The role of activated Protein C in severe sepsis
By Dr Rashmi Yadav, Senior House Officer, Cardiothoracic Surgery, Leeds General Infirmary, UK
May 20, 2006, 03:46

Protein C is an endogenous plasma protein. It is the precursor of activated protein C (APC). Protein C is converted to activated protein C by binding the thrombin-thrombomodulin complex, and via another endothelial surface receptor, endothelial protein C receptor.

Protein C is an important player in the body’s response to inflammation, systemic sepsis and the concomitant intravascular coagulopathy. The main effect of protein C is to reduce the production of thrombin, by inactivating factors Va and VIII. As thrombin is proinflammatory, procoagulant and antifibrinolytic, the overall effect of activated protein C brings a beneficial effect in acute severe sepsis. Sepsis is associated with both reduced levels of protein C and impaired conversion of protein C to activated protein C.

Protein C also inhibits the influence of tissue factor on the clotting system, reduces the production of IL-1, IL-6, and TNF-α by monocytes, and has profibrinolytic properties by inactivating Plamsinogen Activator Inhibitor-1 (PAI-1)

Studies have shown that plasma levels of protein C are reduced in over 80% of severely septic patients, and correlate inversely with morbidity and mortality. This relationship is independent of age, illness severity, the presence of shock and the nature of the infecting organisms1.

The low levels of protein C and haemostatic derangement persist throughout sepsis, whilst these parameters return towards normal in other, non-septic, critically ill patients.

However, it should be noted that there is impaired conversion of protein C to activated protein C in sepsis, laregly due to sepsis induced endothelial dysfunction. Therefore, activated protein C levels do not increase despite protein C infusion.

The PROWESS study compared activated protein C with placebo in 1690 randomized patients with severe sepsis and organ dysfunction. The activated protein C group demonstrated a 6.1% absolute reduction in the risk of death. Activated protein C levels attained were equivalent to 20 times normal endogenous levels.

Although the methodology of the PROWESS study has been questioned, the general consensus is that, activated protein C should be considered early (within 4-12 hours) in certain clinical scenarios-purpura fulminans, toxic shock syndrome, severe community acquired pneumonia, and meningitis with multiple organ dysfunction.

However, despite the reported beneficial effect of recombinant human activated protein C (rhAPC) in the phase III PROWESS trial, this agent’s approval was controversial . Unresolved issues included the safety of rhAPC in clinical practice, the efficacy of rhAPC in less severely ill septic patients, and the utility of rhAPC compared with alternative immunomodulatory therapies.

The Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial was a global, single-arm, phase-3B clinical trial of drotrecogin alfa (activated) that was designed to gather additional mortality and safety data among patients with severe sepsis in a monitored clinical trial setting.

Bleeding is the most important serious adverse event that is related to the administration of drotrecogin alfa. The most common sites of bleeding in patients in the ENHANCE US trial were GI, skin/soft tissue, and bone/joint. However, cases of intracranial bleeding is also reported.

However overzealistic use of activated protein C should be discouraged. Both these studies presented data from a relatively small smaple size. Again, the studies lacked randomization. No individual was blinded to the use of activated Protein C.

Again when the advantage of the early use of activated protein C is observed in cases of severe sepsis as an obvious imporovement in the mortality rates, the bleeding complications cannot be overlooked, especially in those patients who are heparinized or on warfarin, for obvious indications. Again, almost no advantage of using activated Protein C in relatively milder sepsis should not be forgotten.

More studies are required to prove the safety of use of activated Protein C in patients with severe sepsis, and the product should be used judiciously and all aspects considered for individual patients.

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