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"Contact pathway"

Lisha Lin, Mingyi Wu, Jinhua Zhao
The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial...
November 15, 2016: International Journal of Hematology
M Gissel, K E Brummel-Ziedins, S Butenas, A E Pusateri, K G Mann, T Orfeo
BACKGROUND: Disruption of hydrogen ion homeostasis is a consequence of traumatic injury often associated with clinical coagulopathy. Mechanisms by which acidification of the blood lead to aberrant coagulation require further elucidation. OBJECTIVE: To examine the effects of acidified conditions on coagulation dynamics using in vitro models of increasing complexity. METHODS: Coagulation dynamics were assessed at pH 7.4 and 7.0 as follows: 1) Tissue factor (TF)-initiated coagulation proteome mixtures (± factor (F)XI, ± fibrinogen/FXIII), with reaction progress monitored as thrombin generation or fibrin formation; 2) Enzyme/inhibitor reactions; 3) TF-dependent or -independent clot dynamics in contact pathway inhibited blood via viscoelastometry...
July 19, 2016: Journal of Thrombosis and Haemostasis: JTH
Haiyun Wu, Qilin Liao, Steven N Chillrud, Qiang Yang, Lei Huang, Jun Bi, Beizhan Yan
Cadmium (Cd) is a toxic metal. This study was aimed to estimate the potential health risks in a Cd-polluted district in China, and examine the relationship between urinary cadmium(UCd) and hypertension and impaired kidney function at low exposure levels (UCd: GM 1.3 μg/g creatinine). Blood pressure measurement, questionnaires, and collection of urinary samples were conducted from 217 residents. Environmental samples, food, and cigarette samples were collected and detected to estimate the risks posed by Cd and the contribution of inhalation, ingestion, and dermal contact pathways to these risks...
2016: Scientific Reports
Alexander J Donovan, Joseph Kalkowski, Magdalena Szymusiak, Canhui Wang, Stephanie A Smith, Robert F Klie, James H Morrissey, Ying Liu
Granular platelet-sized polyphosphate nanoparticles (polyP NPs) were encapsulated in sterically stabilized liposomes, forming a potential, targeted procoagulant nanotherapy resembling human platelet dense granules in both structure and functionality. Dynamic light scattering (DLS) measurements reveal that artificial dense granules (ADGs) are colloidally stable and that the granular polyP NPs are encapsulated at high efficiencies. High-resolution scanning transmission electron microscopy (HR-STEM) indicates that the ADGs are monodisperse particles with a 150 nm diameter dense core consisting of P, Ca, and O surrounded by a corrugated 25 nm thick shell containing P, C, and O...
August 8, 2016: Biomacromolecules
Cristina Puy, Rachel A Rigg, Owen J T McCarty
Coagulation factor (F)XI has been described as a component of the early phase of the contact pathway of blood coagulation, acting downstream of factor XII. However, patients deficient in upstream members of the contact pathway, including FXII and prekallikrein, do not exhibit bleeding complications, while FXI-deficient patients sometimes experience mild bleeding, suggesting FXI plays a role in hemostasis independent of the contact pathway. Further complicating the picture, bleeding risk in FXI-deficient patients is difficult to predict because bleeding symptoms have not been found to correlate with FXI antigen levels or activity...
May 2016: Thrombosis Research
Tomas L Lindahl, Sofia Ramström, Niklas Boknäs, Lars Faxälv
Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets...
February 2016: Biochemical Society Transactions
Charlotte Bouckaert, Silvia Serra, Grégoire Rondelet, Eduard Dolušić, Johan Wouters, Jean-Michel Dogné, Raphaël Frédérick, Lionel Pochet
Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile...
