title: Latent and polymeric antithrombin: clearance and potential thrombotic risk.
abstract: Antithrombin, the most potent anticoagulant in vivo, displays a significant conformational flexibility. The native five-stranded anticoagulant form transforms under different conditions or mutations to inactive six-stranded conformations: latent or polymer. However, the function, potential deleterious effects, and clearance of these forms are not completely known. The dimerization of latent antithrombin with a native molecule has been suggested to have thrombotic potential. We have assessed the potential thrombogenicity of high amounts of latent and polymeric antithrombin by experiments performed in mice and human plasma. Moreover, we have analyzed the clearance of (125)I-labeled native, latent, polymer, and thrombin-complexed antithrombins in rat, as well as the clearance of latent antithrombin from plasma of patients treated with commercial concentrates. Our results show that high plasma levels of latent or polymeric antithrombin do not interfere with the anticoagulant function of native antithrombin. Moreover, we confirm that all monomeric forms of antithrombin have similar turnover. Finally, we show that polymers have the longest half-life of all conformers, being in circulation for prolonged periods of time. In conclusion, our data support that latent and polymeric antithrombin would not likely have a thrombotic effect, thus dispelling doubts about the potential harmful effect of latent antithrombin present in commercial concentrates for therapeutic use. Moreover, the suggested antiangiogenic role of latent antithrombin, together with its stability in plasma and its negligible thrombogenicity raises the possibility of its use as a new antiangiogenic drug.
authors.affiliation: University of Murcia, Centro Regional de Hemodonación, Ronda de Garay S/N, Murcia 30003, Spain. javier.corral@carm.es
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: José
authors.initials: J
authors.lastname: Rivera
authors.forename: José A
authors.initials: JA
authors.lastname: Guerrero
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.forename: Ignacio
authors.initials: I
authors.lastname: Alberca
authors.forename: David
authors.initials: D
authors.lastname: Hernández-Espinosa
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordóñez
authors.forename: Constantino
authors.initials: C
authors.lastname: Martínez
authors.forename: Leyre
authors.initials: L
authors.lastname: Navarro-Núñez
authors.forename: Rocio
authors.initials: R
authors.lastname: González-Conejero
authors.forename: María L
authors.initials: ML
authors.lastname: Lozano
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000378:metabolism / Q000502:physiology*; D001704:Biopolymers; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013927:Thrombosis / Q000503:physiopathology*
chemical_list: D000991:Antithrombins; D001704:Biopolymers; D007457:Iodine Radioisotopes