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Activated factor xiia

Allen P Kaplan, Kusumam Joseph
Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4...
October 2016: Clinical Reviews in Allergy & Immunology
Zonne L M Hofman, Anurag Relan, Sacha Zeerleder, Christian Drouet, Bruce Zuraw, C Erik Hack
Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack...
August 2016: Journal of Allergy and Clinical Immunology
Haley R Gittleman, Alona Merkulova, Omar Alhalabi, Evi X Stavrou, Martina L Veigl, Jill S Barnholtz-Sloan, Alvin H Schmaier
Plasma kallikrein formed from prekallikrein (PK) produces bradykinin from kininogens and activates factor XII. Plasma PK is activated by factors αXIIa, βXIIa, or prolylcarboxypeptidase (PRCP). A cross-sectional investigation determined if there is an association of PRCP and KLKB1 polymorphisms with cardiovascular disease (CVD). DNA was obtained from 2243 individuals from the Prevention of Events with Angiotensin Converting Enzyme trial. Two PRCP SNPs, rs7104980 and rs2298668, and two KLKB1 SNPs, rs3733402 and rs3087505, were genotyped...
2016: Frontiers in Medicine
Pudur Jagadeeswaran, Brian C Cooley, Peter L Gross, Nigel Mackman
Thrombosis is a leading cause of morbidity and mortality worldwide. Animal models are used to understand the pathological pathways involved in thrombosis and to test the efficacy and safety of new antithrombotic drugs. In this review, we will first describe the central role a variety of animal models of thrombosis and hemostasis has played in the development of new antiplatelet and anticoagulant drugs. These include the widely used P2Y12 antagonists and the recently developed orally available anticoagulants that directly target factor Xa or thrombin...
April 29, 2016: Circulation Research
Kjeld Christensen, Huda Kozarcanin, Kristina N Ekdahl, Bo Nilsson
INTRODUCTION: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. METHODS AND PATIENTS: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3days post-percutaneous intervention (PCI) and, in one-third of the patients, 3months after PCI...
May 2016: Thrombosis Research
Sacha Zeerleder, Marcel Levi
Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation...
2016: Annals of Medicine
Nilima Biswas, Adam X Maihofer, Saiful Anam Mir, Fangwen Rao, Kuixing Zhang, Srikrishna Khandrika, Manjula Mahata, Ryan S Friese, C Makena Hightower, Sushil K Mahata, Dewleen G Baker, Caroline M Nievergelt, Sucheta M Vaingankar, Daniel T O'Connor
BACKGROUND: Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder...
2016: BMC Medical Genetics
Yasin Kokoye, Ivan Ivanov, Qiufang Cheng, Anton Matafonov, S Kent Dickeson, Shauna Mason, Daniel J Sexton, Thomas Renné, Keith McCrae, Edward P Feener, David Gailani
Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and α-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and α-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and α-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis...
April 2016: Thrombosis Research
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
Jennifer Krupka, Frauke May, Thomas Weimer, Ingo Pragst, Christoph Kleinschnitz, Guido Stoll, Con Panousis, Gerhard Dickneite, Marc W Nolte
BACKGROUND AND PURPOSE: Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. METHODS: For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min...
2016: PloS One
Marie Worm, Elodie C Köhler, Rachita Panda, Andy Long, Lynn M Butler, Evi X Stavrou, Katrin F Nickel, Tobias A Fuchs, Thomas Renné
The plasma protein factor XII (FXII) is the initiating protease of the procoagulant and proinflammatory contact system. FXII activates both the bradykinin (BK) producing kallikrein-kinin system and the intrinsic pathway of coagulation. Contact with negatively charged surfaces induces auto-activation of zymogen FXII that results in activated FXII (FXIIa). Various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, nucleic acids and polyphosphate. Murine models have established a central role of FXII in arterial and venous thromboembolic diseases...
October 2015: Annals of Translational Medicine
Shan Huang, Anna E Engberg, Nina Jonsson, Kerstin Sandholm, Ian A Nicholls, Tom Eirik Mollnes, Karin Fromell, Bo Nilsson, Kristina N Ekdahl
BACKGROUND: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models. METHODS: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release...