March 3, 2016: European Journal of Medicinal Chemistry
Teresa C Assumpção, Dongying Ma, Daniella M Mizurini, R Manjunatha Kini, José M C Ribeiro, Michail Kotsyfakis, Robson Q Monteiro, Ivo M B Francischetti
BACKGROUND: Hematophagous mosquitos and ticks avoid host hemostatic system through expression of enzyme inhibitors targeting proteolytic reactions of the coagulation and complement cascades. While most inhibitors characterized to date were found in the salivary glands, relatively few others have been identified in the midgut. Among those, Boophilin is a 2-Kunitz multifunctional inhibitor targeting thrombin, elastase, and kallikrein. However, the kinetics of Boophilin interaction with these enzymes, how it modulates platelet function, and whether it inhibits thrombosis in vivo have not been determined...
January 2016: PLoS Neglected Tropical Diseases
Vladimir N Kolyadko, Sofya V Lushchekina, Tatiana A Vuimo, Stepan S Surov, Ruzanna A Ovsepyan, Vera A Korneeva, Ivan I Vorobiev, Nadezhda A Orlova, Leonid Minakhin, Konstantin Kuznedelov, Konstantin V Severinov, Fazoil I Ataullakhanov, Mikhail A Panteleev
Factor XIIa (fXIIa) is a serine protease that triggers the coagulation contact pathway and plays a role in thrombosis. Because it interferes with coagulation testing, the need to inhibit fXIIa exists in many cases. Infestin-4 (Inf4) is a Kazal-type inhibitor of fXIIa. Its specificity for fXIIa can be enhanced by point mutations in the protease-binding loop. We attempted to adapt Inf4 for the selective repression of the contact pathway under various in vitro conditions, e.g., during blood collection and in 'global' assays of tissue factor (TF)-dependent coagulation...
2015: PloS One
Magdalena Szymusiak, Alexander J Donovan, Stephanie A Smith, Ross Ransom, Hao Shen, Joseph Kalkowski, James H Morrissey, Ying Liu
Platelet-sized polyphosphate (polyP) was functionalized on the surface of gold nanoparticles (GNPs) via a facile conjugation scheme entailing EDAC (N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride)-catalyzed phosphoramidation of the terminal phosphate of polyP to cystamine. Subsequent reduction of the disulfide moiety allowed for anchoring to the colloidal surface. The ability of the synthesized polyP-GNPs to initiate the contact pathway of clotting in human pooled normal plasma (PNP) was then assayed by quantifying changes in viscous, mechanical, and optical properties upon coagulation...
January 20, 2016: Bioconjugate Chemistry
Iman H Nasr, Ania L Manson, Humaid A Al Wahshi, Hilary J Longhurst
Hereditary angioedema (HAE) is a rare but serious and potentially life threatening autosomal dominant condition caused by low or dysfunctional C1 esterase inhibitor (C1-INH) or uncontrolled contact pathway activation. Symptoms are characterized by spontaneous, recurrent attacks of subcutaneous or submucosal swellings typically involving the face, tongue, larynx, extremities, genitalia or bowel. The prevalence of HAE is estimated to be 1:50,000 without known racial differences. It causes psychological stress as well as significant socioeconomic burden...
2016: Expert Review of Clinical Immunology
Christina Dicke, Ali Amirkhosravi, Brigitte Spath, Miguel Jiménez-Alcázar, Tobias Fuchs, Monica Davila, John L Francis, Carsten Bokemeyer, Florian Langer
BACKGROUND: In acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood. METHODS: We conducted a prospective study on 69 patients with newly diagnosed AML to further define the correlates of systemic coagulation activation in this hematological malignancy. Tissue factor procoagulant activity (TF PCA) of isolated peripheral blood mononuclear cells (PBMCs) and TF expression by circulating microparticles (MPs) were assessed by single-stage clotting and thrombin generation assay, respectively...
2015: Experimental Hematology & Oncology
B A Herbig, S L Diamond
BACKGROUND: Under severe stenotic conditions, von Willebrand factor (VWF) multimerizes into large insoluble fibers at pathological shear rates. OBJECTIVE: Evaluate the mechanics and biology of VWF fibers without the confounding effects of endothelium or collagen. METHODS: Within a micropost-impingement microfluidic device, > 100-μm long VWF fibers multimerized on the post within 10 min using EDTA-treated platelet-free plasma (PFP) perfused at wall shear rates > 5000 s(-1) ...
