whether this elevation in C4bBP directly contrib- 
uted to the organ damage found in the shock pro- 
cess. To resolve this question, the C4bBP levels 
were elevated to equal those found in patients with 
disseminated intravascular coagulation (DIG) and 
challenged with a sublethal level of bacteria that 
normally only causes the acute-phase response and 
no DIG. Elevation of the G4bBP levels resulted in 
DIG and organ failure. This response could be re- 
versed in part by elevating protein S. These studies 
indicate that reversing the G4bBP-protein S com- 
plex formation would aid in the treatment of gram- 
negative sepsis. 
Previous studies from Dr. Esmon's laboratory in- 
dicated that activated protein C can protect animals 
from gram-negative shock. Since activated protein 
G is an anticoagulant, the question arises as to 
whether this protection from septic shock is due to 
the capacity to block clotting. To resolve this ques- 
tion, Dr. Esmon designed a new anticoagulant 
based on knowledge that factor Xa binding to fac- 
tor Va was independent of the active center of fac- 
tor Xa. Therefore factor Xa was inhibited with a 
specific chloromethyl ketone. This inactive factor 
Xa worked as an anticoagulant both in vitro and in 
vivo, presumably by competing with factor Xa for 
binding with factor Va on cellular surfaces. Al- 
PUBLICATIONS 
though the active site-blocked factor Xa was more 
effective than activated protein G in blocking DIG, 
this inhibitor was completely without effect in pre- 
venting organ damage. Thus the action of activated 
protein G appears to be other than the capacity to 
inhibit fibrin formation. Ultimately these studies 
should provide a much better rationale for the 
treatment of septic shock. This work was con- 
ducted in collaboration with Dr. Fletcher Taylor. 
It is well recognized that thrombus formation in 
the coronary artery is responsible for most heart at- 
tacks. The role of clotting or protein C in ischemic 
injury is not well understood. In collaboration with 
Dr. Thomas Snow, studies were initiated to investi- 
gate the influence of activated protein G or the in- 
hibition of activated protein G on recovery after 
coronary artery occlusion. The results show that 
blocking protein G activation increases the fre- 
quency of fibrillation after reperfusion and that ac- 
tivated protein G infusion increases the rate of re- 
covery of cardiac function. 
Dr. Esmon is also Member of the Gardiovascular 
Biology Research Program at the Oklahoma Medical 
Research Foundation and OMRF Associate Professor 
of Biochemistry and of Pathology at the University 
of Oklahoma Health Sciences Genter. 
Books and Chapters of Books 
Esmon, G.T. 1988. Assembly and function of the protein G anticoagulant pathway on endothelium. In Endo- 
thelial Cell Biology (Simionescu, N., and Simionescu, M., Eds.). New York: Plenum, pp 191-206. 
Articles 
Esmon, G.T. 1989. The roles of protein G and thrombomodulin in the regulation of blood coagulation. J Biol 
Chem 264:4743-4746. 
Laue, T.M., Lu, R., Krieg, U.G., Esmon, G.T., and Johnson, A.E. 1989. Ga^"*" -dependent structural changes in 
bovine blood coagulation factor Va and its subunits. Biochemistry 28:4762-4771. 
Lu, R., Esmon, N.L., Esmon, G.T, and Johnson, A.E. 1989. The active site of the thrombin-thrombomodulin 
complex: a fluorescence energy transfer measurement of its distance above the membrane surface. / Biol 
Chem 264:12956-12962. 
Luckow, E.A., Lyons, D.A., Ridgeway T.M., Esmon, G.T, and Laue, TM. 1989. Interaction of clotting factor V 
heavy chain with prothrombin and prethrombin 1 and role of activated protein G in regulating this inter- 
action: analysis by analytical ultracentrifugation. Biochemistry 28:2348-2354. 
Moore, K., Esmon, G.T., and Esmon, N.L. 1989. Tumor necrosis factor leads to the internalization and degra- 
dation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 73:159- 
165. 
Ofosu, F.A., Hirsh, J., Esmon, G.T , Modi, GJ., Smith, L.M., Anvari, N., Buchanan, M.R., Fenton, J.W, II, and 
Blajchman, M.A. 1989. Unfractionated heparin inhibits thrombin-catalyzed amplification reactions of coag- 
ulation more efficiently than those catalyzed by factor Xa. Biochem / 257: 143-150. 
Continued 
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