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Thrombosis and Metabolism

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (1 December 2021) | Viewed by 28965

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Special Issue Editors

Prof. Dr. Jan E. Dyr †

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Guest Editor

Institute of Hematology and Blood Transfusion, Prague, Czech Republic
Interests: posttranslation modification of proteins; oxidative changes in hematological disorders; analysis of vein and arterial thrombosis; oxidative changes in fibrinogen to fibrin conversion; fibrin degradation products; proteomics; interactomics; and metabolomics; in silico methods in the field of thrombosis and hemostasis; optical methods – surface plasmon resonance; advanced image analysis

Dr. Martin Maly

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Guest Editor

Department of Medicine, First Faculty of Medicine, Charles University in Prague and the Military University Hospital, 16902 Prague, Czech Republic
Interests: interventional cardiology; acute coronary syndromes; arterial thrombosis; vessel wall biology

Special Issue Information

Dear Colleagues,

This Special Issue highlights the use of metabolomics in the field of thrombosis. Metabolomics data-analytical approaches are developing with accelerating speed, alongside technical improvements in instrumentation in the field. Thrombosis in the arterial bed leads to its obstruction and subsequent clinical manifestation as an acute atherothrombotic syndrome, where the most catastrophic are acute myocardial infarction and acute stroke. These two entities are the leading cause of mortality and morbidity in high-income countries. That is why research in this area is very important. Deep vein thrombosis (DVT) and pulmonary embolism have high morbidity, reduce quality of life, and can cause death. Only a few biomarkers or genetic risk factors have been identified so far in patients with DVT.

Specific areas for the Special Issue include but are not limited to changes in metabolic pathways, including carbohydrate metabolism, lipid metabolism, and thrombosis-induced amino acid metabolism; metabolomic changes in thrombus onset, growth and termination; analysis of thrombus composition, changes in fibrinogen to fibrin conversion, and fibrin degradation products; metabolomics of microbiome leading to thrombosis; analysis of thrombogenesis steps, markers of oxidative stress, inflammation; lipid analysis using state-of-the-art molecular methods, such as lipidomics and metabolomics, in association with clinical thrombotic syndromes; and thrombosis and metabolomics associated with cancer.

We invite review and viewpoint manuscripts devoted to various aspects within metabolite profiling. We also invite manuscripts with innovative and integrative solutions applicable in the near future. Reports of altered metabolomics pathways related to thrombosis and genetics providing the basis for undersanding the pathological mechanism and new pharmacological targets of thrombosis. The Special Issue is open for submission now, though a proper extension may be granted if you can kindly let us know in advance. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the Special Issue website.

Prof. Dr. Jan E. Dyr
Dr. Martin Maly
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Thrombosis and metabolism
Metabolic biomarkers of thrombosis
Oxidative stress
Reactive oxygen species
Nitrative stress
Reactive nitrogen species
Thrombus initiation, growth, and termination
Vein and arterial thrombosis
Cancer and thrombosis

Published Papers (11 papers)

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Research

Jump to: Review, Other

9 pages, 1286 KiB

Open AccessArticle

Long-Term Effects on the Lipidome of Acute Coronary Syndrome Patients

by Vít Kosek, Martin Hajšl, Kamila Bechyňská, Ondřej Kučerka, Jiří Suttnar, Alžběta Hlaváčková, Jana Hajšlová and Martin Malý

Metabolites 2022, 12(2), 124; https://doi.org/10.3390/metabo12020124 - 27 Jan 2022

