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鉴定凝血因子 XII 的接触激活位点可实现灵敏的凝血诊断。

Identification of the factor XII contact activation site enables sensitive coagulation diagnostics.

机构信息

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.

出版信息

Nat Commun. 2021 Sep 22;12(1):5596. doi: 10.1038/s41467-021-25888-7.

DOI:10.1038/s41467-021-25888-7
PMID:34552086
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8458485/
Abstract

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.

摘要

接触激活是指表面诱导的因子 XII（FXII）活化过程，它启动血液凝固，并被活化部分凝血活酶时间（aPTT）测定法捕获。在这里，我们展示了 FXII 接触激活的机制和诊断意义。对重组 FXII 突变体的筛选确定了一个连续的残基 Gln317-Ser339 区域，该区域对于 FXII 表面结合和激活、凝血酶生成和凝血至关重要。跨越这些 23 个残基的肽与表面诱导的 FXII 激活竞争。尽管缺乏残基 Gln317-Ser339 的 FXII 突变体容易被纤溶酶和血浆激肽释放酶激活，但它们在支持小鼠动脉和静脉血栓形成方面无效。针对 Gln317-Ser339 区域的抗体诱导 FXII 活化，并在溶液中引发可控的接触激活，导致凝血的内在途径生成凝血酶。抗体激活的 aPTT 可实现颗粒 aPTT 试剂的标准化，并灵敏监测凝血因子 VIII、IX、XI。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/524fe2dee0ac/41467_2021_25888_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/c97c3dc8279e/41467_2021_25888_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/a093a92922ac/41467_2021_25888_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/6ae328bf9532/41467_2021_25888_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/898af78059f8/41467_2021_25888_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/bfc00b158a76/41467_2021_25888_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/40a2ade2c2c3/41467_2021_25888_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/2717c0b1ecb4/41467_2021_25888_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/524fe2dee0ac/41467_2021_25888_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/c97c3dc8279e/41467_2021_25888_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/a093a92922ac/41467_2021_25888_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/6ae328bf9532/41467_2021_25888_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/898af78059f8/41467_2021_25888_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/bfc00b158a76/41467_2021_25888_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/40a2ade2c2c3/41467_2021_25888_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/2717c0b1ecb4/41467_2021_25888_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c634/8458485/524fe2dee0ac/41467_2021_25888_Fig8_HTML.jpg

相似文献

[1]
Identification of the factor XII contact activation site enables sensitive coagulation diagnostics.

Nat Commun. 2021-9-22

[2]
Factor XII truncation accelerates activation in solution.

J Thromb Haemost. 2018-12-10

[3]
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J Thromb Haemost. 2013-7

[4]
Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo.

Arterioscler Thromb Vasc Biol. 2018-8

[5]
Immobilized transition metal ions stimulate contact activation and drive factor XII-mediated coagulation.

J Thromb Haemost. 2012-10

[6]
Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates.

J Thromb Haemost. 2013-7

[7]
The second exon-encoded factor XII region is involved in the interaction of factor XII with factor XI and does not contribute to the binding site for negatively charged surfaces.

Blood. 1998-12-1

[8]
Factor XII inhibition reduces thrombus formation in a primate thrombosis model.

Blood. 2014-1-9

[9]
Identification of a putative binding site for negatively charged surfaces in the fibronectin type II domain of human factor XII--an immunochemical and homology modeling approach.

Thromb Haemost. 2000-12

[10]
Factor XII regulates the pathological process of thrombus formation on ruptured plaques.

Arterioscler Thromb Vasc Biol. 2014-5-22

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A brief comparison of human factor XII-Ala and factor XII-Pro.

Res Pract Thromb Haemost. 2025-7-16

[2]
Crystal structure of coagulation factor XII N-terminal domains 1-5.

Acta Crystallogr D Struct Biol. 2025-7-1

[3]
Advancements in research on the thrombo-inflammation mechanisms mediated by factor XII in ischemic stroke.

J Thromb Thrombolysis. 2025-4-26

[4]
Improvement in XIa Selectivity of Snake Venom Peptide Analogue BF9-N17K Using P2' Amino Acid Replacements.

Toxins (Basel). 2025-1-5

[5]
Antithrombotic coating with sheltered positive charges prevents contact activation by controlling factor XII-biointerface binding.

Nat Mater. 2025-4

[6]
A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation.

Nat Commun. 2024-9-12

[7]
Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease.

Nat Commun. 2024-9-11

[8]
Magnetic coagulometry: towards a new nanotechnological tool for monitoring coagulation in human whole blood.

Nanoscale. 2024-2-15

[9]
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Int J Implant Dent. 2023-11-17

[10]
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本文引用的文献

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Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.

EBioMedicine. 2021-5

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Polyanions in Coagulation and Thrombosis: Focus on Polyphosphate and Neutrophils Extracellular Traps.

Thromb Haemost. 2021-8

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Orphanet J Rare Dis. 2020-10-9

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Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate.

Blood. 2021-3-11

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Thromb Haemost. 2020-1-15

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J Biol Chem. 2020-1-10

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Front Immunol. 2019-8-22

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Semin Thromb Hemost. 2019-1-10

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A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain.

Blood. 2018-12-27

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