Join Mailing List   |   Jobs   |   Print Page   |   Contact Us   |   Sign In   |   Join
Annual Minutes
Group Home Group Home Group Pages
Moderator(s):
Page 1 of 1
Forum Actions

Topics   Replies Author Latest Post
2016 Annual Minutes 0 J. Meijers SSC Factor XI and the Contact System 2016, Montpellier, France Chairman: Joost Meijers Co-chairs: Jonas Emsley, Edward P. Feener, Jose W. Govers-Riemslag, Heiko Herwald, James Morrissey, Evi X. Stavrou The Factor XI and Contact System session on May 27 drew approximately 120 attendees.  The session was preceded by the best scoring abstract by Charlotte Bouckaert from Belgium in which she presented novel coumarin-like molecular weight inhibitors of the contact pathway that may be useful in the treatment of thrombotic diseases. Heiko Herwald from Sweden gave an educational lecture to discuss the interaction of the contact system with pathogens. The contact system is a natural defense system that targets bacteria and other pathogens. The link between contact system and pathogens was further demonstrated by a talk by Ingrid Stroo from the Netherlands who showed that factor XI improves host defense during pneumonia-derived sepsis. Strikingly, this effect was independent from factor XII activation. Steffen Rosén from Sweden described novel methods to detect the enzymes of the contact pathway. With specific dilutions in buffered media, he could independently and sensitively measure activity of factor XIIa, kallikrein and factor XIa. Helen Wilmot from the United Kingdom discussed the functional and antigen levels of the 2nd International Standard for factor XI. This standard has been endorsed by SSC and submitted for acceptance. In a separate presentation Helen Wilmot proposed to establish an international standard for factor XII. This was well received and it is expected that a standard will be available in the coming years. Alvin Schmaier from the United States discussed the multitude of names and abbreviations of the proteins of the contact system. He proposed to harmonize names and abbreviations. His presentation was followed by an extensive discussion in which arguments for and against harmonization were mentioned and several options were given. It was decided that a small committee including Alvin Schmaier, Jonas Emsley, Edward Feener, José Govers, Johannes Sidelmann and Joost Meijers will prepare a draft proposal that will be sent to interested investigators. This should lead to a final proposal that could be voted upon during the next SSC session in Berlin, and followed by a publication in JTH. Bubacarr Karia from the United Kingdom used structural studies to demonstrate zinc binding to fibronectin type II domain in factor XII and identified the involved residues. Edward Feener from the United States summarized literature and his latest data about the role of prekallikrein and prekallikrein inhibition in hemostasis. Although long thought that there is no effect of prekallikrein on coagulation, he demonstrated bleeding in normal and diabetic mice in the absence of prekallikrein by inhibition of platelet aggregation. Jeff Weitz from Canada gave an update on the clinical development of factor XI inhibitors. The holy grail of antithrombotic research is to attenuate thrombosis without increasing the risk of bleeding. He summarized the current interest of pharmaceutical industries that are focusing on antisense oligonucleotides and presented the phase II study that demonstrated efficacy without associated risk of bleeding using factor XI antisense oligonucleotides. Stephanie Smith from the United States provided an overview on how polyphosphates influence coagulation with emphasis on the contact system. There are multiple interactions between polyphosphates and the different members of the contact system with probably the most important effect the stimulation of thrombin-mediated activation of factor XI.    This talk was followed by a presentation of Coen Maas from the Netherlands who described the presence and functionality of polyphosphate crystals on the platelet surface and demonstrated two different pools of polyphosphates with different sizes: a soluble form and an insoluble form as polyphosphate in nanoparticles. Evi Stavrou from the United States described the role of the contact system on leukocyte function. Both enzymatic and non-enzymatic functions were observed. Leukocyte migration in skin wounds was less in factor XII deficient mice. Factor XII deficient neutrophils demonstrated reduced chemotaxis. Factor XII in leukocytes contributed to thrombosis. Alvin Schmaier from the United States presented his data on the modulation of thrombotic risk by prekallikrein and the bradkykinin B2 receptor. He identified a role of the renin-angiotensin system whereby prostacyclin was enhanced. Furthermore, he demonstrated a reduced concentration of vessel wall tissue factor in the prekallikrein knockout mice. Erik Tucker from the United States showed his latest data on animal preclinical studies on inhibition of the contact system as antithrombotic therapy. In venous models, both factor XI and factor XII targeting provided similar effects. In arterial models, targeting factor XI was superior. 
