YSTEMIC ACTIVATION OF COAGUlation and thrombus formation in the microvasculature accompanies organ dysfunction and excess mortality in severe sepsis. 1 Tissue factor (thromboplastin) is a major initiator of the blood coagulation process. 2 Tissue factor is a transmembrane cell surface receptor for plasma clotting factor VII and exhibits homol-Author Affiliations, Financial Disclosure, and the OPTIMIST Study Group are listed at the end of this article.

Target practice: The target of the antibiotic cyclomarin A was identified in Mycobacterium. Cyclomarin A (see structure) binds the regulatory subunit of the Clp protease complex with high affinity resulting in elevated proteolysis and cell death. The property of cyclomarin to kill both growing and nonreplicating mycobacteria makes the Clp protease a promising target for antitubercular drug discovery.

Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.