Iron and carbon monoxide enhance coagulation and attenuate fibrinolysis by different mechanisms

Two parallel lines of investigation elucidating novel mechanisms by which iron (scanning electron microscopy-based) and carbon monoxide (viscoelastic-based) enhance coagulation and diminish fibrinolysis have emerged over the past few years. However, a multimodal approach to ascertain the effects of iron and carbon monoxide remained to be performed. Such investigation could be important, as iron and carbon monoxide are two of the products of heme catabolism via heme oxygenase-1, an enzyme upregulated in a variety of disease states associated with thrombophilia. Human plasma was exposed to ferric chloride, carbon monoxide derived from carbon monoxide-releasing molecule-2, or their combination. Viscoelastic studies demonstrated ferric chloride and carbon monoxide mediated enhancement of velocity of growth, and final clot strength, with the combination of the two molecules noted to have all the prothrombotic kinetic effects of either separately. Parallel ultrastructural studies demonstrated separate types of fibrin polymer cross-linking and matting in plasma exposed to ferric chloride and carbon monoxide, with the combination sharing features of each molecule. In conclusion, we present the first evidence that iron and carbon monoxide interact with key coagulation and fibrinolytic processes, resulting in thrombi that begin to form more quickly, grow faster, become stronger, and are more resistant to lysis.http://journals.lww.com/bloodcoagulation2015-10-30hj201

Carbon monoxide : anticoagulant or procoagulant?

Within the past decade there have been several investigations attempting to define the impact of exogenous and endogenous carbon monoxide exposure on hemostasis. Critically, two bodies of literature have emerged, with carbon monoxide mediated platelet inhibition cited as a cause of in vitro human and in vitro/in vivo rodent anticoagulation. In contrast, interaction with heme groups associated with fibrinogen, α2-antiplasmin and plasmin by carbon monoxide has resulted in enhanced coagulation and decreased fibrinolysis in vitro in human and other species, and in vivo in rabbits. Of interest, the ultrastructure of platelet rich plasma thrombi demonstrates an abnormal increase in fine fiber formation and matting that are obtained fromhumans exposed to carbonmonoxide. Further, thrombi obtained from humans and rabbits have very similar ultrastructures, whereas mice and rats have more fine fibers and matting present. In sum, there may be species specific differences with regard to hemostatic response to carbon monoxide. Carbon monoxide may be a Janus-faced molecule, with potential to attenuate or exacerbate thrombophilic disease.http://www.elsevier .com/locate/thromreshb201

Iron-enhanced coagulation is attenuated by chelation : a thrombelastographic and ultrastructural analysis

Increased circulating ferritin and free iron have been found in a variety of disease states associated with thrombophilia. When blood or plasma is exposed to iron addition, characteristic changes in thrombus formation are observed by scanning electron microscopy, which include fusion of fibrin polymers, matting, and even sheeting of fibrin. A primary mechanism posited to explain iron-mediated hypercoagulability is hydroxyl radical formation and modification of fibrinogen; however, iron has also been demonstrated to bind to fibrinogen. We have recently demonstrated that iron enhances coagulation, manifested as a decrease in the time of onset of coagulation. Using clinically encountered concentrations of iron created by addition of FeCl3 to human plasma, we demonstrated that iron-mediated changes in reaction time determined by thrombelastography or changes in thrombus ultrastructure were significantly, but not completely, reversed by iron chelation with deferoxamine. Thus, reversible iron binding to fibrinogen mechanistically explains a significant portion of coagulation kinetic and ultrastructural hypercoagulability. Further investigation is needed to determine whether residual iron binding or other iron-mediated effects is responsible for hypercoagulability observed after chelation.Departments of Anesthesiology and Physiology.http://ovidsp.tx.ovid.com2015-12-31hb201

Viscoelasticity and ultrastructure in coagulation and inflammation : two diverse techniques, one conclusion

