Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI.
BACKGROUND
Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity.


OBJECTIVE
To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas.


METHODS
Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies.


RESULTS
At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL(-1).


CONCLUSIONS
The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.
Livnat
T
T
The Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Centre, Tel Hashomer, Israel.
Zivelin
A
A
Martinowitz
U
U
Salomon
O
O
Seligsohn
U
U
D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology; D020147:Coagulation Protein Disorders / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000378:metabolism / Q000494:pharmacology; D005167:Factor VII / Q000494:pharmacology*; D015942:Factor VIIa; D005170:Factor X / Q000378:metabolism / Q000494:pharmacology; D005173:Factor XI Deficiency / Q000188:drug therapy / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy / Q000378:metabolism; D002836:Hemophilia B / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010743:Phospholipids / Q000494:pharmacology; D010949:Plasma / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis* / Q000187:drug effects; D013925:Thromboplastin / Q000494:pharmacology / Q000502:physiology
D010743:Phospholipids; D011994:Recombinant Proteins; D005167:Factor VII; D005164:Factor IX; D005170:Factor X; D013925:Thromboplastin; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin