Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A.
BACKGROUND
Recombinant coagulation factor VIIa (rFVIIa) is generally accepted for treatment of patients with inhibitor-complicated hemophilia. Recently, rFVIIa variants with a specific enhancement of the tissue factor (TF)-independent proteolytic activity have been described.


OBJECTIVE
The procoagulant and [thrombin-activatable fibrinolysis inhibitor (TAFI)-dependent] antifibrinolytic potentials of two superactive rFVIIa variants were compared with those of wild-type rFVIIa in a hemophilic setting.


METHODS
Clot lysis assays were performed in plasma from six patients with inhibitor-complicated hemophilia A or in antibody-induced factor VIII-deficient platelet-rich plasma in the presence of different concentrations of the rFVIIa variants.


CONCLUSIONS
In the plasma model, M298Q-rFVIIa had a moderately increased procoagulant and antifibrinolytic potential, whereas V158D/E296V/M298Q/K337A-rFVIIa had a strongly increased procoagulant and antifibrinolytic activity compared with wild-type rFVIIa. The increased antifibrinolytic potential of the rFVIIa variants was completely dependent on enhancement of TAFI activation. In the platelet-rich plasma model similar results were obtained. The presence of TF was mandatory for clot formation in the absence of exogenous rFVIIa. At lower concentrations of rFVIIa (wild-type or variants), clot formation did occur but was significantly slower when TF activity was blocked. At increasing concentrations of rFVIIa, clotting times were no longer dependent on TF. In conclusion, should a TF-independent mechanism be involved in the efficacy of rFVIIa in patients with hemophilia, the superactive rFVIIa variants studied here might be clinically advantageous, as both procoagulant and antifibrinolytic potencies are significantly enhanced compared with those of wild-type rFVIIa. This ought to result in more efficient cessation of bleeding episodes and reduced risk of rebleeding.
Lisman
T
T
Thrombosis and Hemostasis Laboratory, G03.647, Department of Hematology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. j.a.lisman@azu.nl
de Groot
P G
PG
Lambert
T
T
Røjkjaer
R
R
Persson
E
E
D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000378:metabolism; D025901:Carboxypeptidase B2 / Q000378:metabolism; D003029:Coagulants / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000627:therapeutic use; D015942:Factor VIIa / Q000378:metabolism / Q000627:therapeutic use*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006470:Hemorrhage; D006801:Humans; D066298:In Vitro Techniques; D010949:Plasma / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use*; D013925:Thromboplastin / Q000378:metabolism
D000933:Antifibrinolytic Agents; D003029:Coagulants; D011994:Recombinant Proteins; D005167:Factor VII; D013925:Thromboplastin; C103587:recombinant FVIIa; D025901:Carboxypeptidase B2; D015942:Factor VIIa