title: Improvement of spatial fibrin formation by the anti-TFPI aptamer BAX499: changing clot size by targeting extrinsic pathway initiation.
abstract: BACKGROUND
  Tissue factor pathway inhibitor (TFPI) is a major regulator of clotting initiation and a promising target for pro- and anticoagulation therapy. The aptamer BAX499 (formerly ARC19499) is a high-affinity specific TFPI antagonist designed to improve hemostasis. However, it is not clear how stimulation of coagulation onset by inactivating TFPI will affect spatial and temporal clot propagation.
  
  
  OBJECTIVE
  To examine the BAX499 effect on clotting in a spatial, reaction-diffusion experimental system in comparison with that of recombinant activated factor VII (rVIIa).
  
  
  METHODS
  Clotting in plasma activated by immobilized tissue factor (TF) was monitored by videomicroscopy.
  
  
  RESULTS
  BAX499 dose-dependently improved coagulation in normal and hemophilia A plasma activated with TF at 2 pmole m(-2) by shortening lag time and increasing clot size by up to ~2-fold. The effect was TFPI specific as confirmed by experiments in TFPI-depleted plasma with or without TFPI supplementation. Clotting improvement was half-maximal at 0.7 nm of BAX499 and reached a plateau at 10 nm, remaining there at concentrations up to 1000 nm. The BAX499 effect decreased with TF surface density increase. RVIIa improved clotting in hemophilia A plasma activated with TF at 2 or 20 pmole m(-2) , both by shortening lag time and increasing spatial velocity of clot propagation; its effects were strongly concentration dependent.
  
  
  CONCLUSIONS
  BAX499 significantly improves spatial coagulation by inhibiting TFPI in a spatially localized manner that is different to that observed with rVIIa.
authors.affiliation: Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia.
authors.forename: L A
authors.initials: LA
authors.lastname: Parunov
authors.forename: O A
authors.initials: OA
authors.lastname: Fadeeva
authors.forename: A N
authors.initials: AN
authors.lastname: Balandina
authors.forename: N P
authors.initials: NP
authors.lastname: Soshitova
authors.forename: K G
authors.initials: KG
authors.lastname: Kopylov
authors.forename: M A
authors.initials: MA
authors.lastname: Kumskova
authors.forename: J C
authors.initials: JC
authors.lastname: Gilbert
authors.forename: R G
authors.initials: RG
authors.lastname: Schaub
authors.forename: K E
authors.initials: KE
authors.lastname: McGinness
authors.forename: F I
authors.initials: FI
authors.lastname: Ataullakhanov
authors.forename: M A
authors.initials: MA
authors.lastname: Panteleev
mesh_terms: D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D003198:Computer Simulation; D015942:Factor VIIa / Q000008:administration & dosage / Q000494:pharmacology; D005337:Fibrin / Q000096:biosynthesis*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D008297:Male; D018715:Microscopy, Video; D008954:Models, Biological; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D052157:Aptamers, Nucleotide; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D015942:Factor VIIa