Cited by 3 | Viewed by 2034

Abstract

Lipids modified by oxidative stress are key players in atherosclerosis progression. Superimposed thrombosis with subsequent closure of the coronary artery leads to the clinical manifestation of acute coronary syndrome (ACS). While several studies focusing on alterations in lipid metabolism in the acute phase have been conducted, no information is available on patients’ lipidome alterations over longer time periods. In the current follow-up study, we analyzed plasma samples obtained from 17 patients three years after their ACS event (group AC). Originally, these patients were sampled 3–5 days after an index event (group B). Lipidome stability over time was studied by untargeted lipidomics using high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC–HRMS). Multi-dimensional statistics used for data processing indicated that plasmalogen lipids were the most prominent lipids separating the above patient groups and that they increased in the follow-up AC group. A similar trend was observed for lysophosphatidylethanolamine (LPE) and phosphatidylethanolamine (PE). The opposite trend was observed for two fatty acyls of hydroxy fatty acid (FAHFAs) lipids and free stearic acid. In addition, a decrease in the “classic” oxitadive stress marker, malondialdehyde (MDA), occurred during the follow-up period. Our findings present unique information about long-term lipidome changes in patients after ACS. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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12 pages, 3532 KiB

Open AccessArticle

CD74 in Apoptotic Macrophages Is Associated with Inflammation, Plaque Progression and Clinical Manifestations in Human Atherosclerotic Lesions

by Wei Li, Nargis Sultana, Linda Yuan, Claes Forssell and Xi-Ming Yuan

Metabolites 2022, 12(1), 54; https://doi.org/10.3390/metabo12010054 - 10 Jan 2022

Cited by 8 | Viewed by 2546

Abstract

The aim of this study was to investigate whether CD74 levels in atherosclerotic lesions are associated with inflammation, apoptosis, plaque severity, and clinical symptoms among patients with carotid atherosclerosis. We further studied whether CD74 expression is associated with apoptosis in macrophages induced by 7ketocholesterol (7keto). Sixty-one carotid samples (39 males and 22 females) were immunostained with macrophages, smooth muscle cells, CD74, ferritin, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling), and thrombin receptors. Double immunocytochemistry of CD74 and caspase 3 or CD74 and Annexin V was performed on THP-1 macrophages exposed to 7keto. In human carotid plaques, CD74 expression is lesion-dependently increased and is associated with necrotic core formation and plaque rupture, clinical symptoms, macrophage apoptosis, ferritin, and thrombin receptors. CD74 levels were inversely correlated to high-density lipoproteins and statin treatment, and positively correlated to triglycerides. In THP-1 macrophages, 7keto induced a significant increase in levels of CD74, ferritin, and apoptotic cell death. This study suggests that CD74 in apoptotic macrophages is linked to inflammation and thrombosis in progression of human atherosclerotic plaques, lipid metabolism, and clinical manifestation in atherosclerosis. Surface CD74 in apoptotic macrophages and ferritin production induced by oxidized lipids may contribute to inflammation and plaque vulnerability in atherosclerosis. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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17 pages, 3622 KiB

Open AccessArticle

Serum Metabolic Profiles Based on Nuclear Magnetic Resonance Spectroscopy among Patients with Deep Vein Thrombosis and Healthy Controls

by Melissa Quintero Escobar, Ljubica Tasic, Tassia Brena Barroso Carneiro da Costa, Danijela Stanisic, Silmara Montalvão, Stephany Huber and Joyce Maria Annichino-Bizzacchi

Metabolites 2021, 11(12), 874; https://doi.org/10.3390/metabo11120874 - 16 Dec 2021

Cited by 6 | Viewed by 2583

Abstract

Deep venous thrombosis (DVT) is associated with significant morbidity and mortality. Studies on changes in the level of metabolites could have the potential to reveal biomarkers that can assist in the early detection, diagnosis, monitoring of DVT progression, response to treatment, or recurrence of DVT. In this scenario, the metabolomic analysis can provide a better understanding of the biochemical dysregulations of thrombosis. Using an untargeted metabolomic approach through magnetic resonance spectroscopy and multi- and univariate statistical analysis, we compared 40 patients with previous venous thrombosis and 40 healthy individuals, and we showed important serum differences between patients and controls, especially in the spectral regions that correspond to glucose, lipids, unsaturated lipids, and glycoprotein A. Considering the groups depending on risk factors and the local of the previous episode (lower limbs or cerebral system), we also noticed differences in metabolites linked to lipids and lactate. Comparative analyses pointed to altered ratios of glucose/lactate and branched-chain amino acids (BCAAs)/alanine, which might be associated with the fingerprints of thrombosis. Although samples for metabolomic analysis were collected months after the acute episode, these results highlighted that, alterations can still remain and may contribute to a better understanding of the complications of the disease. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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14 pages, 4165 KiB

