Factor XI as a target for antithrombotic therapy

Abstract

Anticoagulants currently used in clinical practice to treat thromboembolic disorders are effective but increase the risk of severe bleeding because they target proteins that are essential for normal coagulation (hemostasis). Drugs with better safety profiles are required for prevention and treatment of thromboembolic disease. Coagulation factor XIa has emerged as a novel target for safer anticoagulant therapy because of its role in thrombosis and its relatively small contribution to hemostasis.

Figure 1

Models of thrombin generation. (a) Tissue factor (TF)-initiated thrombin generation. Factor (f)VIIa binds to TF, a membrane protein expressed on the surface of cells underlying the blood vessel endothelium. The fVIIa–TF complex activates fX to fXa (the traditional extrinsic pathway of coagulation), and fIX to fIXa. FXa converts prothrombin to thrombin in the presence of fVa. fIXa sustains the process by activating additional fX in the presence of fVIIIa. The reactions indicated by the black arrows form the core of the thrombin generation mechanism in vertebrate animals. Mammals have fXIa, which provides another mechanism for fIX activation. In the traditional intrinsic pathway of coagulation fXIIa converts fXI to fXIa. fXI can also be activated by thrombin generated early in the coagulation process (gray arrow), explaining the lack of a bleeding disorder in people lacking fXII. (b) Contact-activation-initiated thrombin generation. In the cascade or waterfall model of thrombin generation, fXII is converted to fXIIa by a process called contact activation (gray circle) that requires prekallikrein (PK), high molecular weight kininogen (HK) and a negatively charged surface. fXIIa then activates fXI, setting off the sequence of proteolytic reactions that culminates in thrombin generation. In both panels zymogens of trypsin-like enzymes are indicated in black lettering, with active forms indicated by a lower case ‘a’. Non-enzyme cofactors are indicated by red circles.

Figure 2

Schematic diagram of factor (f)XI. Shown are the primary amino acid sequence, disulfide bonds (cysteine residues shown in black circles) and domain structure of human plasma fXI. The histidine (413), aspartic acid (462) and serine (557) residues of the protease active site catalytic triad are shown in red. Conversion of fXI to fXIa involves a single proteolytic cleavage after Arg369 (indicated in blue) that can be produced by fXIIa or thrombin. Residues that are required for fIX binding to the A3 domain are indicated in yellow, and residues that comprise a polyanion (heparin) binding site on the catalytic domain are in green. Mature fXI is a dimer of the protein shown in this figure. The unpaired cysteine residue at position 321 (Cys321) in a fXI subunit forms an inter-chain disulfide bond with Cys321 from the other subunit of the dimer. Image reproduced, with permission, from [41].