Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.
BACKGROUND
Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial.


METHODS
Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products.


RESULTS
Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes.


CONCLUSIONS
Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.
de Kleijn
Ester D
ED
Department of Pediatrics, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands.
de Groot
Ronald
R
Hack
C Erik
CE
Mulder
Paul G H
PG
Engl
Werner
W
Moritz
Berta
B
Joosten
Koen F M
KF
Hazelzet
Jan A
JA
D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D011695:IgA Vasculitis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D007223:Infant; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008589:Meningococcal Infections / Q000188:drug therapy* / Q000401:mortality; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D012044:Regression Analysis; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D015996:Survival Rate
D000925:Anticoagulants; D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D011486:Protein C; C036309:fibrin fragment D