Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation

Abstract

Complex associations exist between inflammation and thrombosis, with the inflammatory state tending to promote coagulation. Fibrinogen, an acute phase protein, has been shown to interact with the amyloidogenic ß-amyloid protein of Alzheimer’s disease. However, little is known about the association between fibrinogen and serum amyloid A (SAA), a highly fibrillogenic protein that is one of the most dramatically changing acute phase reactants in the circulation. To study the role of SAA in coagulation and thrombosis, in vitro experiments were performed where purified human SAA, in concentrations resembling a modest acute phase response, was added to platelet-poor plasma (PPP) and whole blood (WB), as well as purified and fluorescently labelled fibrinogen. Results from thromboelastography (TEG) suggest that SAA causes atypical coagulation with a fibrin(ogen)-mediated increase in coagulation, but a decreased platelet/fibrin(ogen) interaction. In WB scanning electron microscopy analysis, SAA mediated red blood cell (RBC) agglutination, platelet activation and clumping, but not platelet spreading. Following clot formation in PPP, the presence of SAA increased amyloid formation of fibrin(ogen) as determined both with auto-fluorescence and with fluorogenic amyloid markers, under confocal microcopy. SAA also binds to fibrinogen, as determined with a fluorescent-labelled SAA antibody and correlative light electron microscopy (CLEM). The data presented here indicate that SAA can affect coagulation by inducing amyloid formation in fibrin(ogen), as well as by propelling platelets to a more prothrombotic state. The discovery of these multiple and complex effects of SAA on coagulation invite further mechanistic analyses.

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

“…slips. This has also previously been noted in various publications (Page et al, 2018;Pretorius et al, 2018d;Page et al, 2019).…”

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

“…[132][133][134] The same aberrant clot formation has also been demonstrated in a purified fibrinogen model in the presence of certain inflammatory stimuli such as bacterial LPS 27,135 and SAA. 136 It therefore begs the question whether any interaction may occur between the processes of citrullination and amyloid transformation of fibrin(ogen) as outlined in ►Fig. 3, and if it could play a major role in disease outcome in RA.…”

“…149 Recently our group has demonstrated the ability of SAA to bind to fibrin(ogen), and that relatively low concentrations of SAA-induced amyloid fibrillation of fibrin clots. 136 Amyloidogenic formation of proteins occurs when α-helices uncoil resulting in β-sheet structure 125 with misfolded proteins leading to an increased thrombotic tendency. 150 With previous reported findings of significantly elevated levels of A-SAA in RA patients, including patients with improved clinical symptoms, A-SAA may significantly contribute to coagulopathy seen in RA individuals and should thus be closely monitored in clinical settings.…”

Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients

“…These factors include changes in levels of C‐reactive protein and acute‐phase serum amyloid A (SAA) . Recent studies show that acute‐phase SAA can directly bind to fibrin and affect coagulation by promoting amyloid formation in fibrin …”

“…9 Recent studies show that acute-phase SAA can directly bind to fibrin and affect coagulation by promoting amyloid formation in fibrin. 10 The SAA gene family has 4 members. SAAs can be divided into 2 subgroups, comprising acute-phase SAA1 and SAA2 associated with HDL and inflammation in the first subgroup 11 and SAA4 in the second subgroup.…”