Mechanism, Functions, and Diagnostic Relevance of FXII Activation by Foreign Surfaces

Konrath, Sandra; Mailer, Reiner K.; Renné, Thomas

doi:10.1055/a-1528-0499

Cited by 11 publications

(9 citation statements)

References 139 publications

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“…Namely, the FXII protein is composed of light and heavy chains. The catalytic domain is located in the light chain, while the heavy chain contains positively charged regions that promote binding to anionic surfaces . We thus propose that AuMBA binding to the heavy chain of FXIIa may induce less perturbation to the active site geometry of FXIIa, compared to Try and Thr, due to the overall size of FXII.…”

Section: Resultsmentioning

confidence: 95%

Time Evolution of Ultrasmall Gold Nanoparticle–Protein Interactions

et al. 2023

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To date, much effort has been devoted toward the study of protein corona formation onto large gold nanoparticles (GNPs). However, the protein corona concept breaks down for GNPs in the ultrasmall size regime (<3 nm), and, as a result, our understanding of ultrasmall GNP (usGNP)–protein interactions remains incomplete. Herein, we used anionic usGNPs and six different proteins as model systems to systematically investigate usGNP–protein interactions, with particular focus on the time evolution and long-term behavior of complex formation. The different proteins comprised chymotrypsin (Cht), trypsin (Try), thrombin (Thr), serum albumin (HSA), cytochrome c (Cyt c), and factor XII (FXII). We used a range of biochemical and biophysical methods to estimate binding affinities, determine the effects of usGNPs on protein structure and function, assess the reversibility of any protein structural and functional changes, and evaluate usGNP–protein complex stability. Among the main findings, we observed that prolonged (24 h)but not short-term (10 min)interactions between proteins and usGNPs permanently altered protein function, including enzyme activities (Try, Thr, and FXIIa), peroxidase-like activity (Cyt c), and ligand-binding properties (HSA). Remarkably, this occurred without any large-scale loss of the native global conformation, implying time-dependent effects of usGNPs on local protein conformation or dynamics. We also found that both short-(10 min) and long-term (24 h) interactions between proteins and usGNPs yielded short-lived complexes, i.e., there was no time-dependent “hardening” of the interactions at the binding interface as usually seen with large GNPs. The present study increases our fundamental understanding of nano-bio interactions in the ultrasmall size regime, which may assist the safe and effective translation of usGNPs into the clinic.

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Section: Resultsmentioning

confidence: 95%

Time Evolution of Ultrasmall Gold Nanoparticle–Protein Interactions

et al. 2023

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“…An uncommon preanalytic factor is FXII deficiency, which causes marked prolongation of both APTT and ACT. The condition does not cause bleeding tendency, but excludes the use of APTT and ACT for heparin therapeutic monitoring in these patients [ 25 ]. Preoperative APTT testing will reveal this condition.…”

Section: Discussionmentioning

confidence: 99%

Laboratory Assessment of Unfractionated Heparin (UFH) with Activated Clotting Time (ACT) and Anti-Xa Activity during Peripheral Arterial Angiographic Procedure

et al. 2023

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Activated clotting time (ACT) is used in cardiac surgery for monitoring unfractionated heparin (UFH). In endovascular radiology, ACT use is less established. We aimed to test the validity of ACT in UFH monitoring in endovascular radiology. We recruited 15 patients undergoing endovascular radiologic procedure. ACT was measured with ICT Hemochron® device as point-of-care (1) before standard UFH bolus, (2) immediately after the bolus, and in some cases (3) 1 h into the procedure or a combination thereof (altogether 32 measurements). A total of two different cuvettes, ACT-LR and ACT+ were tested. A reference method of chromogenic anti-Xa was used. Blood count, APTT, thrombin time and antithrombin activity were also measured. UFH levels (anti-Xa) varied between 0.3–2.1 IU/mL (median 0.8) and correlated with ACT-LR moderately (R2 = 0.73). The corresponding ACT-LR values were 146–337 s (median 214). ACT-LR and ACT+ measurements correlated only modestly with one another at this lower UFH level, with ACT-LR being more sensitive. Thrombin time and APTT were unmeasurably high after the UFH dose, rendering them of limited use in this indication. We adopted an ACT target of >200–250 s in endovascular radiology based on this study. While ACT correlation with anti-Xa is suboptimal, the readily available point-of-care nature increases its suitability.

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“…45 46 While PK and FXI are structurally similar, the latter undergoes reciprocal activation with FXII weakly in solution and is a poor FXIIa substrate in the absence of a surface. 2 3…”

Section: Disease Processes Involving the Kallikrein-kinin Systemmentioning

confidence: 99%

“…4 5 7 While FXII serves a limited role in stemming injury-induced bleeding (hemostasis), it contributes to several host–defense and injury-response pathways, and a variety of pathologic processes. 1 2 8 9 There is particular interest in the protein as a therapeutic target because of its roles in inflammation and thrombosis, and its limited contribution to hemostasis. 10 11 12 13 14 15 In this review, we discuss recent work on the structure and enzymology of FXII that provides insights into mechanisms by which it contributes to thrombo-inflammatory processes.…”

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confidence: 99%

“…

Factor XII (FXII), the precursor of the trypsin-like protease factor XIIa (FXIIa), [1][2][3] was first identified as a blood constituent missing in a few individuals whose plasmas clotted slowly when exposed to Pyrex glass (borosilicate), but that clotted normally on addition of tissue factor. 4,5 The missing entity was originally called Hageman factor after the index case and was subsequently designated FXII in recognition of its presumed importance to blood clotting.

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Factor XII Structure–Function Relationships

Shamanaev

Litvak

Ivanov

et al. 2023

Semin Thromb Hemost

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Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a “closed” form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders.

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Mechanism, Functions, and Diagnostic Relevance of FXII Activation by Foreign Surfaces

Cited by 11 publications

References 139 publications

Time Evolution of Ultrasmall Gold Nanoparticle–Protein Interactions

Time Evolution of Ultrasmall Gold Nanoparticle–Protein Interactions

Laboratory Assessment of Unfractionated Heparin (UFH) with Activated Clotting Time (ACT) and Anti-Xa Activity during Peripheral Arterial Angiographic Procedure

Factor XII Structure–Function Relationships

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