) "classical - Mon1", CD14(++)CD16(+) "intermediate - Mon2" and CD14(+)CD16(++) "nonclassical - Mon3"), endothelial function and risk factor profiles in 130 patients with CAD undergoing coronary artery bypass grafting. This allowed for direct nitric oxide (NO) bioavailability assessment using isometric tension studies ex vivo (acetylcholine; ACh- and sodium-nitropruside; SNP-dependent) in segments of internal mammary arteries. The expression of CD14 and CD16 antigens and activation markers were determined in peripheral blood mononuclear cells using flow cytometry. Patients with high CD14(+)CD16(++) "nonclassical" and low CD14(++)CD16(-) "classical" monocytes presented impaired endothelial function. High frequency of CD14(+)CD16(++) "nonclassical" monocytes was associated with increased vascular superoxide production. Furthermore, endothelial dysfunction was associated with higher expression of activation marker CD11c selectively on CD14(+)CD16(++) monocytes. Nonclassical and classical monocyte frequencies remained independent predictors of endothelial dysfunction when major risk factors for atherosclerosis were taken into account (β=0.18 p=0.04 and β=-0.19 p=0.03, respectively). In summary, our data indicate that CD14(+)CD16(++) "nonclassical" monocytes are associated with more advanced vascular dysfunction measured as NO- bioavailability and vascular reactive oxygen species production.

PMID: 28229168 [PubMed - as supplied by publisher]




Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerisation.
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Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerisation.

Thromb Haemost. 2017 Feb 23;:

Authors: Iwaki T, Nagahashi K, Takano K, Suzuki-Inoue K, Kanayama N, Umemura K, Urano T

Abstract
Serpinopathy is characterised as abnormal accumulation of serine protease inhibitors (SERPINs) in cells and results in clinical symptoms owing to lack of SERPIN function or excessive accumulation of abnormal SERPIN. We recently identified a patient with functional deficiency of plasminogen activator inhibitor-1 (PAI-1), a member of the SERPIN superfamily. The patient exhibited life-threatening bleeding tendencies, which have also been observed in patients with a complete deficiency in PAI-1. Sequence analysis revealed a homozygous single-nucleotide substitution from guanine to cytosine at exon 9, which changed amino acid residue 397 from glycine to arginine (c.1189G>C; p.Gly397Arg). This glycine was located in strand 5B and was well conserved in other serpins. The mutant PAI-1 was polymerised in the cells, interfering with PAI-1 secretion. The corresponding mutations in SERPINC1 (anti-thrombin III) at position 456 (Gly456Arg) and SERPINI1 (neuroserpin) at position 392 (Gly392Glu) caused an anti-thrombin deficiency and severe dementia due to intracellular retention of the polymers. Glycine is the smallest amino acid, and these mutated amino acids were larger and charged. To determine which factors were important, further mutagenesis of PAI-1 was performed. Although the G397A, C, I, L, S, T, and V were secreted, the G397D, E, F, H, K, M, N, P, Q, W, and Y were not secreted. The results revealed that the size was likely triggered by the polymerisation of SEPRINs at this position. Structural analyses of this mutated PAI-1 would be useful to develop a novel PAI-1 inhibitor, which may be applicable in the context of several pathological states.

PMID: 28229167 [PubMed - as supplied by publisher]




Are cardiovascular risk factors also associated with the incidence of atrial fibrillation? A systematic review and field synopsis of 23 factors in 32 population based cohorts of 20 million participants.
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Are cardiovascular risk factors also associated with the incidence of atrial fibrillation? A systematic review and field synopsis of 23 factors in 32 population based cohorts of 20 million participants.

Thromb Haemost. 2017 Feb 23;:

Authors: Allan V, Honarbakhsh S, Casas JP, Wallace J, Hunter R, Schilling R, Perel P, Morley K, Banerjee A, Hemingway H

