Factor XI and factor XII as targets for new anticoagulants

Abstract

Although the non-vitamin antagonist oral anticoagulants produce less intracranial bleeding than warfarin, serious bleeding still occurs. Therefore, the search for safer anticoagulants continues. Factor XII and factor XI have emerged as promising targets whose inhibition has the potential to prevent thrombosis with little or no disruption of hemostasis. Thus, thrombosis is attenuated in mice deficient in factor XII or factor XI and patients with congenital factor XII deficiency do not bleed and those with factor XI deficiency rarely have spontaneous bleeding. Strategies targeting factor XII and XI include antisense oligonucleotides to decrease their synthesis, inhibitory antibodies or aptamers, and small molecule inhibitors. These strategies attenuate thrombosis in various animal models and factor XI knockdown with an antisense oligonucleotide in patients undergoing knee replacement surgery reduced postoperative venous thromboembolism to a greater extent than enoxaparin without increasing bleeding. Therefore, current efforts are focused on evaluating the efficacy and safety of factor XII and factor XI directed anticoagulant strategies.

Introduction

The holy grail of anticoagulation is to attenuate thrombosis without affecting hemostasis. Although the non-vitamin K antagonist oral anticoagulants (NOACs) come closer to this goal than vitamin K antagonists such as warfarin, we still have a long way to go. Thus, the NOACs have been shown to be at least as effective as warfarin for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism (VTE), but produce less serious bleeding, particularly intracranial bleeding [1, 2]. Nonetheless, serious bleeding still occurs with the NOACs. Thus, the annual rate of major bleeding with the NOACs in patients with AF is 2% to 3%, while the annual rate of intracranial bleeding is 0.3% to 0.5% [1]. Therefore, there remains a need for safer anticoagulants for long-term indications.

Development of safer anticoagulants depends on identification of targets beyond thrombin and factor Xa, the enzymes inhibited by dabigatran and the oral factor Xa inhibitors, respectively. Recent interest has focused on components of the contact pathway, particularly factors XI and XII, as potential targets [3, 4]. Interest in these upstream clotting factors stems from epidemiological evidence that patients with congenital deficiency of factor XI are at lower risk for VTE and ischemic stroke [5, 6], the observation that mice deficient in factor XI or XII have attenuated thrombosis at sites of arterial or venous injury [7, 8], the recent identification of naturally-occurring polyphosphates as potential physiological activators of the contact system [9, 10, 11, 12], and the fact that patients with congenital factor XII deficiency do not bleed [3, 4], and those with congenital factor XI deficiency have only a mild bleeding diathesis [13]. Therefore, if factor XII and XI are important in thrombosis, they are promising targets for development of safer anticoagulants because they have little or no role in hemostasis.

Focusing on factors XI and XII, this review (a) describes the contact activation pathway, (b) identifies the roles of factors XI and XII in thrombosis, (c) lists the factor XI and factor XII directed anticoagulant strategies under development, (d) highlights the relative advantages and limitations of factor XI versus factor XII as targets for new anticoagulants, (e) describes the clinical data with these agents, and (f) summarizes the opportunities and challenges for factor XI or factor XII directed anticoagulant strategies for various indications.