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2016 Annual Minutes
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6/8/2016 at 5:36:48 PM GMT
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2016 Annual Minutes

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. 

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