Abstract
Established primary prevention strategies of cardiovascular diseases are based on understanding of risk factors, but whether the same risk factors are associated with atrial fibrillation (AF) remains unclear. We conducted a systematic review and field synopsis of the associations of 23 cardiovascular risk factors and incident AF, which included 84 reports based on 28 consented and four electronic health record cohorts of 20,420,175 participants and 576,602 AF events. We identified 3-19 reports per risk factor and heterogeneity in AF definition, quality of reporting, and adjustment. We extracted relative risks (RR) and 95 % confidence intervals [CI] and visualised the number of reports with inverse (RR [CI]<1.00), or direct (RR [CI]>1.00) associations. For hypertension (13/17 reports) and obesity (19/19 reports), there were direct associations with incident AF, as there are for coronary heart disease (CHD). There were inverse associations for non-White ethnicity (5/5 reports, with RR from 0.35 to 0.84 [0.82-0.85]), total cholesterol (4/13 reports from 0.76 [0.59-0.98] to 0.94 [0.90-0.97]; 8/13 reports with non-significant inverse associations), and diastolic blood pressure (2/11 reports from 0.87 [0.78-0.96] to 0.92 [0.85-0.99]; 5/11 reports with non-significant inverse associations), and direct associations for taller height (7/10 reports from 1.03 [1.02-1.05] to 1.92 [1.38-2.67]), which are in the opposite direction of known associations with CHD. A systematic evaluation of the available evidence suggests similarities as well as important differences in the risk factors for incidence of AF as compared with other cardiovascular diseases, which has implications for the primary prevention strategies for atrial fibrillation.

PMID: 28229164 [PubMed - as supplied by publisher]




Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction.
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Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction.

Thromb Haemost. 2017 Feb 23;:

Authors: Hayakawa M, Kushimoto S, Watanabe E, Goto K, Suzuki Y, Kotani T, Kiguchi T, Yatabe T, Tagawa J, Komatsu F, Gando S

Abstract
Recombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated. In an open-label, multicentre, prospective, clinical pharmacological study, we investigated the pharmacokinetics and safety of ART-123 upon repeated administration to DIC patients. ART-123 was administered to patients at a dose of 130 or 380 U/kg/day for six consecutive days. Plasma concentrations of ART-123 were measured at 21 time points until eight days after the final administration. Urinary excretion rates during the first 24 hours (h) were calculated. Patient renal functions were evaluated by measuring 24-h creatinine clearance (Ccr). Forty-three patients were enrolled in the present study. The urinary excretion rates of ART-123 correlated closely with 24-h Ccr. Total body clearance of ART-123 was also weakly related with 24-h Ccr. However, the plasma concentrations of ART-123 were not considerably different among patients with different renal function. Two patients had subcutaneous haemorrhage as an adverse event related to ART-123. In conclusion, plasma concentrations of ART-123 may not be different among patients with different renal functions. ART-123 was well tolerated in these patients.

PMID: 28229162 [PubMed - as supplied by publisher]




High levels of latent antithrombin in plasma from patients with antithrombin deficiency.
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High levels of latent antithrombin in plasma from patients with antithrombin deficiency.

Thromb Haemost. 2017 Feb 23;:

Authors: de la Morena-Barrio M, Sandoval E, Llamas P, Wypasek E, Toderici M, Navarro-Fernández J, Rodríguez-Alen A, Revilla N, López-Gálvez R, Miñano A, Padilla J, de la Morena-Barrio B, Cuesta J, Corral J, Vincente V

Abstract
Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma antithrombin in healthy subjects. The analysis of latent antithrombin in 141 unrelated patients with antithrombin deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42ºC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of antithrombin (and potentially of all serpins). High levels of endogenous latent antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation.

PMID: 28229161 [PubMed - as supplied by publisher]




Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment.
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Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment.

Thromb Haemost. 2017 Feb 23;:

Authors: Hüttel E, Padberg S, Meister R, Beck E, Schaefer C

Abstract
The aim of this observational cohort study was to specify the risk of the vitamin K antagonist (VKA) phenprocoumon during first trimester of pregnancy, in particular to estimate the risk of birth defects and spontaneous fetal loss. Four hundred eight pregnancies with phenprocoumon exposure were compared to 1,642 pregnancies neither exposed to VKA nor to other major teratogens or fetotoxicants. There was no typical warfarin embryopathy in our exposed cohort. However, the overall rate of major birth defects was significantly increased (7.4 % vs 2.3 %; adjusted odds ratio [ORadj] 2.14; 95 % confidence interval [CI] 1.4-3.4). With early cessation until five completed gestational weeks the birth defect risk was similar to the comparison cohort (2.4 % vs 2.3 %; ORadj 1.07; 95 % CI 0.2-3.6). With treatment duration exceeding seven gestational weeks the rate of major birth defects increased up to five-fold (10.8 % vs 2.3 %; ORadj 5.18; 95 % CI 2.0-11.6). The overall risk of spontaneous abortion (SAB) was 38.0 % vs 17.5 % in the comparison cohort (adjusted hazard ratio (HRadj) 2.9; 95 % CI 2.2-3.9). The treatment duration had a significant effect on the hazard of SAB (HRadj 1.12; 95 % CI 1.01-1.25 per each additional exposure week). Phenprocoumon and other VKA carry an embryotoxic risk. This risk seems to be time-dependent with a steep risk increase for birth defects and also for fetal loss after week 5. If maternal disease permits, VKA therapy should be switched to safer alternatives such as heparins immediately after early recognition of pregnancy.