September 2015: Journal of Thrombosis and Haemostasis: JTH
J H Morrissey, S A Smith
Inorganic polyphosphate (polyP), a linear polymer of phosphates, is present in many infectious microorganisms and is secreted by mast cells and platelets. PolyP has recently been shown to accelerate blood clotting and slow fibrinolysis, in a manner that is highly dependent on polymer length. Very long-chain polyP (of the type present in microorganisms) is an especially potent trigger of the contact pathway, enhances the proinflammatory activity of histones, and may participate in host responses to pathogens...
June 2015: Journal of Thrombosis and Haemostasis: JTH
Shu Zhu, Richard J Travers, James H Morrissey, Scott L Diamond
Factor XIIa (FXIIa) and factor XIa (FXIa) contribute to thrombosis in animal models, whereas platelet-derived polyphosphate (polyP) may potentiate contact or thrombin-feedback pathways. The significance of these mediators in human blood under thrombotic flow conditions on tissue factor (TF) -bearing surfaces remains inadequately resolved. Human blood (corn trypsin inhibitor treated [4 μg/mL]) was tested by microfluidic assay for clotting on collagen/TF at TF surface concentration ([TF]wall) from ∼0.1 to 2 molecules per μm(2)...
September 17, 2015: Blood
Stephanie A Smith, Richard J Travers, James H Morrissey
The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world...
2015: Critical Reviews in Biochemistry and Molecular Biology
Yi Wu
The contact system, also named as plasma kallikrein-kinin system, consists of three serine proteinases: coagulation factors XII (FXII) and XI (FXI), and plasma prekallikrein (PK), and the nonenzymatic cofactor high molecular weight kininogen (HK). This system has been investigated actively for more than 50 years. The components of this system and their interactions have been elucidated from in vitro experiments, which indicates that this system is prothrombotic by activating intrinsic pathway, and proinflammatory by producing bioactive peptide bradykinin...
2015: Thrombosis Journal
Vinai C Bhagirath, Dhruva J Dwivedi, Patricia C Liaw
PURPOSE: Cell-free DNA (CFDNA) is elevated in sepsis and correlates with mortality. This DNA may come from nuclear, mitochondrial, or bacterial sources. Cell-free DNA from all three sources may play a pathogenic role in sepsis via activation of coagulation through the contact pathway, whereas CpG motifs on bacterial and mitochondrial DNA may additionally stimulate inflammatory responses via Toll-like receptor 9. This study elucidates the relative effects of nuclear, mitochondrial, and bacterial DNA on inflammatory and procoagulant pathways with relevance to sepsis...
September 2015: Shock
Atif Kamal, Riffat Naseem Malik, Tania Martellini, Alessandra Cincinelli
The aim of this study was to determine the abundance and distribution of polycyclic aromatic hydrocarbons (PAHs) in dust samples collected from the selected professional cooking workplaces (WCs) and residential household cooking areas (WRs), where traditional and primitive cooking practices are still prevelent. Another aim of this study was to investigate the carcinogenic risk for Pakistani human exposure to dust-bound PAHs via the routes of inhalation, ingestion, and dermal contact. Generally, the concentration of individual congeners of PAHs in surface dust samples of WC sites was higher than those measured in WR sites (p < 0...
August 2015: Environmental Science and Pollution Research International
Sukanya Rajiv, Susan Rodgers, Ahmed Bassiouni, Sarah Vreugde, Peter-John Wormald
BACKGROUND: Use of muscle grafts for hemostasis during surgery has re-emerged; recent animal model studies have shown effective bleeding control with their use. However, the mechanism of action is unknown. The aim of this study is to evaluate the action of muscle extracts on the coagulation pathways and platelet aggregation. METHODS: Muscle extracts were prepared by dissolving crushed snap-frozen muscle tissue (0.04 to 0.8 mg) in 1 mL saline. Saline was used as control...
May 2015: International Forum of Allergy & Rhinology
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