The Therapeutic Potential of Anticoagulation in Organ Fibrosis

Abstract

Fibrosis, also known as organ scarring, describes a pathological stiffening of organs or tissues caused by increased synthesis of extracellular matrix (ECM) components. In the past decades, mounting evidence has accumulated showing that the coagulation cascade is directly associated with fibrotic development. Recent findings suggest that, under inflammatory conditions, various cell types (e.g., immune cells) participate in the coagulation process causing pathological outcomes, including fibrosis. These findings highlighted the potential of anticoagulation therapy as a strategy in organ fibrosis. Indeed, preclinical and clinical studies demonstrated that the inhibition of blood coagulation is a potential intervention for the treatment of fibrosis across all major organs (e.g., lung, liver, heart, and kidney). In this review, we aim to summarize our current knowledge on the impact of components of coagulation cascade on fibrosis of various organs and provide an update on the current development of anticoagulation therapy for fibrosis.

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

“…Plasmin not only degrades fibrin but also induces MMP and PAR activity. Fibrin and PAR activation promotes fibrosis, and MMPs play an important role in ECM degradation [ 76 , 77 ]. In addition, plasmin-induced hepatocyte growth factor (HGF) activation and vascular endothelial growth factor (VEGF) release may affect fibrosis progression [ 78 , 79 ].…”

“…Hypercoagulation involving fibrin formation contributes to fibrosis progression [ 77 ]. The uPA/uPAR system plays a pivotal role in fibrin degradation through plasmin production.…”

“…uPA and plasmin inhibitors, PAI-1 and α2AP, are elevated in several fibrotic tissue types [ 11 ], and the increase in the expression of these factors may cause the impairment of fibrinolysis through the direct inhibition of uPA and plasmin. The impairment of fibrinolysis causes fibrosis, and improvement in fibrinolysis restores fibrosis [ 77 ]. In addition, fibrin degradation product fragment can potentiate TGF-β-induced myofibroblast formation [ 181 ].…”

Non-coding RNAs: targets for Chinese herbal medicine in treating myocardial fibrosis

“…Medication methods are more commonly used at the early stage of cardiovascular diseases to prevent the development of MF. These drug mainly include angiotensin-converting enzyme inhibitors ( Francis Stuart et al, 2016 ), diuretics ( Liu and Yu, 2022 ), β-blockers ( Kobayashi et al, 2004 ), and anticoagulants ( Oh et al, 2022 ). Surgical methods are used at the late stage of cardiovascular diseases, mainly including endocardial resection, atrioventricular valve repair/replacement, and heart transplantation.…”

Editorial: Pathogenic aspects of the innate immune system of the kidney

“…Based on the previous findings on the association of the coagulation process with organ fibrosis ( 6 ), Oh et al evaluated the expression of coagulation factors on Mφ in renal tissues with ischemia–reperfusion injury at acute (AKI) and chronic phases (CKD, fibrosis) in mice. Interestingly, they found increased production of key coagulation factors both by infiltrating and resident renal Mφ, suggesting the novel mechanism of renal fibrosis through fibrinogenesis induced by upregulated production of coagulation factors by renal Mφ and subsequent matrix deposition.…”