Open AccessEditor’s ChoiceArticle

Lipidomic Analysis to Assess Oxidative Stress in Acute Coronary Syndrome and Acute Stroke Patients

by Martin Malý, Martin Hajšl, Kamila Bechyňská, Ondřej Kučerka, Martin Šrámek, Jiří Suttnar, Alžběta Hlaváčková, Jana Hajšlová and Vít Kosek

Metabolites 2021, 11(7), 412; https://doi.org/10.3390/metabo11070412 - 23 Jun 2021

Cited by 11 | Viewed by 2755

Abstract

Alterations in lipid metabolism mediated by oxidative stress play a key role in the process of atherosclerosis and superimposed thrombosis; these can lead to acute coronary syndrome (ACS) and acute ischemic stroke (AIS). Multiple studies have shown that the formation of atheromatous lesions is initiated by oxidation of low-density lipoproteins incorporated into the intima of the vessel wall. Here, we studied lipids in plasma samples from three cohorts: 61 patients with ACS (group A), 49 patients with AIS (group D), and 82 controls (group K). Untargeted lipidomics based on high-performance liquid chromatography coupled to mass spectrometry (UHPLC-HRMS) was employed to obtain comprehensive information on whether relationships exist between these patient categories based on lipid patterns. In addition, malondialdehyde (MDA) as a standard marker of oxidative stress was monitored. The most characteristic lipids in group K were fatty acyls of hydroxyfatty acids (FAHFAs). As expected, MDA concentrations were the lowest in group K. Our findings can better explain ongoing pathologies, both acute and chronic, with the potential for future diagnosis and treatment. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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14 pages, 2309 KiB

Open AccessArticle

Effects of Hyperhomocysteinemia on the Platelet-Driven Contraction of Blood Clots

by Rustem I. Litvinov, Alina D. Peshkova, Giang Le Minh, Nail N. Khaertdinov, Natalia G. Evtugina, Guzel F. Sitdikova and John W. Weisel

Metabolites 2021, 11(6), 354; https://doi.org/10.3390/metabo11060354 - 01 Jun 2021

Cited by 7 | Viewed by 2825

Abstract

Hyperhomocysteinemia (HHcy) is associated with thrombosis, but the mechanistic links between them are not understood. We studied effects of homocysteine (Hcy) on clot contraction in vitro and in a rat model of HHcy. Incubation of blood with exogenous Hcy for 1 min enhanced clot contraction, while 15-min incubation led to a dose-dependent suppression of contraction. These effects were likely due to direct Hcy-induced platelet activation followed by exhaustion, as revealed by an increase in fibrinogen-binding capacity and P-selectin expression determined by flow cytometry. In the blood of rats with HHcy, clot contraction was enhanced at moderately elevated Hcy levels (10–50 μM), while at higher Hcy levels (>50 μM), the onset of clot contraction was delayed. HHcy was associated with thrombocytosis combined with a reduced erythrocyte count and hypofibrinogenemia. These data suggest that in HHcy, platelets get activated directly and indirectly, leading to enhanced clot contraction that is facilitated by the reduced content and resilience of fibrin and erythrocytes in the clot. The excessive platelet activation can lead to exhaustion and impaired contractility, which makes clots larger and more obstructive. In conclusion, HHcy modulates blood clot contraction, which may comprise an underappreciated pro- or antithrombotic mechanism. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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15 pages, 19039 KiB

