Mechanisms Involved in Preventing Unwanted Blood Clots 
C4bBP-protein S complex cause the inflamma- 
tory response to low levels of bacteria to convert 
from a mild response to a severe response with all 
of the characteristics of toxic shock. Moreover, 
under certain conditions the shift in amounts of 
G4bBP-protein S complex can change the re- 
sponse from that of circulating small clots to oc- 
clusion of small vessels. Most data suggest that 
bacteria cause clotting by causing the formation 
of inflammatory mediators, called cytokines. In- 
flammatory cytokines do not lead to the small 
clots characteristic of bacterial infection but 
rather to blood clots in the major vessels. This 
response occurs only when the C4bBP-protein S 
levels are high. In every case tested to date, the 
deleterious effects of the C4bBP can be reversed 
by adding protein S. 
Why then do bacterial infections lead to the 
small clots in the circulation? Possible insights 
were gained from the observation that small cell 
fragment-like particles can convert this throm- 
botic response back into the small-clot syndrome 
seen in septic shock. Complement is known to 
cause such cell fragments to be formed. These 
studies may provide insights into how different 
inflammatory and coagulation components work 
in concert to generate such distinct — but 
related — thrombotic complications. 
These results suggest that the balance between 
free protein S and that bound to C4bBP may be 
critical to thrombotic complications as a result of 
inflammation. The data imply that increasing 
protein S would prevent these thrombotic com- 
plications, suggesting new therapeutic ap- 
proaches to thrombotic diseases. If we could 
block the decrease in free protein S, the risk of 
thrombosis might be reduced. This unique ap- 
proach could potentially return the patient to 
normal status without significantly increasing the 
risk of bleeding. 
A major interest in our laboratory has been to 
understand how thrombomodulin causes throm- 
bin to change its function from a clotting to a 
clot-inhibiting enzyme. To understand this, we 
have examined the binding of thrombin to throm- 
bomodulin and to its other targets. Of particular 
interest is the ability of thrombin to activate cells 
and platelets, leading to platelet plugs and clots, 
especially in the arteries. Thrombomodulin can 
block platelet activation by thrombin, but how it 
does so had been a mystery. In collaboration with 
Shaun Coughlin's group, we demonstrated that 
the thrombin receptor on platelets and thrombo- 
modulin bind thrombin at the same place, 
thereby explaining the earlier observations. Both 
protein C and the thrombin receptor share com- 
mon sequences near the cleavage sites, and both 
sequences are inherently poor sequences for 
cleavage by thrombin. Binding of thrombomodu- 
lin fragments or the fragments from the thrombin 
receptor results in changing how thrombin 
cleaves its substrates. Thus both receptors have a 
built-in switch that allows thrombin to function. 
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