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Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

1Leeds Institute of Cardiovascular & Metabolic Medicine (LICAMM), University of Leeds, Leeds, West Yorkshire, United Kingdom, Leeds, England, United Kingdom, 2Case Western Reserve University, Cleveland, Ohio, United States, 3CWRU School of Medicine, Cleveland, Ohio, United States, 4University of Leeds, Leeds, England, United Kingdom, 5Unversity of Leeds, Leeds, England, United Kingdom, 6National Institute for Biological Standards and Control, Hertfordshire, England, United Kingdom, 7Institute for Clinical Chemistry and Laboratory Medicine, Eppendorf, Hamburg, Germany, 8Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

Abstract Number: OC 03.4

Meeting: ISTH 2022 Congress

Theme: Coagulation and Natural Anticoagulants » Contact Pathway

Background: Factor(F) XII is a coagulation factor at the frontier of coagulation, inflammation, innate immunity, and fibrinolysis. Misfolded proteins are factor XII (FXII) activators that can trigger the proinflammatory kallikrein-kinin system (KKS) and the intrinsic pathway of coagulation, via plasma kallikrein (PKa) and activated Factor XI (FXIa), respectively. The chronic hyperglycaemic conditions in diabetes mellitus (DM) patients induce a non-enzymatic Maillard reaction that denatures plasma proteins to form advanced glycation end products (AGEs) which accumulate within the vasculature and tissues.

Aims: Human serum albumin (HSA) is the most abundant protein in plasma and is sensitive to glycation in vivo. We investigated the relationship between plasma glycation levels and activation of the contact pathway in diabetic patients and characterised the effects of HSA-AGE on FXII, PK, FXI activation, and thrombus formation.

Methods: Plasma was obtained from 10 DM patients (2 T1DM, 8 T2DM), 10 age-matched euglycemic volunteers and were subjected to immunoblotting for activated FXII(a) and cleaved high molecular weight kininogen (cHK). Plasma PKa activity was measured via chromogenic assay. Kinetic modulation of FXII, PK, FXI and their respective full active serine proteases by 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 DM patients has increased plasma AGEs, FXIIa, cHK, along with increased plasma PKa enzymatic activity levels which positively correlated with HbA1C levels. In vitro generated HSA-AGE triggered FXIIa-dependent PKa activation but limits procoagulant intrinsic pathway activation by directly inhibiting FXIa, and separately, activated Factor IX (FIXa)-dependent Factor X (FX) activation in plasma.

Conclusion(s): These data suggest a proinflammatory role of AGEs in the pathophysiology of DM via FXII and KKS activation. The expected procoagulant signal from FXII activation was lost through the inhibition of FXIa and (FIXa)-dependent Factor X (FX) activation.

To cite this abstract in AMA style:

Hardy L, Bohinc D, Bane K, Heal S, Hethershaw E, Ali M, Foster R, Longstaff C, Renne T, Stavrou E, Philippou H. Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems [abstract]. https://abstracts.isth.org/abstract/glycated-albumin-modulates-the-contact-system-with-implications-for-the-kallikrein-kinin-and-intrinsic-coagulation-systems/. Accessed September 22, 2023.

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