Factor XI and the Contact System
DRAFT Subcommittee Minutes
24 July 2011
08:00-12:00
Room E
Chairman: Thomas Renne (SE)
Co-chairmen: David Gailani (US), Keith McCrae (US)
Factor XI and the Contact System, 24. July 2011, 8:00 am, Room A
This was the first SSC session of the Factor XI and the Contact System subcommittee that was previously entitled as the Plasma Kallikrein Kinin-System after having changed name. Similarly to the previous meetings in Boston and Cairo the session was very well attended with up to 210 participants and had lively and constructive discussions. The session was divided into an educational portion with more review type presentations and scientific presentations showing latest not yet published results in the field.
Educational Session
Dr. Hideiko Saito, Nagoja, Japan: In a highly stimulating lecture Dr. Saito presented original data and classical patient histories leading to the identification, characterization and purification of Fletcher factor (now known as plasmakallikrein) and Fitzgerad factor (High-molecular weight kininogen). He also showed original functional in vivo data that characterized the proinflammatory activity of the kallikrein kinin-system in vivo and the importance of the system for leukocyte recruitment and increase of vascular leak.
Dr. James H. Morrissey, Urbana, USA: Starting from his original publication (Smith S. et al., PNAS 2006) Dr. Morrissey reviewed the current knowledge on synthesis, expression, and biochemistry including half life etc. of polyphosphates that have recently been recognized as the endogenous activator of factor XII. He showed functions of the inorganic polymer that is enriched in intracellular vesicles called acidocalcisomes in bacteria. In addition to activating factor XII, polyphosphates propagate factor V activation and interfere with fibrinolysis in a TAFI-dependent manner. Dr. Morrissey concluded his presentation reporting recent data from his laboratory showing polyphosphate-driven factor XI activation that involves increased autoactivation and alpha-thrombin-driven activation of factor XI.
Dr. Thomas Renné, Stockholm, Sweden: He reviewed papers showing activation of the contact system by naturally occurring and synthetic negatively charged polysaccharides such as heparin and dextran sulfate, respectively. Dr. Renné presented data from his group showing a role of mast cell-released heparin for anaphylactic reaction and edema in vivo that were published recently (Oschatz et al., Immunity 2011). Mast cell triggered activation of the plasma contact system resulting in bradykinin formation seems of critical importance for triggering the onset of swellings in hereditary angioedema patients. Similarly to mast cell heparin, contaminants in heparins such as oversulfated chondroitin sulfate trigger contact system activation and account for severe anaphylactic side affects and life threatening reactions of some heparin preparations in 2007-08.
SSC SCIENTIFIC SESSION
Dr. Joost C. M. Meijers, Amsterdam, The Netherlands: Dr. Meijers introduced structure and biochemical characterization of factor XI. He reviewed the importance of the factor for thrombosis in genetically altered mouse models and in patients with inherited factor deficiency. Based on the critical role of factor XI for thrombosis an antisense-based strategy using ASO was developed to interfere with factor XI expression. Dr. Meijers showed protection from thrombosis in various models and vascular beds in ASO-treated mice that was not associated with increased bleeding. Ongoing work indicated that targeting factor XI in baboons in using ASO provides thromboprotection that is not associated with abnormal increased bleeding.
Dr. Erik Tucker, Portland, USA: The topic of Dr. Tucker’s presentation was the role of factor XI and the contact system for sepsis. He showed that factor XI homozygous gene deficient mice and wildtype animals treated with a factor XI-blocking antibody (14E11) had improved survival and reduced coagulopathy in a polymicrobial sepsis models (CLP) and Listeriosis/Gram-positive bacteria-infection models. In contrast factor XI appeared of minor importance in LPS-induced endotoxemia models. He concluded his presentation showing preliminary results with 14E11 in baboon thrombosis and sepsis models.
Dr. Alvin H. Schmaier, Cleveland, USA: Dr. Schaier presented a comprehensive overview about the functions of factor XII zymogen form that were generated in his laboratory in the recent years. He showed factor XII binding to cell surfaces involves a multi-protein acceptor complex involving the urokinase receptor. Factor XII zymogen stimulates cell proliferation by ERK1/2- and Akt-dependent pathways. Beta1-integrins seem to have a role in factor XII-driven signalling events in endothelial cells. Dr. Schmaier showed a role of factor XII for angiogenesis in ex vivo assays and correspondingly defective neoangiogenesis in factor XII gene deficient mice. Preliminary data from ongoing experiments suggest a role of factor XII for macrophage migration and wound healing that is independent on the enzymatic activity of the protease and not mediated by bradykinin.
Dr. José Govers-Riemslag, Maastricht, The Netherlands: Dr. Govers-Riemslag showed a comprehensive overview on the role of activated factor XII for thrombin formation and especially thrombus stability. Her central information was that clots that were produced in the presence of active factor XII are more stable and more resistant to fibrinolyses. She showed that the formation of the tighter clots is a direct effect of FXIIa on fibrin formation, independent of additional thrombin formation. She used a set of state-of-the-art ex vivo technology to analyze the effect of factors XII on fibrin clot structure including ex vivo clot lysisassays, microscopy and for elasticity of the clot magnetic tweezers.
Dr. Owen McCarty, Portland, USA: Dr. McCarty presented recent data and ongoing research from his laboratory dealing with the interaction of factor XI with neutrophils and the importance of the protein for signalling cascades in these cells. He showed that active factor XI interferes with oxidative stress-driven pathways in PMN. Using flow chamber real time analysis he analyzed roles of factor XI for PMN migration. Identification and characterization of the structures and receptors involved in factor XI binding to PMNs remain a major challenge in his field.
Dr. Uri Seligsohn, Tel Aviv, Israel: Dr. Seligsohn presented an update on the clinical functions of factor XI. The first part of his clear presentation dealt with the observation that bleeding tendency in factor XI deficient individuals from Isreal was not related to factor XI antigen plasma levels. He then compared incidence, clinical presentation, genetics and epidemiology of the three types of hereditary factor XI deficiency (types I, II, III). Dr. Seligsohn concluded his presentation showing that severe factor XI deficiency protects from DVT and ischemic stroke but not from MI. Mechanisms and differences in factor XI-driven procoagulant activities in these distinct vascular beds were discussed.
End of the meeting: 12:10.
