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.

The interactions between inflammation and coagulation

“…Clinical observations indicate that the degree of protein C reduction correlates with a negative prognosis in septic patients (Fisher & Yan, 2000). Indeed, protein C supplementation has been found to decrease purpura fulminans (Rivard et al, 1995) in patients with meningococcemia and apparently to increase survival (White et al, 2000a). The impact on the superficial thrombotic lesions is quite consistent with the demonstrated ability of protein C supplementation to reverse the purpura fulminans that develops in patients with severe protein C deficiency (Dreyfus et al, 1991).…”

Protein C concentrate in preterm neonates with sepsis

“…In contrast, non-activated plasma-derived human protein concentrate (hPC) has been successfully used in paediatric, neonatal and adult patients at high-risk of haemorrhage, especially in those suffering from meningococcal septic shock (7)(8)(9)(10)(11)(12)(13).…”

Characterization of protein C receptor expression in monocytes

“…Over the past decade, a number of case reports and one small series has suggested that PC replacement therapy is associated with a reduction in morbidity and mortality in patients with severe meningococcaemia and purpura fulminans (Rivard et al, 1995;Smith et al, 1997;Rintala et al, 1998;Smith & White, 1999). In the past year, further evidence to support the dual functional property (anticoagulant and anti-inflammatory) of PC/APC has emerged from two published clinical studies (White et al, 2000a;Bernard et al, 2001). The first was an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicaemia, purpura fulminans and multiorgan failure, and its use was associated with a significant reduction in predicted morbidity and mortality (White et al, 2000a).…”

“…In the past year, further evidence to support the dual functional property (anticoagulant and anti-inflammatory) of PC/APC has emerged from two published clinical studies (White et al, 2000a;Bernard et al, 2001). The first was an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicaemia, purpura fulminans and multiorgan failure, and its use was associated with a significant reduction in predicted morbidity and mortality (White et al, 2000a). The second was the first randomized trial to use this anticoagulant in patients with severe sepsis and again the study showed a significant reduction in mortality associated with the use of APC despite an increase in haemorrhagic events (Bernard et al, 2001).…”