title: A new regulatory function of activated factor V: inhibition of the activation by tissue factor/factor VII(a) of factor X.
abstract: BACKGROUND
  We observed that minute amounts of thrombin or the enzyme Russell's viper venom activating factor V (RVV-V) added to plasma strongly diminish the potential of that plasma to generate thrombin after being triggered by tissue factor.
  
  
  OBJECTIVE
  To find the mechanism behind this phenomenon.
  
  
  RESULTS
  Thrombin generation (TG) initiated by tissue factor (TF) is strongly and dose-dependently inhibited by addition of activated factor V (FVa) or by addition of a factor V activator (thrombin or RVV-V). No inhibition is seen when TG is triggered via the intrinsic pathway or by direct activation of factor X. The effect is independent of proteins C and S and tissue factor pathway inhibitor (TFPI). In factor VII-deficient plasma the effect is seen when it is spiked with recombinant factor VII (FVII) and to a much lesser extent when spiked with recombinant FVIIa. In a purified system, FVa also dose-dependently inhibits the activation of FX by TF/FVII(a). The inhibitory effect is neutralized by antibodies against the light chain of FVa but not by antibodies against the heavy chain.
  
  
  CONCLUSIONS
  Our observations can be explained by assuming that FVa, via its light chain, binds to the complex TF/FVII(a) and prevents it from activating FX. We assume that this mechanism reduces the possibility that thrombin and factor Xa escaping from a wound area into the circulation, together with blood-borne tissue factor, would trigger intravascular coagulation.
authors.affiliation: Synapse BV, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands. r.aldieri@thrombin.com
authors.forename: R
authors.initials: R
authors.lastname: Al Dieri
authors.forename: S
authors.initials: S
authors.lastname: Bloemen
authors.forename: H
authors.initials: H
authors.lastname: Kelchtermans
authors.forename: R
authors.initials: R
authors.lastname: Wagenvoord
authors.forename: H C
authors.initials: HC
authors.lastname: Hemker
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015943:Factor Va / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D065427:Factor Xa Inhibitors; D008074:Lipoproteins; D021122:Protein Subunits; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D015943:Factor Va; D013925:Thromboplastin; D012697:Serine Endopeptidases; D015942:Factor VIIa; D013917:Thrombin; D015951:Factor Xa; C057675:snake venom factor V activator