Drotrecogin alfa (activated, Xigris) in combination with heparin or melagatran: an in vitro investigation.
BACKGROUND
The present in vitro study of human plasma investigated the anticoagulant effects of recombinant human activated protein C (rhAPC; drotrecogin alfa [activated, Xigris]), combined with either unfractionated heparin (UH) or the direct thrombin inhibitor melagatran.


METHODS
Prolongation of clotting time and generation of prothrombin fragments 1 and 2 (F1 + 2) and of thrombin-antithrombin (TAT) complex were measured in vitro. Clot formation was induced by adding low levels (final concentration, 20 pmol/L) of lipidated tissue factor (TF) to citrated venous plasma samples from healthy human volunteers (n = 16). It has been suggested that experimental activation of plasma with low levels of TF more closely simulates conditions in vivo.


RESULTS
rhAPC, melagatran, or UH alone concentration-dependently prolonged the clotting time and suppressed F1 + 2 and TAT generation. rhAPC-mediated prolongation of clotting time concentration-dependently increased with the addition of either UH or melagatran, the effect being more pronounced with the addition of melagatran. Similarly, rhAPC-mediated generation of F1 + 2 and TAT also increased concentration-dependently with the addition of either UH or melagatran; the effect being, in this case, more pronounced with the addition of UH.


CONCLUSIONS
This study demonstrated the effects of rhAPC, alone and combined with either UH or melagatran, on clotting time and markers of thrombin generation in human plasma. These results may guide facilitate estimation of appropriate doses of rhAPC and melagatran in future clinical trials.
Koestenberger
Martin
M
Ludwig Boltzmann Research Institute for Pediatric Hemostasis and Thrombosis, Medical University of Graz, Auenbruggerplatz 30, A-8036 Graz, Austria. koestenbergerm@hotmail.com
Cvirn
Gerhard
G
Gallistl
Siegfried
S
Baier
Katrin
K
Leschnik
Bettina
B
Muntean
Wolfgang
W
D000925:Anticoagulants / Q000008:administration & dosage; D001384:Azetidines; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005998:Glycine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D011486:Protein C / Q000008:administration & dosage*; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000008:administration & dosage*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D004338:Drug Combinations; D011486:Protein C; D011994:Recombinant Proteins; C109573:melagatran; D006493:Heparin; C421124:drotrecogin alfa activated; D005998:Glycine