PMID: 28229160 [PubMed - as supplied by publisher]




Platelet turnover predicts outcome after coronary intervention.
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Platelet turnover predicts outcome after coronary intervention.

Thromb Haemost. 2017 Feb 23;:

Authors: Freynhofer MK, Iliev L, Bruno V, Rohla M, Egger FS, Weiss TW, Hübl W, Willheim M, Wojta J, Huber K

Abstract
Elevated platelet turnover contributes to high platelet reactivity. High platelet reactivity after percutaneous coronary intervention (PCI) is associated with major adverse cardiovascular events (MACE). The purpose of this study was to determine the prognostic value of platelet turnover and function with regard to MACE after PCI with stent implantation. In this prospective observational study, 486 consecutive patients after PCI on aspirin and clopidogrel were included to determine platelet turnover (mean platelet volume (MPV), reticulated platelet fraction (RPF)) and platelet function (multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay). At six-months follow-up, MACE occurred in 10.7 % of patients. RPF (odds ratio [OR]=1.173 (95% confidence interval [CI 95 %] 1.040-1.324), p=0.009) and MPV (OR=1.459 (CI 95 % 1.059-2.008), p=0.021) were univariable predictors of MACE, whereas VASP-P (OR=1.016 (CI 95 % 1.000-1.032), p=0.052) and MEA (OR=0.999 (CI 95 % 0.980-1.017), p=0.895) failed to predict MACE. RPF remained the only platelet variable independently associated with MACE. The best model to predict MACE included: troponin I (OR=1.007 (CI 95 % 1.002-1.012), p=0.009), RPF (OR=1.136 (CI 95 % 1.001-1.288), p=0.048), CRP (OR=1.008 (CI 95 % 1.001-1.014), p=0.023) and history of myocardial infarction (OR=2.039 (CI 95 % 1.093-3.806), p=0.025). RPF (OR=1.211 (CI 95 % 1.042-1.406), p=0.012) was also independently associated with in-hospital bleedings. In conclusion, RPF as index of platelet turnover is an independent predictor of MACE and bleeding events in PCI patients on dual antiplatelet therapy. Since RPF can reliably be quantified along with routine haemograms, RPF might easily be applied in the setting of cardiovascular risk prediction.

PMID: 28229159 [PubMed - as supplied by publisher]




Detection of procoagulant imbalance. Modified endogenous thrombin potential with results expressed as ratio of values with-to-without thrombomodulin.
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Detection of procoagulant imbalance. Modified endogenous thrombin potential with results expressed as ratio of values with-to-without thrombomodulin.

Thromb Haemost. 2017 Feb 23;:

Authors: Tripodi A

Abstract
Each individual possesses his/her own endogenous-thrombin-potential (ETP) (i. e. the ability to generate thrombin) which depends on the relative strength of the pro- and anticoagulant drivers operating in plasma. This ability depends in turn on the clinical conditions in which the balance between the two drivers is variably affected. One of the major determinants of this balance is the factor (F)VIII-protein C(PC) axis and its effect can be conveniently explored by the thrombin generation procedures with results expressed as ETP ratio with/without thrombomodulin (TM) (ETP-TM ratio). Furthermore, owing to the many feedback mechanisms mediated by thrombin (e. g. activation of PC, FXI, FV, FVIII, platelets etc.) it is also possible that any perturbation of the balance between pro- and anticoagulants that may occur in plasma even outside the FVIII-PC axis could result in an increased ETP-TM ratio and therefore may suggest a procoagulant imbalance. Indeed, other non-coagulation moieties (e. g. microparticles, neutrophil extracellular traps, pro-inflammatory cytokines and others) circulating in blood of patients with various clinical conditions may also contribute to the procoagulant imbalance even when FVIII and/or PC are apparently normal. It can be postulated that dual ETP measurements performed in the presence and absence of TM with results expressed as their ratio may be the candidate procedure to detect subtle procoagulant imbalance in many clinical conditions characterised by an increased risk of thromboembolism. This article aimed at reviewing the clinical conditions in which evidence for the value of the ETP-TM ratio has been provided.

PMID: 28229158 [PubMed - as supplied by publisher]