by J. Meijers
Wednesday, June 8, 2016
2015 Annual Minutes 0 L. Schmeidler Chairman:  Jonas Emsley Co-Chairs:  Jose W. Govers-Riemslag, Christine Mannhalter, Joost Meijers, James Morrissey,  Ophira Salomon, Evi X. Stavrou   The factor XI and contact system was attended with 200 attendees Bernd Engelmann (Germany):  Propagation of blood coagulation by extracellular nucleosomes/neutrophil extracellular traps was presented. This talk emphasised the importance of neutophils/platelets/contact system in thrombus formation. particularly in venous thrombosis where FXIIa seems to be more important than neutophil elastase. This talk also showed the association of DNA from NETs with factor XII and DNA as an activator of the contact system. Jonas Emsley (UK): Data on the structure of PK and the interaction with HK was presented together with Ammar Majeed (Sweden): The Factor XII Registry Database. This talk reported a new website FXII registry website URL is (www.factor12.net) where patient information will be stored on FXII deficient. There are several reasons why this important. 1. There are few reports characterising factor XII deficient patients and currently no systematic collection of data. This is important as FXII is considered an important novel target for the treatment of thrombosis and yet there is no epidemiological data on the effects of deficiency in humans. This contrasts with the case of Factor XI where and established website is available and >200 cases of FXI deficiency have been characterised together with the genes sequenced. It was discussed that it would be beneficial to have sequencing carried out for the FXII genes and that patients with a defect but normal FXII plasma levels (CRM+) be entered into the database. The audience was encouraged to submit information on FXII deficient patients. Nicola Mutch (UK): Driving plasminogen activation by factor XIIa. This talk described new data on FXII association fibrinolyisis - polyp modulated the fibrinolytic side of the FXIIa activity and polyp enhances fibrinolysis. PolyP binding characterised to FXII and plasminogen. The contribution of platelets to fibrinolysis was characterised as platelets secrete PolyP. PolyP accumulates in fibrin knots. A pathway was described for to contribute to fibrinolysis. FXII and fibrinogen were imaged localised on the surface of platelets at the cap with polyp. Keith McCrae (USA): This talk presented an update on kininogen in thrombosis and stroke models and as an anti-angiogenic protein. Toshitaka Sugi (Japan): Autoantibodies to FXII and kininogens in patients with recurrent pregnancy loss were described. This talk presented data on a series of FXII deficient patients characterised with recurrent pregnancy loss and also antibody interactions with FXII and kininogen in the present of phosphpolipid. A mechanism of FXII-antibody complexes with platelets is proposed for promoting thrombosis. Theme: Inhibitors of FXI and the contact system: Safer anticoagulation Maria Luiza Vilela Oliva (Brazil): Effect of plant inhibitors of the contact system on a mouse thrombosis model. CTI is a well know plant protein that is used as an inhibitor of the contact system. A further plan kunitz type inhibitor was presented which inhibits kallikirein and its properties were characterised as inhibiting thrombus formation in a mouse model. It was also proposed the inhibitor is bi-functional affecting the collagen receptor.   David Gailani (USA): New data were described for FXI anion binding sites and the effects of mutations here on PolyP and nucleic acid activation. Sanjay Bhanot could not attend so David Gailani presented a second talk (USA): Antisense Reduction of FXI for Thromboprophylaxis: A Novel Therapeutic Approach. This data showed the first clinical trial of and antisense RNA targeting FXI (N Engl J Med. 2015 Jan 15;372(3):232-40.) This showed effective reduction in circulating FXI levels over a period of weeks such that thrombosis was mitigated with no bleeding side effect. Data on factor XI contribution to venous thromboembolism was also presented. Open discussion José Govers-Riemslag (the Netherlands), and Joost Meijers, (the Netherlands), presented in an open discussion several topics to the audience. Since a factor XII registry was proposed, the first question was if each contact factor needs its own registry, which was nearly unanimously accepted. A combination of registries for the 4 contact proteins was found to be logistically unrealistic. Furthermore, an inventory was made of the interest of the audience for the mechanisms that can be activated by the contact system. In order of interest, the audience voted for the coagulation system, the complement system, the kallikrein-kinin system and the fibrinolytic system. Finally, the development of assays for the contact system was discussed. A general test that could determine outcome of all the affected mechanisms was not found to be practical, but there was great interest in the design and execution of specific tests that could measure contact system mediated activation of the coagulation, kallikrein-kinin system, fibrinolytic system and complement system. The audience felt that there was a role for the SSC subcommittee in developing such assays.  