Open AccessArticle

Molecular Dynamic Simulations Suggest That Metabolite-Induced Post-Translational Modifications Alter the Behavior of the Fibrinogen Coiled-Coil Domain

by Zofie Sovova, Jiri Suttnar and Jan E. Dyr

Metabolites 2021, 11(5), 307; https://doi.org/10.3390/metabo11050307 - 11 May 2021

Cited by 3 | Viewed by 2095

Abstract

Fibrinogen is an abundant blood plasma protein that, inter alia, participates in blood coagulation. It polymerizes to form a fibrin clot that is among the major components of the thrombus. Fibrinogen reactions with various reactive metabolites may induce post-translational modifications (PTMs) into the protein structure that affect the architecture and properties of fibrin clots. We reviewed the previous literature to find the positions of PTMs of fibrinogen. For 7 out of 307 reported PTMs, we used molecular dynamics simulations to characterize their effect on the behavior of the fibrinogen coiled-coil domain. Interactions of the γ-coil with adjacent chains give rise to π-helices in Aα and Bβ chains of even unmodified fibrinogen. The examined PTMs suppress fluctuations of the γ-coil, which may affect the fibrinolysis and stiffness of the fibrin fibers. Citrullination of AαR104 and oxidations of γP70 and γP76 to glutamic semialdehyde unfold the α-helical structure of Aα and Bβ chains. Oxidation of γM78 to methionine sulfoxide induces the formation of an α-helix in the γ-coil region. Our findings suggest that certain PTMs alter the protein secondary structure. Thus, the altered protein structure may indicate the presence of PTMs in the molecule and consequently of certain metabolites within the system. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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12 pages, 2327 KiB

Open AccessArticle

Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms Associated with Cardiovascular Risk Factors Involved in Cerebral Venous Sinus Thrombosis

by Anca Elena Gogu, Andrei Gheorghe Motoc, Alina Zorina Stroe, Any Docu Axelerad, Daniel Docu Axelerad, Ligia Petrica and Dragos Catalin Jianu

Metabolites 2021, 11(5), 266; https://doi.org/10.3390/metabo11050266 - 23 Apr 2021

Cited by 9 | Viewed by 2850

Abstract

Cerebral venous sinus thrombosis (CVST), accounting for less than 1% of stroke cases, is characterized by various causes, heterogeneous clinical presentation and different outcome. The plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms has been found to be associated with CVST. The aim of this retrospective study was to determine the potential association of PAI-1 675 4G/5G polymorphisms and homocysteine levels with cardiovascular risk factors in a group of young patients with CVST. Eighty patients with CVST and an equal number of age and sex matched controls were enrolled. The protocol included demographic and clinical baseline characteristics, neuroimagistic aspects, genetic testing (PAI-1 675 4G/5G polymorphisms), biochemical evaluation (homocysteine—tHcy, the lipid profile, blood glucose, glycohemoglobin—HbA1c, high-sensitive C-reactive protein—hsCRP) data, therapy and prognosis. The PAI-1 675 4G/5G gene polymorphisms were significantly correlated with increased homocysteine level (tHcy) (p < 0.05), higher total cholesterol (TC) (p < 0.05), low- density lipoprotein cholesterol (LDLc) (p = 0.05) and high- sensitive C- reactive protein (hsCRP) (p < 0.05) in patients with CVST when compared with controls. From the PAI-1 gene polymorphisms, the PAI-1 675 4G/5G genotype presented statistically significant values regarding the comparisons of the blood lipids values between the CVST group and control group. The homocysteine (tHcy) was increased in both groups, patients versus controls, in cases with the homozygous variant 4G/4G but the level was much higher in the group with CVST (50.56 µmol/L vs. 20.22 µmol/L; p = 0.03). The most common clinical presentation was headache (91.25%), followed by seizures (43.75%) and focal motor deficits (37.5%). The superior sagittal sinus (SSS) was the most commonly involved dural sinus (56.25%), followed by the lateral sinus (LS) (28.75%). Intima—media thickness (IMT) values were higher in the patients’ group with CVST (0.95 mm vs. 0.88 mm; p < 0.05). The fatal outcome occurred 2.5% of the time. PAI-1 675 4G/5G gene polymorphisms and higher homocysteine concentrations were found to be significantly associated with CVST in young patients. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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17 pages, 4567 KiB

