EXOGENOUS HEMOSTATIC FACTORS: Registry

6 July 2001
13:00 to 17:00
Room 243
Palais des Congrès

Chairman: R. M. Kini--Singapore
Co-Chairmen: C. Bon--France; F. Markland--USA; N. Marsh--Australia

Eight members of the Registry were in attendance plus about 75 guests (Largest gathering for our subcommittee meeting).

  1. Meeting was brought to order by the Chair Dr. Manjunatha Kini.
  2. The new members of the Registry, Dr. Tur Fu Huang, Taiwan and Dr. Aura S. Kamiguti, UK were introduced.
  3. The minutes of the last meeting were read and there were no questions. It was proposed to be accepted by Dr. Frank Markland and seconded by Dr. Mary Ann McLane.
  4. Publications of subcommittee reports: Three subcommittee reports have been completed. So far two of these reports on exogenous factors affecting platelet aggregation have been published in Thrombosis and Haemostasis. The third report on the Classification and Nomenclature of the prothrombin activators from snake venoms will be published in August or September issue of Thrombosis and Haemostasis.
  5. A short report was made on the organization of the International Conference on the Exogenous Factors affecting Thrombosis and Haemostasis at Pasteur Institute on July 12 and 13.
  6. Work on a new inventory on Disintegrins by Dr. McLane is progressing well. This will cover the interaction of disintegrins with various integrins and cell types.
  7. Dr. C. Bon presented the role of phospholipase A2 in various biologic activities. He described the classification of secretory phospholipase A2 enzymes and the importance of interface binding site and penetrability to their anticoagulant effects. He discussed the mechanism of inhibition of the prothrombinase complex by Naja nigricollis snake venom enzyme as well as human platelet enzyme. Both these enzymes bind to human coagulation factor Xa at the same site as factor Va and interfere in the formation of the prothrombinase complex.
  8. Dr. R. M. Kini presented the four groups of prothrombin activators from snake venoms and the new classification. Group A and B prothrombin activators are metalloproteinases and their structure-function studies would contribute to segments that are important for substrate specificity and recognition of prothrombin by these activators. Group C and D prothrombin activators are structurally and functionally similar to mammalian coagulation factor Xa-Va complex and factor Xa, respectively. Structure-function relationships of these prothrombinase activators contribute directly to our understanding of the prothrombinase complex formation.
  9. Dr. A. S. Kamiguti described antiplatelet effects of a metalloproteinase Jarrarhagin. This enzyme cleaves vWF and renders it inactive in platelet adhesion. It also hydrolyzes b1 subunit of a2b1 integrin and thus interferes in the collagen-induced platelet aggregation.
  10. Dr. F. S. Markland described the clinical effects of fibrolase in removing clots in both ex vivo and in vivo models. This enzyme at high concentrations also induces transient hypotension. He discussed the target substrate specificity and kinetics of cleavage of various synthetic peptide substrates of fibrolase. These studies indicate the possibility that the transient hypotensive effect is most likely is due to its ability to cleave low molecular weight kininogen with ultimate release of bradykinin and then cleavage of kallidin and bradykinin.
  11. Dr. M. A. McLane described the functional diversity of disintegrins. In addition to their role in inhibiting platelet aggregation, various disintegrins and related proteins interact with many different normal and cancer cells. This is due to their ability to bind and distinguish closely related integrins. She also described both in vivo and in vitro studies and their role in angiogenesis, anti-cancer and bone resorption effects.
  12. Dr. T. F. Huang described the effect of accutin on neovascularization in both in vitro and in vivo models. This disintegrin inhibited the bFGF induced but not VEGF-induced angiogenesis. It also slows the growth of melanoma in mice. It is a avb3antagonist and inhibits HUVEC proliferation by affecting the cell cycle.
  13. Dr. T. Morita discussed the structural and functional diversity of C-type lectin related proteins. He described the three dimensional structure of several proteins of this class and their importance in recognition of the Gla domain of vitamin K-dependent coagulation factors, vWF and other ligands. He also discussed the importance of Mg2+ in blood coagulation and binding of Mg2+ ions to Gla domain of factor IX.
  14. Dr. N. A. Marsh described some new hemorrhagic proteinases and the possibility of putting them in an inventory. The last inventory is currently seven year old. He discussed textilinins, the proteinases inhibitors that specifically inhibit plasmin. They bind to plasmin and inhibit it with a Ki of 10-9 M. It prevents blood loss using mouse tail vein bleeding model. It appears to be more effective then aprotonin.
  15. In the new business, Dr. R. M. Kini proposed to institute a review on the importance of exogenous hemostatic factors as research tools, diagnostic agents and prototypes of therapeutic agents. Dr. C. Bon asked whether such a review should include both exogenous animal and plant sources. It was decided that the review should focus only on the animal factors for the time.
  16. We also discussed the importance of proper taxonomical identification of the sources as there is a significant geographic variation among animals and plants. In addition, there are significant changes in taxonomy and our inventories should reflect most recent taxonomic classification of the sources.
  17. The next meeting of our subcommittee will be held in Birmingham during XIX congress of the ISTH, 2003.
  18. Meeting adjourned. The Registry will not meet formally in 2002.