title: Factor XI enhances fibrin generation and inhibits fibrinolysis in a coagulation model initiated by surface-coated tissue factor.
abstract: In-vitro studies have shown that thrombin-mediated factor XI activation enhances thrombin and fibrin formation, rendering the clot more thrombogenic and protecting it from lysis by activation of thrombin activatable fibrinolysis inhibitor. These effects of factor XI are only observed when coagulation is initiated by a low concentration of soluble tissue factor. At high concentrations of soluble tissue factor no effects of factor XI are seen on coagulation and fibrinolysis. In vivo, tissue factor is present in large amounts in the vascular wall. This makes it difficult to extrapolate these in-vitro findings on factor XI to the in-vivo situation. To address the question of whether factor XI could play a role in coagulation initiated on a tissue factor-containing surface we devised a static in-vitro coagulation model in which clotting is initiated in recalcified citrated plasma by tissue factor coated on the bottom of microtiter plates. The effect of factor XI was studied with an antibody that blocked the activation of factor IX by activated factor XI. The tissue factor coating strategy produced clotting times similar to those obtained with cultured tissue factor-expressing vessel wall cells (smooth muscle cells, fibroblasts and activated endothelial cells) grown to confluence in the same wells. A factor XI-dependent effect on clot formation and clot lysis was observed depending on the plasma volume used. In clots formed from small amounts of plasma (100 microl) no effect of factor XI was detected. In larger clots (200-300 microl) factor XI not only increased prothrombin activation and the fibrin formation rate but also inhibited fibrinolysis. Effects of factor XI were observed at short clotting times (3-4 min) similar to the clotting times found on cultured tissue factor-expressing vessel wall cells. This is in contrast with earlier studies using soluble tissue factor, in which effects of factor XI were only observed at much longer clotting times using low soluble tissue factor concentrations. We conclude that factor XI not only enhances coagulation initiated by surface bound tissue factor but also protects the clot against lysis once it is formed. On the basis of these results, we propose a coagulation model in which initial clot formation in the proximity of the tissue factor surface is not factor XI dependent. Clot formation becomes dependent on factor XI in the propagation phase when the clot is increasing in size. These findings support a role for factor XI in the propagation of clot growth after tissue factor-dependent initiation.
authors.affiliation: Department of Hematology, University Medical Center Utrecht, Utrecht The Netherlands. petborne@xs4all.nl
authors.forename: Peter A
authors.initials: PA
authors.lastname: von dem Borne
authors.forename: Linda M P
authors.initials: LM
authors.lastname: Cox
authors.forename: Bonno N
authors.initials: BN
authors.lastname: Bouma
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D005172:Factor XI / Q000494:pharmacology*; D005337:Fibrin / Q000096:biosynthesis / Q000187:drug effects*; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D011516:Prothrombin / Q000378:metabolism*; D013499:Surface Properties; D013917:Thrombin / Q000096:biosynthesis; D013997:Time Factors
chemical_list: D011516:Prothrombin; D005337:Fibrin; D005172:Factor XI; D013917:Thrombin