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).
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Meeting was brought to order by the Chair Dr. Manjunatha Kini.
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The new members of the Registry, Dr. Tur Fu Huang, Taiwan and Dr. Aura
S. Kamiguti, UK were introduced.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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The next meeting of our subcommittee will be held in
Birmingham during XIX congress of the ISTH, 2003.
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Meeting adjourned. The Registry will not meet formally
in 2002.