{"doi":"10.1016/j.jtha.2022.12.015","title":"Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems","abstract":"BACKGROUND: Human serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. OBJECTIVES: This study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. METHODS: The plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro-generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. RESULTS: Plasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. CONCLUSION: These data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.","journal":"Journal of Thrombosis and Haemostasis","year":2023,"id":369709,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":850615,"name":"Dillon Bohinc","orcid":"0000-0002-9590-3063","position":1,"is_corresponding":false},{"id":850618,"name":"Kara L. Bane","orcid":"0000-0001-7099-8951","position":2,"is_corresponding":false},{"id":1128638,"name":"Samantha L. Heal","orcid":"0000-0001-9355-8414","position":3,"is_corresponding":false},{"id":1128639,"name":"Emma Hethershaw","orcid":"0000-0002-4366-278X","position":4,"is_corresponding":false},{"id":1128640,"name":"Majid Ali","orcid":"0000-0001-8365-252X","position":5,"is_corresponding":false},{"id":1129014,"name":"Thomas Palmer-Dench","orcid":null,"position":6,"is_corresponding":false},{"id":1128641,"name":"Richard Foster","orcid":"0000-0002-2361-3884","position":7,"is_corresponding":false},{"id":726947,"name":"Colin Longstaff","orcid":"0000-0001-7608-208X","position":8,"is_corresponding":false},{"id":287690,"name":"Thomas Renné","orcid":"0000-0003-4594-5975","position":9,"is_corresponding":false},{"id":618815,"name":"Evi X. Stavrou","orcid":"0000-0002-6075-7609","position":10,"is_corresponding":false},{"id":1128642,"name":"Helen Philippou","orcid":"0000-0002-9199-4201","position":11,"is_corresponding":false},{"id":1128637,"name":"Lewis Hardy","orcid":"0000-0002-3567-3518","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:15:32.670954Z","pmid":"36990522","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}