Factor XI and contact activation as targets for antithrombotic therapy

Abstract

The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa (FXa) or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and FX. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage. Studies in animals demonstrate that components of the plasma contact activation system contribute to experimentally induced thrombosis, despite playing little or no role in hemostasis. Attention has focused on FXII, the zymogen of a protease (FXIIa) that initiates contact activation when blood is exposed to foreign surfaces, and FXI, the zymogen of the protease FXIa, which links contact activation to the thrombin generation mechanism. In the case of FXI, epidemiologic data indicate this protein contributes to stroke and venous thromboembolism, and perhaps myocardial infarction, in humans. A phase 2 trial showing that reduction of FXI may be more effective than low molecular weight heparin at preventing venous thrombosis during knee replacement surgery provides proof of concept for the premise that an antithrombotic effect can be uncoupled from an anticoagulant effect in humans by targeting components of contact activation. Here, we review data on the role of FXI and FXII in thrombosis and results of preclinical and human trials for therapies targeting these proteins.

Keywords: anticoagulant; factor XI; factor XII; thrombosis; venous thrombosis.

Figure 1. Thrombin Generation and Contact Activation in Thrombosis

Thrombin Generation (Left Large Panel). Depicted are the calcium and phospholipid (PL) dependent proteolytic reactions that generate thrombin at a site of vascular injury. The process is initiated by activation of factors X and IX by the factor VIIa/tissue factor (TF) complex. Vitamin-K dependent protease zymogens are shown in black type with the active protease forms indicated by a lower case “a”. Cofactors are shown as red ovals. FXI can contribute to hemostasis through its conversion to FXIa by thrombin (white arrows), with subsequent calcium-dependent proteolysis of FIX (green arrow). Contact activation (Right Large Panel). On a surface, FXII undergoes autoactivation to FXIIa. FXIIa converts prekallikrein (PK) to the active protease α-kallikrein, which then activates additional FXII and cleaves the cofactor high-molecular-weight kininogen (HK) to liberate bradykinin (BK). HK cleavage can also produce antimicrobial peptides (AMPs). This system can contribute to thrombin generation through FXIIa-mediated activation of FXI (white arrow). FXIa, in turn can contribute to contact activation through activation of FXII (green arrow). In plasma, PK and FXI circulate as complexes with HK. During contact activation, HK serves as a cofactor by facilitating PK and FXI binding to the surface. Panels 1 and 2 list factors that may contribute to TF-induced thrombin generation or contact activation during thrombosis. Panels 3, 4 and 5 list some consequences of thrombin generation and contact activation that may contribute to thrombus formation and growth.