by L. Schmeidler
Sunday, June 21, 2015
2014 Annual Minutes 0 J. Emsley Factor XI and the Contact System Chairman: Jonas Emsley (UK) Co-Chairmen: Jose Govers-Riemslag (the Netherlands), Christine Mannhalter (Austria), Joost Meijers (Netherlands), James Morrissey (USA), Thomas Renne (Sweden), Ophira Salomon (Israel) Thursday, 26 June (8:45-12:45)  Owen McCarty –  (Portland, USA) FXI activation and the virulence of infectious agents - The presentation of the cleavage of TFPI by factor XIa further defining the nature of the the pathway leading to thrombosis as opposed to hemostasis.   Ricky Travers –  (Urbana, USA) Visualizing polyP in thrombi and using novel anti-polyP compounds to stop thrombosis. This showed imaging of polyP emerging from cells and  described data on compounds capable of binding to polyP and inhibiting thrombosis with minimal bleeding risk.  Thomas Renné – (Karolinska Stockholm, Sweden) Factor XII function in thrombosis and hemostasis This was a description of the use of an antibody 3F7, which bound to the FXII protease domain. It was shown to to thromboprotection in extracorporeal circulation without increasing bleeding risk.   Evi Stavrou – (Cleveland, USA) Contact Activation Murine KOs: Unexpected Findings When Characterizing Mechanisms Related to Thrombosis Protection. This talk described contact system independent functions of plasma kallikrein.  Coen Maas – (Utrecht, the Netherlands) Plasmin triggers proteolytic Factor XII activation on endothelial cells, which is accelerated by the lysine substitution T328K that causes type III angioedema. This presentation detailed a new mechanism for the activation og mutant FXII.  Judith Cosemans – (Maastricht, the Netherlands) Factor XII regulates the pathological process of thrombus formation on ruptured plaques. This talk described novel in vivo functions of FXII for plaque-driven thrombosis and show FXII to contribute to thrombus stability.  Elaine Gray – (NIBSC, Potters Bar, UK) An International Standard for Activated Factor XI (FXIa). A standard was presented on FXIa in response to problems with immunoglobulin preparations being linked to thrombosis due to contact protein contamination in purification of immunoglobulins . This described an indirect assay involving FIX and FX and a chromogenic readout of FXa production. Different laboratories utilised this technique and were able to show very similar results in quantifying FXIa. The SSC board recommended the adoption of this standard. As a comment at the meeting it was mentioned that immunogobulin preparations should all be tested with this standard together with FXI replacement therapy.  Theme: Inhibitors of FXI and the contact system: Safer anticoagulation  Umesh Desai – (Richmond, USA) Allosteric inhibitors of FXIa. This described compounds which allosterically inhibit FXIa activity by binding to the anion binding exosite in the protease domain. The first part described the discovery and characterisation which was published and subsequent part of th  Jon Kennisten – (Burlington, USA) – Discovery and characterization of a highly specific antibody inhibitor of plasma kallikrein. This talk described a crystal structure of an inhbitory antibody Fab fragment bound to the protease domain of kallikrein. This antibody is in clinical trials for the treatment of edema.  Rebecca Smock –  (Seattle, USA) - Inhibiting the contact pathway with RNA aptamers . This was a very elegant presentation and in the first part published data was described showing nucleic acid aptamers which bind to FXII and inhibit its activity. The pattern of inhibition inhibited contact activation as measured by FXII activity varied based on which activator is used. In the second part of the talk new data aptamers which inhibit FXI  Vladimir Kolyadko – (Russia) Characterisation and development of factor XIIa inhibitors for assaying tissue factor triggered coagulation. TOP ABSTRACT. This presentation described the effect of corn trypsin inhibitor CTI on various assays.   