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THE COUNCIL FOR TOBACCO RESEARCH-U.S.A.. INC. Memotandum To: Dr. J.F.Glenn and Staff Re: Site visit with Dr. J. Jesty, SUNY Stony Brook, NY, July 26, 1990. Grant No.2255R2 entitled "Plasma Inhibitors of factor X activation." Goals: To obtain a better understanding of the relationships between clotting factors in plasma (Factor X and such activating factors as factor VIIa) and plasma inhibitors of clotting pro- teases, such as antithrombin. Results:Much of Dr. Jesty's work during the first year was directed toward obtaining pure fractions of the plasma materials he needed in order to be able to work with a pure system. The end result of his current investigations is a manuscript accepted by JBC entitled "Analysis of the generation and inhib- ition of Factor Xa: Area under generation curves is independent of enzyme generation rate." Thus, the activation of clotting is dependent on two factors: the amount of factor X activated and by the rate of inhibition by antithrombin.and is independent of the rate of factor X activation. So, it is not how fast factor X is activated, but how much which is important. In making the observation just noted, Dr. Jesty has observed that there appears to be some form of negative feed-back mechanism which is opera- ting in the system. This remains to be determined and will be the focus of his next year's work. Thus, this program is becoming a study of the kinetic balance of factor Xa generation by both intrinsic and extrinsic clotting pathways and the inhibition by various plasma antithrombic systems. Although Dr. Jesty discussed at some length his concept of a 'negative feed-back system' involved in the prevention of clotting, I am-afraid I failed to understand how the kinetics of this would apply or where the feedback regulation would be occurring, since he did not seem to feel it occurred in the liver, but as yet has no alternative site in mind. Comment: I find it difficult to evaluate the work undertaken by Dr. Jesty inasmuch as so much of it depends on mathmatical modeling, and will be even more so in the future. However, there is no question but that this is an important area of research and that a better understanding of clotting mechanisms is needed. DHF