Mechanisms Involved in Preventing Unwanted 
Blood Clots 
Charles T. Esmon, Ph.D. — Investigator 
Dr. Esmon is also a member of the Oklahoma Medical Research Foundation and Professor of Pathology 
and Associate Professor of Biochemistry at the University of Oklahoma Health Sciences Center, Oklahoma 
City. He received his B.S. degree in chemistry from the University of Illinois and his Ph.D. degree 
in biochemistry from Washington University. He conducted his postdoctoral research at the University 
of Wisconsin before joining the faculty at the University of Oklahoma Health Sciences Center. 
later he joined the Oklahoma Medical Research Foundation. 
PROTEIN C, protein S, and thrombomodulin 
constitute one of the natural anticoagulant 
complexes that prevents unwanted blood clots. 
We have focused our attention on this system be- 
cause we have been able to identify patients with 
a history of unwanted blood clots who have ab- 
normal protein C, protein S, or thrombomodulin. 
To understand how the system functions, it is 
useful to review the function of the components. 
Thrombomodulin is found primarily on the sur- 
face of endothelial cells, the cells that line the 
blood vessels. Thrombin, the enzyme that causes 
blood to clot, can bind to thrombomodulin; 
when thrombin is bound, it no longer clots the 
blood but instead converts protein C into the ac- 
tive blood clotting inhibitor, activated protein C. 
Activated protein C then binds to protein S on the 
surface of platelets (small cells in the blood) or 
endothelial cells, where it functions as an antico- 
agulant. The activated protein C-protein S com- 
plex works as an anticoagulant by cutting up and 
inactivating two of the clotting proteins, factor 
VIII (the protein missing in hemophilia) and fac- 
tor V. 
This broad outline of how the system functions 
fails to tell us much about where, when, or how 
the system might function in human disease pro- 
cesses. This knowledge is important both in 
terms of understanding the basic properties of the 
system and in the design of new therapeutic ap- 
proaches to diagnosis and prevention of blood 
clots. Of particular interest, and still unex- 
plained, is the observation that administration of 
activated protein C at levels that can prevent un- 
wanted blood clots does not increase blood loss 
at surgical sites. This contrasts with available anti- 
coagulants, such as heparin, which block un- 
wanted clot formation but also dramatically in- 
crease blood loss at surgical sites. One of our 
goals is to understand how this natural anticoagu- 
lant can accomplish this remarkable specificity. 
New therapeutic agents with these properties 
could greatly decrease morbidity and mortality 
associated with thrombotic complications. 
Most healthy individuals have adequate 
amounts of protein C and the other components 
of the system that control blood clot formation 
under normal circumstances. When people be- 
come sick, unwanted clotting is often a problem. 
Studies from other laboratories have shown that 
protein S circulates in humans both free and 
bound to an inhibitor of the complement system 
(the system that helps protect from infection), 
called C4b-binding protein (C4bBP). 
We found that only the free form of protein S 
could work to form the anticoagulant. Patients 
with clinical conditions known to cause an in- 
creased risk of blood clots also had reduced lev- 
els of free protein S and more C4bBP-protein S 
complex. Families with inherited thrombotic 
complications were identified in which the fam- 
ily members who developed blood clots had high 
levels of the complex. These observations sug- 
gested that alteration in the levels of free protein 
S might contribute to the clotting complications 
observed in these patients. To test this hypothe- 
sis, we developed some animal models that in- 
volved blood clotting as a complication. 
Clearly thrombosis is caused by more than sim- 
ply an alteration of C4bBP levels. Infection and 
agents that cause inflammation are known to trig- 
ger coagulation by a variety of mechanisms. 
Three very different responses occur. The first is 
related to bacterial infection, which can result in 
septic shock, a process characterized by small 
blood clots in the circulation, damage to organs, 
and death. Once this process begins, treatment is 
very difficult. A second response is formation of 
solid blood clots in the small vessels. This results 
in death of the affected organs. A third response is 
occlusion of the large vessels. Why inflammation 
causes these three dramatically different re- 
sponses is unknown, complicating rational ap- 
proaches for both early diagnosis and effective 
therapy. 
Animal models for these three processes were 
developed in collaboration with Fletcher Taylor. 
These models indicate that shifts in the balance 
between free protein S and protein S bound to 
C4bBP contribute to the dift'crent disease pro- 
cesses and can be involved in shifting the ob- 
served type of thrombosis. Increased levels of 
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