The process of blood clotting has been studied for centuries. A synopsis of current knowledge pertaining to haemostasis and the blood components, including platelets and fibrin networks which are closely involved in coagulation, are discussed. Special emphasis is placed on tissue factor (TF), calcium and thrombin since these components have been implicated in both the coagulation process and inflammation. Analysis of platelets and fibrin morphology indicate that calcium, tissue factor and thrombin at concentrations used during viscoelastic analysis (with thromboelastography or TEG) bring about alterations in platelet and fibrin network ultrastructure, which is similar to that seen in inflammation. Scanning electron microscopy indicated that, when investigating platelet structure in disease, addition of TF, calcium or thrombin will mask disease-induced alterations associated with platelet activation. Therefore, washed platelets without any additives is preferred for morphological analysis. Furthermore, morphological and viscoelastic analysis confirmed that thrombin activation is the preferred method of fibrin activation when investigating fibrin network ultrastructure.http://link.springer.com/journal/107532016-08-04hb201

The clinical relevance of altered fibrinogen packaging in the presence of 17β-estradiol and progesterone

BACKGROUND : The effect of endogenous hormone concentrations, specifically 17β-estradiol and progesterone, on fibrin network formation has not been established. OBJECTIVES : It is essential to understand natural hormone mechanisms since these hormones are still present in circulation while hormonal contraceptives, which are associated with increased risk of venous thromboembolism, are used. METHODS : Due to the fact that these hormones are known to increase hypercoagulability and the prothrombotic state scanning electron microscopy (SEM), atomic force microscopy (AFM), thromboelastography (TEG) and turbidimetry were employed to investigate the morphology, surface roughness, viscoelastic properties and formation and lysis of fibrin. RESULTS : 17β-estradiol and progesterone showed hypercoagulable viscoelastic properties and decreased the diameter and surface roughness of fibrin while increasing dense matted deposit occurrence. Our results suggest that the additional burden of hormonal load, together with the presence of endogenous estrogen and progesterone, may result in a prothrombotic and hypercoagulable state in females with an inflammatory predisposition. CONCLUSION : Our results are of clinical importance when considering hormones as either pathological agent or therapeutic intervention as will be assessed in future investigation.Swanepoel received funding from the National Research Foundation (NRF) of South Africa and Pretorius received funding from the Medical Research Council (MRC) of South Africa.http://www.elsevier.com/locate/thromres2017-10-31hb2016Physiolog

Carbon monoxide and iron modulate plasmatic coagulation in Alzheimer's disease

Alzheimer’s disease (AD) is a significant source of morbidity and mortality for millions of people worldwide, and multiple potential etiologies have been postulated to contribute to AD. Among these, spontaneous cerebral emboli and increased cerebral and circulating heme oxygenase (Hmox) activity in AD patients are of particular interest, as two of the products of Hmox activity, carbon monoxide (CO) and iron enhance plasmatic coagulation and modify the ultrastructure of thrombi. We hypothesized that patients afflicted with AD would have coagulation kinetics modulated by CO and iron. Using viscoelastic assessments of coagulation, it was determined with a small cohort (n=11) of AD patients that all had enhancement of coagulation by CO, iron, or both. In a complementary fashion, it was determined that a separate cohort (n=12) of AD patients had thrombi with ultrastructural features consistent with iron and CO exposure as assessed with scanning electron microscopy. Further, when stratified by normal or abnormally increased serum ferritin concentrations (which can be increased by Hmox), the AD patients with abnormal ferritin concentrations had significantly thinner fibrin fiber diameters, not unlike that noted when normal plasma is mixed with iron or CO. In sum, AD patients were noted to have plasmatic coagulation kinetic and thrombus ultrastructural changes consistent with exposure to CO and iron. Future investigation of CO and iron in the pathogenesis of Alzheimer’s disease is warranted.Departments of Anesthesiology and Physiology.http://benthamscience.com/journal/index.php?journalID=cnr2016-01-31hb201

Forward and midrapidity like-particle ratios from p+p collisions at sqrt(s)=200 GeV

