Abstract
Drotrecogin alfa - Recombinant Human Activated Protein C (Xigris) is FDA approved for the reduction of mortality in adult patients with severe sepsis who have a high risk of death as determined by APACHE II. Patients with sepsis have decreased circulating levels of protein C and that is associated with increased mortality. Drotrecogin alfa presumably has three main mechanisms of action: anticoagulant, anti-inflammatory and pro-fibrinolytic. In the protein C pathway, protein C circulates as a zymogen which is converted to activated protein C (APC) when thrombin complexes with thrombomodulin, further augmented by Endothelial Protein C Receptor (EPCR). This APC, alongwith protein S, inactivates Factors Va and VIIIa, thereby limiting thrombin generation. Endogenous protein C activation is blunted in severe sepsis due to down-regulation of thrombomodulin and EPCR. PROWESS study was the first phase III landmark study to demonstrate an absolute 6.1% reduction in 28 day all cause mortality. The only significant toxicity was a 3.5% bleeding risk, especially with laboratory parameters of aPTT>120 secs, INR>3 and platelet count < 30,000/microliter as well as gastrointestinal ulceration and traumatic injury. Since then several other studies have been conducted with slightly varying results and as many as 19 different systemic biomarkers of thrombosis, coagulation, fibrinolysis and inflammation have been used. But practically, in the ICU setting, the anticoagulant activity of Drotrecogin alfa may be demonstrated by the prolongation of aPTT and PT during the drug infusion. No significant difference has been found in platelet counts in the major studies. The hematocrit is insignificantly changed in the absence of a bleeding complication. We report here a retrospective review of 10 adult patients with sepsis from our ICU who met the criteria to get drotrecogin alfa based on APACHE II. Their PT, INR, aPTT, Hb, Hct and platelet counts were recorded prior to drug infusion not exceeding 24 hours pre infusion. These counts were again looked at post infusion. The highest post infusion coagulation profile was selected and concordant Hb and Hct were recorded. We found the following mean changes in the selected parameters: Increase in aPTT of 58% (20.32 sec); increase in PT of 15% (2.61 sec); decrease in platelet count of 16% (26,000/microliter); decrease in Hb of 13% (1.44 gm/dl); decrease in Hct of 13% (4.09 %). Despite the seeming worsening of coagulopathy and some drop in Hb, Hct and platelets, patients did not have any major bleeding episodes attributable to Drotrecogin alfa. Out of our 10 patients, 7 have expired and 3 have survived for a mean of 130 days (range 118 days to 141 days) till today. Thus in our small retrospective sample, Drotrecogin alfa was found to be a safe and effective drug, based on routine blood tests and clinical observation alone in the ICU of a community hospital.
Testing of anti-activated protein C antibodies in four drotrecogin alfa (activated) severe sepsis studies