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

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Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems. / Hardy, Lewis J; Bohinc, Dillon; Bane, Kara L; Heal, Samantha L; Hethershaw, Emma; Ali, Majid; Palmer-Dench, Thomas; Foster, Richard; Longstaff, Colin; Renné, Thomas; Stavrou, Evi X; Philippou, Helen.

In: J THROMB HAEMOST, Vol. 21, No. 4, 04.2023, p. 814-827.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hardy, LJ, Bohinc, D, Bane, KL, Heal, SL, Hethershaw, E, Ali, M, Palmer-Dench, T, Foster, R, Longstaff, C, Renné, T, Stavrou, EX & Philippou, H 2023, 'Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems', J THROMB HAEMOST, vol. 21, no. 4, pp. 814-827. https://doi.org/10.1016/j.jtha.2022.12.015

APA

Hardy, L. J., Bohinc, D., Bane, K. L., Heal, S. L., Hethershaw, E., Ali, M., Palmer-Dench, T., Foster, R., Longstaff, C., Renné, T., Stavrou, E. X., & Philippou, H. (2023). Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems. J THROMB HAEMOST, 21(4), 814-827. https://doi.org/10.1016/j.jtha.2022.12.015

Vancouver

Hardy LJ, Bohinc D, Bane KL, Heal SL, Hethershaw E, Ali M et al. Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems. J THROMB HAEMOST. 2023 Apr;21(4):814-827. https://doi.org/10.1016/j.jtha.2022.12.015

Bibtex

@article{69ca1edae72c4feab9effbbfe4e28a6c,
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.",
keywords = "Humans, Kallikreins/metabolism, Plasma Kallikrein/metabolism, Kinins, Factor XIIa/metabolism, Kininogen, High-Molecular-Weight/metabolism, Prekallikrein/metabolism, Albumins, Glycation End Products, Advanced",
author = "Hardy, {Lewis J} and Dillon Bohinc and Bane, {Kara L} and Heal, {Samantha L} and Emma Hethershaw and Majid Ali and Thomas Palmer-Dench and Richard Foster and Colin Longstaff and Thomas Renn{\'e} and Stavrou, {Evi X} and Helen Philippou",
note = "Copyright {\textcopyright} 2023 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = apr,
doi = "10.1016/j.jtha.2022.12.015",
language = "English",
volume = "21",
pages = "814--827",
journal = "J THROMB HAEMOST",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "4",

}

RIS

TY - JOUR

T1 - Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

AU - Hardy, Lewis J

AU - Bohinc, Dillon

AU - Bane, Kara L

AU - Heal, Samantha L

AU - Hethershaw, Emma

AU - Ali, Majid

AU - Palmer-Dench, Thomas

AU - Foster, Richard

AU - Longstaff, Colin

AU - Renné, Thomas

AU - Stavrou, Evi X

AU - Philippou, Helen

N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

KW - Humans

KW - Kallikreins/metabolism

KW - Plasma Kallikrein/metabolism

KW - Kinins

KW - Factor XIIa/metabolism

KW - Kininogen, High-Molecular-Weight/metabolism

KW - Prekallikrein/metabolism

KW - Albumins

KW - Glycation End Products, Advanced

U2 - 10.1016/j.jtha.2022.12.015

DO - 10.1016/j.jtha.2022.12.015

M3 - SCORING: Journal article

C2 - 36990522

VL - 21

SP - 814

EP - 827

JO - J THROMB HAEMOST

JF - J THROMB HAEMOST

SN - 1538-7933

IS - 4

ER -