Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor X in the absence of tissue factor.
Clinical trials have recently begun using high concentrations of activated recombinant factor VII (rFVIIa) for the treatment of hemophilic patients with inhibitors. Unexpectedly, the activated partial thromboplastin time (aPTT) was observed to be significantly shortened during infusion of the rFVIIa. To determine the mechanism for this shortening, the effect of rFVIIa on both the prothrombin time (PT) and the aPTT of normal and various factor-deficient plasmas was examined. rFVIIa shortened the PT of all plasmas tested except FX and FV deficient plasmas. rFVIIa also shortened the aPTT of all plasmas tested except FX and FV deficient plasmas. Since there is no added tissue factor (TF) in aPTT reagents, rFVIIa appeared to shorten the aPTT in the absence of TF. To investigate this possibility, the activity of rFVIIa in a purified system containing only FX, phospholipid vesicles (1:1 PS:PC), and calcium was examined. In this system, rFVIIa activated factor X in the absence of TF. If any component of the purified system was omitted, there was no detectable activation of FX. Thus it appears that calcium and phospholipids are required for the activation of FX by rFVIIa in the absence of TF. Increasing the concentration of rFVIIa increased the rate of FX activation, but the rate of activation was always much lower than that observed with even trace amounts of tissue factor. We conclude that high concentrations of rFVIIa, in the presence of calcium and phospholipid, can directly activate FX in the absence of TF and hence account for the shortening of the aPTT in inhibitor patients treated with rFVIIa.
Telgt
D S
DS
Department of Medicine, University of North Carolina, Chapel Hill 27599-7035.
Macik
B G
BG
McCord
D M
DM
Monroe
D M
DM
Roberts
H R
HR
D001780:Blood Coagulation Tests; D015942:Factor VIIa / Q000494:pharmacology*; D005170:Factor X / Q000378:metabolism*; D006801:Humans; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000502:physiology
D011994:Recombinant Proteins; D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa