A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia.
Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We improve hemostasis in vivo using a conformationally pliant variant of coagulation factor Xa (FXa(I16L)) rendered partially inactive by a defect in the transition from zymogen to active protease. Using mouse models of hemophilia, we show that FXa(I16L) has a longer half-life than wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXa(I16L) is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXa(I16L) is more efficacious than FVIIa, which is used to treat bleeding in hemophilia inhibitor patients. FXa(I16L) may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions.
Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Lacramioara
L
Ivanciu
Raffaella
R
Toso
Paris
P
Margaritis
Giulia
G
Pavani
Haein
H
Kim
Alexander
A
Schlachterman
Jian-Hua
JH
Liu
Valerie
V
Clerin
Debra D
DD
Pittman
Rosalind
R
Rose-Miranda
Kathleen M
KM
Shields
David V
DV
Erbe
James F
JF
Tobin
Valder R
VR
Arruda
Rodney M
RM
Camire
D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D004195:Disease Models, Animal; D004792:Enzyme Precursors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015942:Factor VIIa / Q000235:genetics / Q000378:metabolism; D015951:Factor Xa / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015870:Gene Expression; D057809:HEK293 Cells; D006467:Hemophilia A / Q000188:drug therapy*; D006470:Hemorrhage / Q000188:drug therapy; D006487:Hemostasis / Q000235:genetics; D006490:Hemostatics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism
D004792:Enzyme Precursors; D006490:Hemostatics; D011994:Recombinant Proteins; D015942:Factor VIIa; D013917:Thrombin; D015951:Factor Xa