title: Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma.
abstract: The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: J Arnoud
authors.initials: JA
authors.lastname: Marquart
authors.forename: Kamran
authors.initials: K
authors.lastname: Bakhtiari
authors.forename: Cees
authors.initials: C
authors.lastname: Weeterings
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Rolf T
authors.initials: RT
authors.lastname: Urbanus
mesh_terms: D000704:Analysis of Variance; D001777:Blood Coagulation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D015943:Factor Va / Q000378:metabolism*; D005172:Factor XI / Q000378:metabolism*; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000378:metabolism*
chemical_list: D015943:Factor Va; D005172:Factor XI; D013917:Thrombin