Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available

Abstract

Objective-Feedback activation of factor XI by thrombin is a likely alternative for tissue factor-dependent propagation of thrombus formation. However, the hypothesis that thrombin can initiate and propagate its formation in a factor XI-dependent and platelet-dependent manner has not been tested in a plasma milieu. Methods and Results-We investigated thrombin generation in recalcified platelet-rich plasma activated with varying amounts of thrombin or factor VIIa. Thrombin initiates and propagates dose-dependently thrombin generation only when platelets and plasma factor XI are present. Incubation of thrombin-activated platelets with a tissue factor neutralizing antibody had no effect on thrombin formation, indicating that platelet-associated tissue factor, if present at all, is not involved. In the absence of factor VIII, thrombin could not initiate its own formation, whereas factor VIIa-induced thrombin generation was reduced. Collagen strongly stimulated both thrombin-initiated and factor VIIa-initiated thrombin generation. Conclusions-These findings support the notion that platelet-localized feedback activation of factor XI by thrombin plays an important role in maintaining normal hemostasis as well as in sustaining thrombus formation when the TF pathway is inhibited by tissue factor pathway inhibitor. Key Words: factor XI Ⅲ thrombin Ⅲ clot formation Ⅲ activated platelets Ⅲ factor VIIa Ⅲ collagen I t is generally appreciated that thrombin-mediated feedback activation of factor XI contributes to the consolidation phase of clot formation. [1][2][3] In this process, thrombin that is initially generated via the tissue factor (TF) pathway, activates factor XI on the surface of (thrombin-activated) activated platelets. 4 The accelerating role of activated platelets in thrombin-catalyzed factor XI activation is thought to result from the colocalization of thrombin and factor XI on the platelet membrane glycoprotein (GP) Ib␣ within the GP Ib-IX-V complex. 5,6 Thrombin-activated factor XI, therefore, could be critical to the propagation of thrombin generation once the TF pathway is inhibited by TF pathway inhibitor (TFPI).Hypothetically, thrombin-catalyzed factor XI activation could play a major role in the development of growing thrombi. Besides circulating cell-bound TF, the continuous supply of factor XI by blood flow to a thrombin-containing thrombus surface might result in a factor XIa-driven thrombin production that in turn will accelerate the rate of thrombus growth. 7 An additional argument for an important contribution of a factor XI-dependent thrombus growth is found in the observation that factor XI activation seems to be confined to the surface of an activated platelet. 8 The latter optimizes the thrombin generating potency because of maintaining high local concentrations of reactants and the inability to be inactivated by plasma protease inhibitors.The present work was undertaken to explore the role of thrombin in initiating its own production by feedback activation of factor XI under physiological conditi...

Factor XI and traveling waves: the key to understanding coagulation in hemophilia?

“…This concept is in accordance with the previous results [3,4,9] and can reinforce the 'fibrinolysis' hypothesis. In the absence of FXI, the moving thrombin peak is not formed and the local concentration of thrombin far from the activator at the time of clot formation is much lower [16].…”

“…Thrombin formation is affected more significantly [2,3]. Still, both effects can be observed only in a limited range of experimental conditions: absence of FXI plays a role when there is low or zero TF concentration [2][3][4][5]. In these cases, FXI deficiency can lead to delayed clot formation and decreased thrombin generation.…”

Polyphosphate is a cofactor for the activation of factor XI by thrombin

“…36 To date, however, the platelet-derived cofactor for FXI activation by thrombin, and the underlying mechanism, has not been well defined. In this study, we showed that platelet releasates enhanced FXI activation by ␣-thrombin, an activity that was not (measured using a mechanical coagulometer).…”

“…Furthermore, previous studies have shown that FXI activation by thrombin is enhanced in the presence of activated platelets. [35][36][37] We recently showed that polyP of the size secreted by human platelets accelerates blood clotting reactions 20,21 and binds with high affinity to ␣-thrombin and FXIa. 24,31 Taken together, these findings led us to formulate and test the hypothesis that polyP, a natural polyanion secreted by activated platelets, 19,22 mediates FXI activation by ␣-thrombin.…”

“…36 To date, however, the platelet-derived cofactor for FXI activation by thrombin, and the underlying mechanism, has not been well defined. In this study, we showed that platelet releasates enhanced FXI activation by ␣-thrombin, an activity that was not diminished by boiling (to denature potentially confounding proteins, including platelet-derived FXI 35 ), but that was abrogated by EcPPXc treatment or rPPX1 digestion.…”