January 2016: Biomaterials
Youngjin Cho, Rachel Silverstein, Max T Geisinger, Stephen Martinkovich, Holly Corkill, Jess M Cunnick, Sonia L Planey, John A Arnott
BACKGROUND: CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-β1 and acts as a mediator of TGF-β1 induced matrix production in osteoblasts and Src is required for CCN2 induction by TGF-β1; however, the molecular mechanisms that control CCN2 induction in osteoblasts are poorly understood. AFAP1 binds activated forms of Src and can direct the activation of Src in certain cell types, however a role for AFAP1 downstream of TGF-β1 or in osteoblats is undefined...
2015: PloS One
Elizabeth Valdivieso, Maria J Perteguer, Carolina Hurtado, Pamela Campioli, Esperanza Rodríguez, Ana Saborido, Victoria Martínez-Sernández, Paulino Gómez-Puertas, Florencio M Ubeira, Teresa Gárate
BACKGROUND: Serine proteinase inhibitors (serpins) finely regulate serine proteinase activity via a suicide substrate-like inhibitory mechanism. In parasitic nematodes, some serpins interact with host physiological processes; however, little is known about these essential molecules in Anisakis. This article reports the gene sequencing, cloning, expression and preliminary biochemical and bioinformatically-based structural characterization of a new Anisakis serpin (ANISERP). METHODS: The full AniSerp gene was cloned by specific RACE-PCR after screening an Anisakis simplex (L3) cDNA library...
2015: Parasites & Vectors
Vladislava A Terentyeva, Anastasia N Sveshnikova, Mikhail A Panteleev
Surface-induced activation of factor XII is critical part of the intrinsic pathway of blood coagulation. The mechanism of this process remains unclear: in particular, it is not known whether the initial amounts of factor XIIa, an active form of factor XII, are produced purely by factor XII contacting a surface or if traces of factor XIIa pre-exist. Furthermore, it is not known whether factor XII first has to bind to a surface before it can interact with the surface-bound factor XIIa in a two-dimensional process to become activated ("bound-substrate model") or if surface-bound factor XIIa activates a fluid-delivered form of factor XII ("free-substrate model")...
October 7, 2015: Journal of Theoretical Biology
Hiroshi Deguchi, Gertrud Wolfbauer, Marian C Cheung, Yajnavalka Banerjee, Darlene J Elias, José A Fernández, John J Albers, John H Griffin
BACKGROUND: Plasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity. METHODS: The in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied...
2015: Thrombosis Journal
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
Marina A Dobrovolskaia, Scott E McNeil
Circulation and oxygenation of blood outside the body is commonly required during complex surgical interventions involving coronary pulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO). Both CPB and ECMO are life-supporting procedures utilizing a heart-lung machine, which subjects the blood to unphysiological conditions, potentially promoting undesirable blood coagulation. Traditionally, thrombotic complications from CPB and ECMO are resolved by heparin, an inexpensive broad spectrum anticoagulant that prevents blood clotting, but often results in bleeding...
May 2015: Annals of Translational Medicine
Vanessa Baeriswyl, Sara Calzavarini, Shiyu Chen, Alessandro Zorzi, Luca Bologna, Anne Angelillo-Scherrer, Christian Heinis
Coagulation factor XII (FXII) inhibitors are of interest for the study of the protease in the intrinsic coagulation pathway, for the suppression of contact activation in blood coagulation assays, and they have potential application in antithrombotic therapy. However, synthetic FXII inhibitors developed to date have weak binding affinity and/or poor selectivity. Herein, we developed a peptide macrocycle that inhibits activated FXII (FXIIa) with an inhibitory constant Ki of 22 nM and a selectivity of >2000-fold over other proteases...
August 21, 2015: ACS Chemical Biology
D Gailani, C E Bane, A Gruber
The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa (FXa) or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and FX. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage...
August 2015: Journal of Thrombosis and Haemostasis: JTH
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