Importantly, the authors of the Nature PAR1 paper DO make direct (if somewhat limited) comment on the effects of antithrombin -- and it isn't all to ATIII's favor.
"The requirement to block thrombin in the lymphatics for antiinflammatory benefit may explain the limited clinical efficacy of intravenously administered plasma protease inhibitors, such as antithrombin."
Overall, in placing blockade of the thrombin receptor as the pivotal point of linkage in sepsis between coagulopathy and inflammation, this paper gives us an obvious mechanism for ATIII to be found useful in DIC. This we like very much, and haven't had to date.
To have a basic mechanism that supports the use of ATIII in sepsis is HUGE, but it is not a slam dunk. That fact that the primary effect of thrombin blockade appears to need to occur EXTRAvascularly (in the lymphatics)-- while ATIII is primarily INTRAvascular -- might not turn out to be important, but is reason to be a bit skeptical.
As noted previous, I have been in contact with the paper's senior author, and his choice of hirudin (a small protein thrombin receptor antagonist) rather than ATIII (a much larger protein that is more likely to remain inside the blood vessels) was based on their wanting to be sure EXTRAvascular concentrations were high enough to have the desired effect.
Take away: To have a basic mechanism that supports the use of ATIII in sepsis is HUGE (and new), but it does not guarantee a slam dunk on the DIC trials.
Cheers,
MTB
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