Factor X (FX) is a vitamin K-dependent plasma protein best known for its central role in coagulation: its functional deficiency is associated with severe bleeding manifestations, such as epistaxis, hemarthroses, or gastrointestinal hemorrhage. Beyond hemostasis, however, FX exerts additional functions, and the diversity of these biological activities makes it essential to understand the mechanisms that maintain its physiological concentrations. The authors had previously shown that this regulation involves interactions with macrophages: their chemical depletion reduces FX levels by 60 to 70%, and the protein accumulates intact at the surface of several macrophage subtypes, where it forms a reservoir rather than being degraded. They had also identified scavenger receptor class A member I (SR-AI) as the principal cell-surface receptor involved.
The present study reveals that a third partner, pentraxin-2 (PTX2), associates with the FX/SR-AI complex. Binding experiments show that FX, SR-AI, and PTX2 bind independently of one another with apparent affinities ranging from 0.2 to 0.7 µM. PTX2 prevents the internalization of FX by SR-AI, and conversely the presence of FX limits the internalization of PTX2: the two proteins thus cooperate to escape capture by macrophages. Immunoprecipitation experiments further establish that FX and PTX2 circulate as a complex in plasma, with approximately 53% of FX bound to PTX2 in normal plasma. This association involves the FX activation peptide, which explains the absence of PTX2 binding to other vitamin K-dependent proteins, whose activation peptides are poorly conserved; once FX is activated to FXa, binding to PTX2 is lost.
The authors also demonstrate the interdependence of the plasma levels of the two proteins. In mice, inhibition of PTX2 by RNA interference reduces its level by approximately 45% and concomitantly lowers FX by 37%, without affecting factor IX. SR-AI-deficient mice display a concurrent decrease in both proteins. In humans, analysis of 71 plasma samples reveals a significant correlation between FX and PTX2 levels (Spearman coefficient of 0.40; p = 0.0006), and patients with FX deficiency (congenital, acquired, or under vitamin K antagonist therapy) show a parallel reduction in PTX2.
The authors propose a model in which the ternary FX/PTX2/SR-AI complex maintained at the cell surface protects both partners from accelerated clearance, a mechanism they liken to the recycling of albumin and immunoglobulins G via the FcRn receptor. They emphasize the clinical relevance of these observations in the context of trials aiming to deplete PTX2 for the treatment of systemic amyloidosis, where monitoring of FX levels appears advisable to them.