Open discussion  Joost Meijers – José Govers-Riemslag (the Netherlands) Polyphosphates and activation of the contact system. Is the contact system involved in both arterial and venous thrombosis? Joost Meijers, Amsterdam, and José Govers-Riemslag, Maastricht, introduced a new addition to the SSC session with an open discussion. The audience was allowed to vote on several questions with controversial opinions that dealt with two topics : 1). Polyphosphates and activation of the contact system, and 2). Is the contact system involved in both arterial and venous thrombosis? With active audience participation, the lively discussion reviewed relevance of platelet polyphosphates for activation of the contact system ex vivo and in vivo. The discussion on the relevance of the contact system for thrombosis gave the consensus that murine data support roles of factors XI and XII in both venous and arterial thrombosis, but that the roles of the factors in especially venous thrombosis in humans needs to be further investigated.
by J. Emsley
Wednesday, June 18, 2014
2013 Annual Minutes 0 T. Renne Factor XI and the Contact System Chairman: Thomas Renne (Sweden) Co-Chairs: Jonas Emsley (UK), David Gailani (USA), Jose W. Govers-Riemslag (Netherlands), Christine Mannhalter (Austria), Joost Meijers (Netherlands), James Morrissey (USA), Ophira Salomon (Israel) June 30, 2013Summary of SSC meeting Factor XI and the contact system The factor XI and contact system was extremely well attended with 250 for the educational session and up to 400 in the main session. The educational session had three talks from jonas emsley, edward feener and james morrisey covering topics on the structure of contact factors, the role BK receptors in hereditary angioedema (fact or fiction), and polyphosphates in coagulation respectively. The subcommittee session contained seven talks on a variety of topics including the involvement of coagulation factor XII in fibrinolysis, the link to NETs, and studying FXI variants using next generation sequencing. The most well attended talks were the last two on new inhibitor developments targeting FXII and FXI for safer anticoagulation. Structures of contact factors. Jonas Emsley. In the first part of the talk an overview of the domain structure for contact factors and FXI was presented and then data presented on a new structure of the FXI complex with a peptide from HK. Later information on the structure of the FXII protease domain and a review of old and new electron microscopy data on contact factors was also presented. The contact system in diabetes. Dr Edward Feener . In the first part of the talk he showed the role of kallikrien in controlling intercerebral hemorrage in hyperglycaemic states. In the second part he was alluding to the activation of the contacts system and BK formation in diabetic retinopathy. Polyphosphates in coagulation. Dr James morrisey presented an elegant overview of the polyphosphatees in coagulaton inlcuding the role of platelet polyphates in activating FXII, role in factor XI feedback activation by thrombin and function of the polymer in fibrinolysis. Hereditary angioedema - facts and fiction. Eric Hack. Highlighted the role of the B1R receptor for increased vascular permeability in edema. He summarised studies on the relative importance of B2R versus B1R for targeting edema. The last part of his talk was on the role of inflammatory stimuli for local and systemic activation of the contact system. Increased factor XIIa activity in patients on extracorporeal membrane oxygenation - a link to NETs. Simon Davidson. He gave a background of the clincial use of extracorproal circulation and summarised classical and new data showing activation of the contact system in ECMO. He discussed potential activators of the contact system in ECMO including NET formation and artifial surfaces. The involvement of coagulation factor XII in fibrinolysis. Joke Konings. This talk summarised the recent blood paper on the crosstalk of the intrinsic pathway and fibrinolytic systems with implications for changes in the density of clot structure in the presence of FXII or FXIIa. Understanding the role of sequence variation in the factor XI gene in