Protein S modulates the anticoagulant action of recombinant human activated protein C: a comparison between neonates and adults.
Recombinant human-activated protein C (rhAPC, Drotrecogin alpha (activated), Xigris) has been shown to reduce organ damage and decrease mortality in severe sepsis. Since protein S (PS) serves as a potentiating cofactor of activated protein C and since PS levels are low in neonatal plasma, we hypothesized that the anticoagulant effect of rhAPC would be decreased in cord plasma compared to adult plasma. We demonstrate that the anticoagulant action of 0.3 microg ml(-1) rhAPC (5 nmol l(-1)) was decreased in cord plasma compared to adult plasma, and dose dependently increased in cord plasma in the presence of increasing activities of PS. Correspondingly, the anticoagulant action of rhAPC decreased in adult plasma in the presence of decreasing activities of PS. The low anticoagulant action of rhAPC in cord compared to adult plasma is attributable to low neonatal levels of PS, and as previously shown, to low neonatal levels of TFPI and AT. Our laboratory experiments do not allow definite conclusions for clinical situations. However, we speculate that the anticoagulant efficacy of rhAPC is impaired in neonates and in clinical situations associated with consumption and/or inhibition of PS, AT, and TFPI, such as severe sepsis.
Cvirn
Gerhard
G
Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University of Graz, Harrachgasse 21/II, Graz A-8010, Austria. gerhard.cvirn@meduni-graz.at
Koestenberger
Martin
M
Leschnik
Bettina
B
Male
Christoph
C
Kutschera
Joerg
J
Ferstl
Ulrika
U
Muntean
Wolfgang
W
Juergens
Guenther
G
Gallistl
Siegfried
S
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D010949:Plasma / Q000737:chemistry / Q000187:drug effects; D011486:Protein C / Q000494:pharmacology*; D017293:Protein S / Q000032:analysis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000925:Anticoagulants; D011486:Protein C; D017293:Protein S; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated