The Role of Factor XI in Coagulation: A Matter of Revision

Abstract

In 1991 it was demonstrated that, besides factor XII, thrombin is capable of activating factor XI in vitro. Thrombin-dependent activation of factor XI is an integral part of the revised theoretical model of coagulation in which coagulation is initiated by the extrinsic pathway and maintained by thrombin-induced activation of clotting factors V, VIII, and XI. In this review, special interest is given to the new role of factor XI in coagulation, with emphasise on data supporting the concept of thrombin-mediated factor XI activation in vivo. Furthermore, activation of factor XI in human disease, especially atherosclerotic disease, measured by newly developed immunologic assays, is discussed. The relation of factor XI to fibrinolysis through activation of the carboxypeptidase, thrombin-activatable fibrinolysis inhibitor (TAFI) by thrombin provides an explanation for the bleeding tendency observed in factor XI-deficient patients. The probable link with factor XI-mediated TAFI activation may have clinical and therapeutic consequences and deserves further study.

Curiouser and curiouser: Recent advances in measurement of thrombin-activatable fibrinolysis inhibitor (TAFI) and in understanding its molecular genetics, gene regulation, and biological roles

“…While the absence of TAFI is clearly compatible with normal development and certain aspects of hemostasis in mice, additional challenges will have to be presented to the TAFI −/− mice in order to elucidate the effect of the absence of the TAFI pathway in these animals. For example, it has been proposed that activation of TAFI by the large amounts of thrombin produced by the Factor XI-dependent pathway after clotting provides a mechanism by which the coagulation cascade can delay fibrinolysis in order to ensure consolidation of the clot [17,83,84]. Human patients with a deficiency in Factor XI are specifically prone to bleeding from areas with a high local fibrinolytic activity (such as the urinary tract, nose, oral cavity, and tonsils) [85].…”

Thrombin Inhibitors from Different Animals

“…After cellular activation by vascular trauma or an inflammatory stimulus, tissue factor becomes exposed and binds to a serine protease, factor VIIa, already present in blood [9, 10], and forms the factor VIIa-tissue factor complex, in the presence of phospholipid and calcium (extrinsic factor tenase), which activates the zymogens factor IX and factor X [11]. The limited amounts of the serine protease factor Xa produced generate picomolar concentrations of thrombin, which initiates several positive feedback reactions that sustain thrombin's own formation and facilitates the rapid growth of the blood clot or thrombus around the area of vascular damage [12]. Thrombin partially activates platelets and cleaves the procofactors factor V and factor VIII generating the active cofactors factor Va and factor VIIIa, respectively [13].…”

Covalently immobilized thrombomodulin inhibits coagulation and complement activation of artificial surfaces in vitro

“…derived from a release of TF in an in vivo situation. The formation of trace amounts of thrombin (either through the action of TF/VIIa or through the activation of the contact system as on some of our surfaces) could induce an amplification loop using thrombin's activating properties on FXI [80]. In vitro experiments using different or less anticoagulants can help to improve the prognostic value of the results [81].…”