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Antithrombin: News about an Old Molecule
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Antithrombin: News about an Old Molecule

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 10504

Special Issue Editor

Dr. Irene Martínez-Martínez

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Guest Editor
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca. Murcia, Spain
Interests: thrombosis, hemostasis, cancer, antithrombin, serpins

Special Issue Information

Dear Colleagues,

Antithrombin is a key inhibitor of the coagulation cascade. Its deficiency is associated with an increased risk of venous thrombosis and pulmonary thromboembolism. Since 1965, when O. Egeberg diagnosed antithrombin deficiency in a family with a high incidence of venous thromboembolism, knowledge about this protein has increased enormously. Although the characterization of antithrombin deficiency has helped to better understand this protein, there are several aspects that are not yet well characterized. In the last decade, some documents have demonstrated the function of antithrombin beyond hemostasis, demonstrating its function by reducing bacterial and viral infection and inhibiting some deregulated proteases in cancer. On the other hand, antithrombin is a glycoprotein and the relevance of glycosylation in its function has not always been considered. In this special issue, we welcome reviews or experimental articles that show significant advances in characterizing antithrombin function beyond inhibition of coagulation targets and those who consider the influence of glycosylation on antithrombin function.

Dr. Irene Martínez-Martínez
Guest Editor

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Keywords

  • antithrombin
  • glycosylation
  • cancer
  • infection

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Published Papers (3 papers)

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Research

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13 pages, 1722 KiB  
Article
Functional Characterization of Antithrombin Mutations by Monitoring of Thrombin Inhibition Kinetics
by Sara Reda, Jens Müller, Anna Pavlova, Behnaz Pezeshkpoor, Johannes Oldenburg, Bernd Pötzsch and Heiko Rühl
Int. J. Mol. Sci. 2021, 22(4), 2119; https://doi.org/10.3390/ijms22042119 - 20 Feb 2021
Cited by 4 | Viewed by 2195
Abstract
Inactivation of thrombin by the endogenous inhibitor antithrombin (AT) is a central mechanism in the regulation of hemostasis. This makes hereditary AT deficiency, which is caused by SERPINC1 gene mutations, a major thrombophilic risk factor. Aim of this study was to assess to [...] Read more.
Inactivation of thrombin by the endogenous inhibitor antithrombin (AT) is a central mechanism in the regulation of hemostasis. This makes hereditary AT deficiency, which is caused by SERPINC1 gene mutations, a major thrombophilic risk factor. Aim of this study was to assess to what extent AT mutations impair thrombin inhibition kinetics. The study population included 36 thrombophilic patients with 19 different mutations and mean AT levels of 65% in a thrombin-based functional assay, and 26 healthy controls. To assess thrombin inhibition kinetics, thrombin (3.94 mU/mL final concentration) was added to citrated plasma. Subsequently, endogenous thrombin inhibition was stopped by addition of the reversible thrombin inhibitor argatroban and the amount of argatroban-complexed thrombin quantified using an oligonucleotide-based enzyme capture assay. The plasma half-life of human thrombin was significantly longer in patients with AT mutations than in the controls (119.9 versus 55.9 s). Moreover, it was disproportionately prolonged when compared with preparations of wild type AT in plasma, in whom a comparable thrombin half-life of 120.8 s was reached at a distinctly lower AT level of 20%. These findings may help to better understand the increased thrombotic risk of SERPINC1 mutations with near normal AT plasma levels in functional assays. Full article
(This article belongs to the Special Issue Antithrombin: News about an Old Molecule)
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9 pages, 1788 KiB  
Article
Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis
by Toshiaki Iba, Jerrold H. Levy, Koichiro Aihara, Katsuhiko Kadota, Hiroshi Tanaka, Koichi Sato and Isao Nagaoka
Int. J. Mol. Sci. 2021, 22(1), 176; https://doi.org/10.3390/ijms22010176 - 26 Dec 2020
Cited by 15 | Viewed by 2887
Abstract
(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in [...] Read more.
(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy. Full article
(This article belongs to the Special Issue Antithrombin: News about an Old Molecule)
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Review

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13 pages, 761 KiB  
Review
Antithrombin and Its Role in Host Defense and Inflammation
by Christine Schlömmer, Anna Brandtner and Mirjam Bachler
Int. J. Mol. Sci. 2021, 22(8), 4283; https://doi.org/10.3390/ijms22084283 - 20 Apr 2021
Cited by 25 | Viewed by 4983
Abstract
Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic [...] Read more.
Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule. Full article
(This article belongs to the Special Issue Antithrombin: News about an Old Molecule)
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