The rebirth of the contact pathway: a new therapeutic target

Abstract

Purpose of review: Anticoagulation with vitamin-K antagonists or direct oral anticoagulants is associated with a significant risk of bleeding. There is a major effort underway to develop antithrombotic drugs that have a smaller impact on hemostasis. The plasma contact proteins factor XI (FXI) and factor XII (FXII) have drawn considerable interest because they contribute to thrombosis but have limited roles in hemostasis. Here, we discuss results of preclinical and clinical trials supporting the hypothesis that the contact system contributes to thromboembolic disease.

Recent findings: Numerous compounds targeting FXI or FXII have shown antithrombotic properties in preclinical studies. In phase 2 studies, drugs-targeting FXI or its protease form FXIa compared favorably with standard care for venous thrombosis prophylaxis in patients undergoing knee replacement. While less work has been done with FXII inhibitors, they may be particularly useful for limiting thrombosis in situations where blood comes into contact with artificial surfaces of medical devices.

Summary: Inhibitors of contact activation, and particularly of FXI, are showing promise for prevention of thromboembolic disease. Larger studies are required to establish their efficacy, and to establish that they are safer than current therapy from a bleeding standpoint.

FIGURE 1.

Contact activation and thrombin generation. (a) Contact activation. Binding of factor XII to a surface initiates its autocatalytic conversion to its activated form factor XIIa. Factor XIIa catalyzes conversion of prekallikrein to plasma kallikrein, which activates additional factor XII (blue dashed arrow) amplifying the contact process. Plasma kallikrein also cleaves high-molecular-weight kininogen to release the vasoactive peptide, bradykinin. In addition to activating prekallikrein, factor XIIa also converts factor XI to factor XIa. (b) Thrombin generation. At a site of injury, thrombin generation is initiated by a complex comprised of factor VIIa and the integral membrane protein tissue factor. This complex activates factor X and factor IX to factor Xa and factor IXa, respectively. Factor IX activates additional factor X in the presence of factor VIIIa. Factor Xa then converts factor II (prothrombin) to factor IIa (thrombin) in a reaction that uses factor Va as a cofactor. In this system, factor XIa generated through contact activation can promote coagulation independently of factor VIIa/tissue factor by activating factor IX. Alternatively, factor XI may be activated independently of factor XII (red dashed arrow) by thrombin. In both parts of the diagram, cofactors for protease reactions are indicated in italics. Some reactions require calcium ions (Ca²⁺) and/or phosphatidylserine-containing phospholipids.

FIGURE 2.

Mechanisms of action of drugs targeting contact activation. Blue figures represent factor XI and factor XIa, and green figures represent factor XII and factor XIIa. The catalytic domains of factor XII and factor XI are indicated by CD, and the serine protease active sites of factor XIIa and factor XIa are indicated by AS. The red T-bars indicate the parts of the molecule with which individual drugs interact. In the case of the antisense oligonucleotide, the drug targets factor XI mRNA in hepatocytes, reducing production of factor XI protein. GAG, glycosaminoglycan; SMI, small molecule inhibitor; MAb, monoclonal antibody. Drugs marked by an asterisk (*) are being studied in phase II trials.