A soluble tissue factor-annexin V chimeric protein has both procoagulant and anticoagulant properties.
Tissue factor (TF) initiates blood coagulation, but its expression in the vascular space requires a finite period of time. We hypothesized that targeting exogenous tissue factor to sites of vascular injury could lead to accelerated hemostasis. Since phosphatidylserine (PS) is exposed on activated cells at sites of vascular injury, we cloned the cDNA for a chimeric protein consisting of the extracellular domain of TF (called soluble TF or sTF) and annexin V, a human PS-binding protein. Both the sTF and annexin V domains had ligand-binding activities consistent with their native counterparts, and the chimera accelerated factor X activation by factor VIIa. The chimera exhibited biphasic effects upon blood coagulation. At low concentrations it accelerated blood coagulation, while at higher concentrations it acted as an anticoagulant. The chimera accelerated coagulation in the presence of either unfractionated or low-molecular-weight heparins more potently than factor VIIa and shortened the bleeding time of mice treated with enoxaparin. The sTF-annexin V chimera is a targeted procoagulant protein that may be useful in accelerating thrombin generation where PS is exposed to the vasculature, such as may occur at sites of vascular injury or within the vasculature of tumors.
Huang
Xin
X
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Ding
Wei-Qun
WQ
Vaught
Joshua L
JL
Wolf
Roman F
RF
Morrissey
James H
JH
Harrison
Roger G
RG
Lind
Stuart E
SE
D000818:Animals; D017304:Annexin A5 / Q000235:genetics / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001808:Blood Vessels / Q000293:injuries / Q000378:metabolism; D003029:Coagulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015944:Factor VIIIa / Q000378:metabolism / Q000494:pharmacology; D005170:Factor X / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000494:pharmacology*
D017304:Annexin A5; D000925:Anticoagulants; D003029:Coagulants; D006495:Heparin, Low-Molecular-Weight; D010718:Phosphatidylserines; D011993:Recombinant Fusion Proteins; D015944:Factor VIIIa; D005170:Factor X; D013925:Thromboplastin