An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans–associated meningococcemia

Abstract

Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis. Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans. In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis. The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans. The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure. The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score. Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean ± SD for plasma PC was 18 ± 7 IU/mL. PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans. A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%). Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality. The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway.

Treatment of adult patients with sepsis‐induced coagulopathy and purpura fulminans using a plasma‐derived protein C concentrate (Ceprotin®)

“…Our observations concerning the reversal of DIC are in accordance with previously published case series [12–21]. Few studies have reported on the pharmacokinetics of protein C in patients with purpura fulminans and overt DIC.…”

“…White et al . [20] conducted an open‐label study treating 36 patients with purpura fulminans and meningococcemia with a protein C zymogen concentrate. They found a mortality rate of only 8%, while the Glasgow Meningococcal Septicemia Prognostic Score (GMSP) [30] predicted a mortality rate of 50%.…”

“…Five patients were treated with a continuous infusion of the protein C concentrate, according to the protocol reported by White et al . [20]. Following administration of a testing dose of 10 U/kg body weight, patients received a single‐shot bolus of 100 U/kg followed by a level‐controlled continuous infusion starting at 10 U/kg/h.…”

“…Protein C is an important regulator of the coagulation cascade and possesses anticoagulatory, profibrinolytic and anti‐inflammatory properties. Data of a series of case reports and of one open‐label study lead to the hypothesis that early substitution of protein C may positively influence the course of DIC in sepsis‐induced purpura fulminans, and thus improve its prognosis [12–21]. Most of these series report on children and teenagers; reports on adults are rare.…”

Prediction of survival in patients suspected of disseminated intravascular coagulation

“…It has been previously shown in septic patients with DIC and in patients with overt DIC that lowered antithrombin and protein C, respectively, associate with increased mortality. To our knowledge, however, in the much larger group of acutely ill patients initially suspected of DIC that never actually develop DIC, it has not been previously shown that lowered antithrombin and especially lowered protein C allows identification of many more patients who are at a high risk of death and would not be identified using the overt DIC criteria alone.…”