What can we learn from the three megatrials using anticoagulants in severe sepsis?

The results of three megatrials investigating the potential beneficial effects of anticoagulant and anti-inflammatory substances in subjects suffering from severe sepsis have been published recently. rhAPC produced an improvement in survival, but AT and TFPI could not. The concomitant use of heparin might be responsible for this difference because a direct interaction exists between heparin and the latter two agents. Heparin-bound AT or rTFPI might have been unable to further bind to EC; thus, the anti-inflammatory function of these agents was canceled. In addition, heparin significantly increased bleeding events. Finally, we have to remember that although these therapies have the potential to improve the survival of severe sepsis/septic shock, the favorable effects come with the increase of bleeding tendency.