However, endogenously produced molecules that dampen the effects of HMGB1 in the circulation are also elevated during severe disease states. Thrombomodulin, which binds to HMGB1 and prevents it binding to RAGE (76) is elevated during severe malaria (77), sepsis (78, 79) and influenza (80) . Paradoxically, it is this binding of HMGB1 to thrombomodulin that also prevents activated protein C generation (81) and thus its ensuing anti-inflammatory activities (82, 83) . Thus the balance between HMGB1 and thrombomodulin in vivo is likely to be important (81) and should also be determined as part of these studies.