the next- generation sequencing era. Stephano Duga. This talk outlined the new of new technologies in next generation sequence to pinpoint novel sequence variants and identify phenotypes. FXI inhibitors. Eric Tucker. Summarised new data on different antibodies targeting FXIIa mediated FXI acitivation or FXIa. The FXI binding antibodies recognising FXI do not affect the thrombin feedback loop and selectively block the FXIIa activation of the intrinsic pathway. The FXI binding antibody that blocks FXIa cleavage of FIX has a more potent antithrombotic effects in a baboon model of thrombosis. Factor XIIa inhibitors. Marc Nolte. A novel phage display based antibody interferes with FXIIa activity and FXIIa driven thrombus formation in mouse models of thrombosis and anterial venous shunt systems in rabbits. This recombinant monoclonal is in a stage 4 clinical trial in humans.
by T. Renne
Wednesday, June 19, 2013
2012 Annual Minutes 0 T. Renne Factor XI and the Contact System Subcommittee Minutes 28 June 2012 Chairman: Thomas Renne (SE) Co-chairmen:Jonas Emsley (UK), David Gailani (USA), Christine Mannhalter (Austria), Keith McCrae (USA), Joost Meijers (The Netherlands), Ophira Salomon (Israel) The SSC session was extremely well attended with more than 200 participants. We had 10 presentations including an overview lecture by Dr. Bolton-Maggs on clinical and diagnostic aspects of FXI deficiency. Presentations covered the three topics "Genetics and Genomics”, "Activation of factor XII”, and "Novel functions of FXI and the contact system in thrombosis”. All presentations were lively and comprehensively discussed. 1. Paula Bolton-Maggs, Manchester: "Factor XI - setting the scene” Dr. Bolton-Maggs gave a comprehensive overview on bleedings and therapeutic options in FXI-deficient patients (hemophilia C). One third of FXI-related bleeding episodes occur in women at childbirth. The majority of hemophilia C patients are CRM negative and in a significant portion of these individuals FXI antigen/clotting in analytical tests does not correlate with clinical severity of bleeding. aPTT tests are insufficient in characterizing bleeding risk in FXI deficiency. As low levels of other coagulation factors may contribute to the clinical picture of bleeding in such patients. Dr. Bolton-Maggs presented results of real time thrombin formation assays (ETP) triggered by low concentrations of tissue factor in hemophilia C patient plasmas. ETP correlated with bleeding risk in various patients and may represent a suitable diagnostic tool for assessing bleeding in FXI deficiency. Management options including rFVIIa and FXI infusions were discussed. The therapeutic use of low-dose recombinant FXI in treatment of FXI deficient patients with FXI inhibitors was also delineated. 2. Christine Mannhalter, Vienna: "Genotypic variations of complement factorsand phenotypic effects” Dr. Mannhalter presented interactions of the coagulation and complement systems. The focus of her presentation was complement factor C5. She presented an overview on C5 SNPs that correlate with C5 plasma levels and risk of thrombotic diseases. High levels of C5 represent a risk factor for stent restenosis. Dr. Mannhalter highlighted the role of platelets and platelet activation as a possible link between the coagulation and complement cascades. Platelets seem to contribute to localize thrombosis in areas of infection through both procoagulant mechanisms and activation of the classical complement pathway. 3. Gordon Lowe, Glasgow: "Epidemiology and genetics of aPTT and contact factors" Dr. Lowe presented recently published genome-wide linkage analyses that have identified genes that affect the aPTT. About 60% of shortened aPTT is attributed to inherited factors. F12, KNG1 and HRG genes were identified to be the main regulatory genes of aPTT shortening. Five genes account for about 30% of inherited effects on aPTT. Since the FXI and contact system proteins have critical functions in thrombosis albeit having minor roles in hemostasis, the work of Dr. Lowe identifies new SNPs associated with a prothrombotic risk and novel targets for safe anticoagulation. 