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Fibrin(ogen): friend and foe
Figure 5. Scheme summarizing the mechanisms of fibrin(ogen) as a friend (in green) and foe (in red) in human disease. Square boxes represent abnormalities that prompt fibrinogen involvement in illness settings. CNS: central nervous system; CVD: cardiovascular diseases; FCP: fibrinogen cleavage products; HFD: high-fat diet; MMP-2: matrix metalloproteinase 2; PTM: post-translational modifications; TLR4: toll-like receptor 4.
syndrome, and renal failure.66 Several renal amyloidogenic mutations in fibrinogen have been described (Online Supplementary Table S2). Patients with these mutations do not have a bleeding disorder and, when measured, the clotting times of patients with these variants are normal, except those with p.Thr544LeufsTer24 who had a pro- longed thrombin time and low fibrinogen level.133
While the kidney is the predominant organ for fibrino- gen-amyloid deposition, the pathology of hereditary fib- rinogen amyloidosis is not restricted to involvement of this organ. Fibrinogen amyloidosis patients show a high incidence of cardiovascular atheromatous disease with a family history of coronary/vascular disease.134 Fibrinogen deposits are found in vascular walls and atheromatous plaques, associating fibrinogen variant amyloidosis and atherosclerosis. While nephrotic syndrome with hyper- lipidemia and hypertension may facilitate atheroma for- mation, the cardiovascular findings are unlikely to be caused by renal failure alone. Thus, hereditary fibrinogen amyloidosis is a complex systemic amyloid disease that is associated with cardiac amyloid deposition, angiopathy and atheromatosis134,135 (Figure 4).
There are currently no treatments available to resolve amyloid deposits. Disease management consists of inter- rupting amyloidogenic protein supply with supportive care to failing organs, and transplantation. Hepato-renal transplantation appears to prevent disease progression and allows reversal of some organ dysfunction.134,135
Conclusions
As the thrombin substrate for generating fibrin, fibrino- gen has a critical role in controlling bleeding upon vascular injury, as well as being a major determinant in wound healing, tissue regeneration and mediation of inflammato- ry responses that help the immune system fight invading pathogens. However, several layers of evidence point to fibrin(ogen) as a contributor in pathological settings (Figure 5). These contributions may result from altered plasma concentration, modified structural properties, or from the impact of polymorphisms on clot permeability, stiffness and resistance to lysis. The presence of fibrin(ogen) in particular locations is a determinant in the development of disease. Here we have discussed human disorders in which the role of fibrin(ogen) is supported by clinical data and animal models. Fibrin(ogen) is also a like- ly protagonist in fibrotic and arthritic diseases. Continued research will allow a better understanding of these com- plex disease settings and the impact of fibrin(ogen). Whether the presence, quality or abundance of fibrin(ogen) has a causal role, or is a consequence of the underlying pathology, should be a focal point. Such research will help to evaluate the usefulness of targeting fibrin(ogen) in a variety of human disease settings.
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