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 Associate Professor of 
Pathology and Biochemistry at the University of Oklahoma Health Sciences Center. 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. 
LIFE in all large animals requires the capacity 
to ship oxygen and food to all organs and the 
cells within the organs. Blood serves this capac- 
ity, but the development of such a delivery sys- 
tem is not without its inherent problems. The 
blood vessels that carry the blood are subject to 
injury. When cut, bleeding is a complication. For- 
tunately, a complex system exists that allows the 
blood to clot at a wound site and prevent fatal 
bleeding in all but the most severe wounds. Rela- 
tively few people are troubled with an inability to 
clot blood. In contrast, the formation of un- 
wanted blood clots either causes or contributes 
to nearly half of all deaths in developed coun- 
tries. The major problems occur in heart attacks, 
strokes, pulmonary embolisms, and septic shock. 
The system that leads to blood clots involves 
more than 1 0 separate proteins and several differ- 
ent cells. To prevent unwanted clots, an equally 
complex collection of systems, referred to as anti- 
coagulant complexes, has evolved to block or 
limit the blood clotting process. Our working hy- 
pothesis is that changes in the activity of these 
anticoagulant complexes may contribute to the 
formation of lethal blood clots. 
Protein C, protein S, and thrombomodulin con- 
stitute one of the natural anticoagulant com- 
plexes that prevents unwanted blood clots. We 
have focused on this system because we have 
been able to identify patients with a history of 
unwanted blood clots who have abnormal pro- 
tein C, protein S, or thrombomodulin. To under- 
stand how the system functions, it is useful to 
review the function of the components. Throm- 
bomodulin is found primarily on the surface 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 active 
blood clotting inhibitor, activated protein C. Ac- 
tivated 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 the 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 of throm- 
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