4. Jonas Emsley, Nottingham: "Structure of the FXII protease domain” Dr. Emsley presented the crystal structure of the FXII enzymatic domain. He characterized kinetics and activation of recombinant FXII protease domain mutants. Key findings of the FXIIa structure are: (i) the FXII S1 substrate pocket is malformed, (ii) the FXII S1 site shares similarities with chymotrypsin, (iii) Aspartates switch to the active site. He characterized FXIIa docking onto FXI. SAXS analysis indicated an elongated FXII zymogen structure comprised of a stalk and head region. 5. Coen Maas, Utrecht: "Functional insights into FXII contact activation” Activated FXII has the capacity to activate its substrates FXI and PK. Regulatory mechanisms and substrate specificity of FXIIa are poorly understood. Dr. Maas presented FXIIa mutants in those cleavage sites involved in activation. Specificity of the mutant proteins was characterized using chromogenic substrates. Two forms of FXII were identified which either cleave PK or FXI? depending on which cleavage takes place in the FXII activation loop. He demonstrated that the FXII protease domain may have tryptase-like activities. 6. Nicola Mutch, Aberdeen: Characterization of FXII activation on a physiological surface Dr. Mutch presented a detailed and comprehensive overview of her work addressing FXII activation on polyphosphate polyP70. Her data indicate existence of a FXIIa single chain form, which activates PK and FXI in the presence of short chain polyP. 7. Helen Phillipou, Leeds: "Contact pathway inhibition: Characterization of effects on Clot Formation. Dr. Phillipou showed that targeting contact system activity using CTI significantly affects the fibrin structure. Increased FXII activity thickens fibrin fibers whereas FXII inhibitors reduced the fibrin meshwork. The underlying mechanisms were discussed and potential implications for embolic disease were shown. 8. Henry Spronk, Maastricht: "Contact system activation by microparticles” Dr. Spronk compared real time thrombin formation and phosphatidylserine (PS) exposure of microparticles from various circulating cells. Platelet-derived particles generate thrombin in a FXIIa-dependent manner. The underlying mechanism is a matter of ongoing analysis. In contrast, monocyte-derived microparticles are procoagulant due to TF exposure. 9. Judith Cosemans, Maastricht: "Targeting FXII inhibits the pathological process of thrombus formation on ruptured plaques in vivo and in vitro” Dr. Coseman analyzed the role of FXII and FXI in thrombus formation using flow chamber systems using murine and human blood and ultrasound-driven plaque rupture in mice. She showed that FXIIa blockage increases thrombus embolization. FXII has implications in thrombus stability whereas TF determines the thrombus size. 10. Steffen Rosén, Mölndal: A chromogenic-FXIa method with low interference for in-process and final testing of immunoglobin preparations. Dr. Rosén explored a new chromogenic FXIa method with a sensitivity of 0.015 pM FXIa for testing of IgG samples as an alternative to NAPTT and thrombin generation methods. There is no use of plasma in this assay. A sample dilution of 1:40 was recommended and interference from sample matrix is then claimed to be minimized as shown by recovery of added FXIa to IgG samples. Interference from contaminating proteins is also minimized with no effect of kallikrein up to 50 nM in the undiluted sample neither in the absence nor presence of FXIa and zymogen FXI. Furthermore, any contaminating zymogen FXI is not activated in the assay.
by T. Renne
Friday, September 14, 2012
Membership Management Software Powered by YourMembership  ::  Legal
This website uses cookies to store information on your computer. Some of these cookies are used for visitor analysis, others are essential to making our site function properly and improve the user experience. By using this site, you consent to the placement of these cookies. Click Accept to consent and dismiss this message or Deny to leave this website. Read our Privacy Statement for more.