Novel factors affecting fibrin clot formation and their clinical implications.

Abstract

Fibrin formation is pivotal in hemostasis, serving as a temporary barrier to blood loss following vascular injury, while in thrombosis this process is involved in thrombus progression, stability, and recurrence. Growing evidence shows an exceptional complexity of processes that determine fibrin clot structure and function, especially lysability, both in health and disease, which might be relevant in the pathogenesis of arterial and venous thromboembolic diseases. In this overview we summarized available data on novel factors that in recent years have been suggested to contribute to prothrombotic fibrin clot properties, involving formation of compact fibrin networks (reduced clot permeability) displaying impaired susceptibility to lysis (prolonged clot lysis time). The factors discussed in this review encompass elevated levels of factor (F)XI, and its activated form (FXIa), protein carbonylation as the most common type of post-translational modification, neutrophil extracellular traps (NETs) formation, increased levels of circulating lipopolysaccharide (LPS) and zonulin, a marker of gut permeability, along with antithrombin deficiency. These factors have been shown to be not only associated with ischemic stroke, myocardial infarction, pulmonary embolism, and cardiovascular death, but also with unfavorably altered fibrin clot characteristics, which underscores clinical relevance of fibrin clot properties. Given preclinical or ongoing studies aimed at modifying some of these factors, in particular FXI / FXIa inhibitors, recent findings might expand our knowledge on fibrin-related mechanisms of emerging therapeutic agents tested and stimulate further research into new targets for future therapeutic interventions to prevent thromboembolic events.