The anticoagulant action of recombinant human activated protein C (rhAPC, Drotrecogin alpha activated): comparison between cord and adult plasma.
The present study was performed to compare the anti-coagulant efficiency of recombinant human activated protein C (rhAPC) in cord with that in adult plasma. RhAPC is a promising candidate to improve the outcome of severe sepsis. However, different anticoagulant efficiency of rhAPC in cord compared with adult plasma has to be expected due to physiological low plasma levels of tissue factor pathway inhibitor (TFPI) and antithrombin (AT) present in neonates, two inhibitors known to markedly influence the anticoagulant action of APC. Clot formation was induced in our experiments by addition of high (30 micro M) or low (20 pM) amounts of lipidated tissue factor (TF). High amounts of TF are conventionally applied in standard clotting assays, whereas plasma activation with low amounts of TF probably better matches the conditions in vivo. We demonstrate that under low coagulant challenge increasing amounts of rhAPC (0.1-0.5 micro g/ml final plasma concentration) dose-dependently prolonged clotting time and suppressed thrombin potential and prothrombin fragment 1+2 generation in both cord and adult plasma. The same was true for experiments performed under high coagulant challenge when 4-16 micro g/ml of rhAPC were added. Whereby, cord plasma was significantly more susceptible to addition of rhAPC in the presence of high amounts of TF and adult plasma was significantly more susceptible to addition of rhAPC in the presence of low amounts of TF. We demonstrate that increased anticoagulant efficiency of rhAPC in adult plasma under low coagulant challenge is attributable to the physiological high levels of TFPI and AT present in adults.
Cvirn
Gerhard
G
Institute of Medical Chemistry and Pregl Laboratory, Karl Franzens University of Graz, Harrachgasse 21/II, A-8010 Graz, Austria. gerhard.cvirn@uni-graz.at
Gallistl
Siegfried
S
Koestenberger
Martin
M
Baier
Katrin
K
Fritsch
Peter
P
Greilberger
Joachim
J
Jürgens
Günther
G
Muntean
Wolfgang
W
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000032:analysis / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood; D006801:Humans; D007231:Infant, Newborn; D008074:Lipoproteins / Q000097:blood / Q000494:pharmacology; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D013925:Thromboplastin / Q000494:pharmacology
D000925:Anticoagulants; D008074:Lipoproteins; D011486:Protein C; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D013925:Thromboplastin; C421124:drotrecogin alfa activated