Thrombin activates factor XI on activated platelets in the absence of factor XII

Thrombin can activate factor XI in the presence of dextran sulfate or sulfa tides. However, a physiological cofactor for thrombin activation of factor XI has not been identified. We examined this question in a cell-based, tiss ue factor-initiated model system. In the absence of factor XII, factor XI e nhanced thrombin generation in this model. The effect on thrombin generatio n was reproduced by 2 to 5 pmol/L factor XIa. A specific inhibitor of facto r XIIa did not diminish the effect of factor XI. Thus, factor XI can be act ivated in a model system that does not contain factor XIIa or nonphysiologi cal cofactors. Preincubation of factor XI with activated platelets and thro mbin or factor Xa enhanced subsequent thrombin generation in the model syst em. Preincubation of factor XI with thrombin or factor Xa, but without plat elets, did not enhance thrombin generation, suggesting that these proteases might activate factor XI on platelet surfaces. Thrombin and factor Xa were then directly tested for their ability to activate factor XI. In the prese nce of dextran sulfate, thrombin or factor Xa activated factor XI. Thrombin , but not factor Xa, also cleaved detectable amounts of factor XI in the pr esence of activated platelets. Thus, thrombin activates enough factor XI to enhance subsequent thrombin generation in a model system. Platelet surface s might provide the site for thrombin activation of functionally significan t amounts of factor XI in vivo.