Thrombin-mediated feedback activation of factor XI on the activated platelet surface is preferred over contact activation by factor XIIa or factor XIa

To study the pathways for initiation of intrinsic blood coagulation, activa ted human platelets were compared with dextran sulfate as surfaces for fact or XI activation by factor XIIa, factor XIa, or thrombin. Activated gel-fil tered platelets promoted the activation of factor XI (60 nM) by thrombin (0 .02-10 nM, EC50 similar to 100 pM, threshold concentration similar to 10 pM ) at initial rates 2- to 5-fold greater than those obtained with dextran su lfate in the presence of either high molecular weight kininogen (45 nM) and ZnCl2 (25 mu M) or prothrombin (1.2 mu M) and CaCl2 (2 mM). The maximum ra tes of factor XI activation achieved in the presence of activated gel-filte red platelets were 30 nM.min(-1) with thrombin, 6 nM.min(-1) with factor XI Ia and 2 nM.min(-1) with factor XIa. Values of turnover number calculated a t various enzyme concentrations (0.05-1 nM) were 24-167 (mean = 86) min(-1) for thrombin, 4.6-50 (mean = 21) min(-1) for factor XIIa, and 1.3-14 (mean = 8) min(-1) for factor XIa. A physiological concentration of fibrinogen ( 9.0 mu M) inhibited factor XI activation by thrombin (but not by factor XII a) in the presence of dextran sulfate but not in the presence of gel-filter ed platelets. Compared with factors XIIa and XIa, thrombin is the preferred factor XI activator, and activated platelets are a relevant physiological surface for thrombin-mediated initiation of intrinsic coagulation in vivo.