We present a measurement of pi-\pi+, K-/K+ and pbar/p from p+p collisions at sqrt(s) = 20 0GeV over the rapidity range 0<y<3.4. For pT < 2.0 GeV/c we see no significant transverse momentum dependence of the ratios. All three ratios are independent of rapidity for y ~< 1.5 and then steadily decline from y ~ 1.5 to y ~ 3. The pi-\pi+ ratio is below unity for y > 2.0. The pbar/p ratio is very similar for p+p and 20% central Au+Au collisions at all rapidities. In the fragmentation region the three ratios seem to be independent of beam energy when viewed from the rest frame of one of the protons. Theoretical models based on quark-diquark breaking mechanisms overestimate the pbar/p ratio up to y ~< 3. Including additional mechanisms for baryon number transport such as baryon junctions leads to a better description of the data.Comment: 15 pages, 4 figures, uses elsart.sty. Changes to references and discussion based on referee comments, resubmitted to Phys. Lett.

Measuring health-related quality of life in young adolescents: Reliability and validity in the Norwegian version of the Pediatric Quality of Life Inventory™ 4.0 (PedsQL) generic core scales

BACKGROUND: Health-Related Quality of Life (HRQOL) studies concerning children and adolescents are a growing field of research. The Pediatric Quality of Life Inventory (PedsQL™) is considered as a promising HRQOL instrument with the availability of age appropriate versions and parallel forms for both child and parents. The purpose of the current study was to evaluate the psychometric properties of the Norwegian translation of the Pediatric Quality of Life Inventory (PedsQL™) 4.0 generic core scale in a sample of healthy young adolescents. METHODS: A cross-sectional study of 425 healthy young adolescents and 237 of their caregivers participating as a proxy. Reliability was assessed by Cronbach's alpha. Construct validity was assessed using exploratory factor analysis and by exploring the intercorrelations between and among the four PedsQL subscales for adolescents and their parents. RESULTS: All the self-report scales and proxy-report scales showed satisfactory reliability with Cronbach's alpha varying between 0.77 and 0.88. Factor analysis showed results comparable with the original version, except for the Physical Health scale. On average, monotrait-multimethod correlations were higher than multitrait-multimethod correlations. Sex differences were noted on the emotional functioning subscale, girls reported lower HRQOL than boys. CONCLUSION: The Norwegian PedsQL is a valid and reliable generic pediatric health-related Quality of Life measurement that can be recommended for self-reports and proxy-reports for children in the age groups ranging from 13–15 years

Lipidomics Analysis Reveals Efficient Storage of Hepatic Triacylglycerides Enriched in Unsaturated Fatty Acids after One Bout of Exercise in Mice

Background: Endurance exercise induces lipolysis, increases circulating concentrations of free fatty acids (FFA) and the uptake and oxidation of fatty acids in the working muscle. Less is known about the regulation of lipid metabolism in the liver during and post-exercise

Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

BACKGROUND: The amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA receptor subunits across the chordates and detail their mode of evolution among mammals. PRINCIPAL FINDINGS: Our analyses support two major monophyletic clades: one clade containing GABA(A) receptor alpha, gamma, and epsilon subunits, and another one containing GABA(A) receptor rho, beta, delta, theta, and pi subunits. The presence of GABA receptor subunits from each of the major clades in the Ciona intestinalis genome suggests that these ancestral duplication events occurred before the divergence of urochordates. However, while gene divergence proceeded at similar rates on most receptor subunits, we show that the mammalian-specific subunits theta and epsilon experienced an episode of positive selection and of relaxed constraints, respectively, after the duplication event. Sites putatively under positive selection are placed on a three-dimensional model obtained by homology-modeling. CONCLUSIONS: Our results suggest an early divergence of the GABA receptor subunits, before the split from urochordates. We show that functional changes occurred in the lineages leading to the mammalian-specific subunit theta, and we identify the amino acid sites putatively responsible for the functional divergence. We discuss potential consequences for the evolution of mammals and of their CNS