Open AccessArticle

LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion—An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-¹³C]Pyruvate

by Gal Sapir, David Shaul, Naama Lev-Cohain, Jacob Sosna, Moshe J. Gomori and Rachel Katz-Brull

Metabolites 2021, 11(4), 210; https://doi.org/10.3390/metabo11040210 - 30 Mar 2021

Cited by 6 | Viewed by 2033

Abstract

Ischemic stroke is a leading cause for neurologic disability worldwide, for which reperfusion is the only available treatment. Neuroimaging in stroke guides treatment, and therefore determines the clinical outcome. However, there are currently no imaging biomarkers for the status of the ischemic brain tissue. Such biomarkers could potentially be useful for guiding treatment in patients presenting with ischemic stroke. Hyperpolarized ¹³C MR of [1-¹³C]pyruvate is a clinically translatable method used to characterize tissue metabolism non-invasively in a relevant timescale. The aim of this study was to utilize hyperpolarized [1-¹³C]pyruvate to investigate the metabolic consequences of an ischemic insult immediately during reperfusion and upon recovery of the brain tissue. The rates of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) were quantified by monitoring the rates of [1-¹³C]lactate and [¹³C]bicarbonate production from hyperpolarized [1-¹³C]pyruvate. ³¹P NMR of the perfused brain slices showed that this system is suitable for studying ischemia and recovery following reperfusion. This was indicated by the levels of the high-energy phosphates (tissue viability) and the chemical shift of the inorganic phosphate signal (tissue pH). Acidification, which was observed during the ischemic insult, has returned to baseline level following reperfusion. The LDH/PDH activity ratio increased following ischemia, from 47.0 ± 12.7 in the control group (n = 6) to 217.4 ± 121.3 in the ischemia-reperfusion group (n = 6). Following the recovery period (ca. 1.5 h), this value had returned to its pre-ischemia (baseline) level, suggesting the LDH/PDH enzyme activity ratio may be used as a potential indicator for the status of the ischemic and recovering brain. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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Review

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18 pages, 602 KiB

Open AccessReview

Metabolomic Profile in Venous Thromboembolism (VTE)

by Beata Franczyk, Anna Gluba-Brzózka, Janusz Ławiński, Magdalena Rysz-Górzyńska and Jacek Rysz

Metabolites 2021, 11(8), 495; https://doi.org/10.3390/metabo11080495 - 29 Jul 2021

Cited by 12 | Viewed by 3015

Abstract

Venous thromboembolism (VTE) is a condition comprising deep venous thrombosis (DVT) and pulmonary embolism (PE). The prevalence of this disease is constantly increasing and it is also a chief reason for morbidity. Therefore, the primary prevention of VTE remains a highly important public health issue. At present, its diagnosis generally relies on subjective clinical examination and ultrasound imaging. D-dimer is also used as a biomarker, but it is considered to be poorly specific and only moderately sensitive. There are also no reliable methods that could accurately guide the type of treatment and potentially identify patients who may benefit from more aggressive therapies without the risk of bleeding. The application of metabolomics profiling in the area of vascular diseases may become a turning point in early diagnosis and patient management. Among the most described metabolites possibly related to VTE are carnitine species, glucose, phenylalanine, 3-hydroxybutarate, lactic acid, tryptophan and some monounsaturated and polyunsaturated fatty acids. The cell response to acute PE was suggested to involve the uncoupling between glycolysis and oxidative phosphorylation. Despite technological advancement in the identification of metabolites and their alteration in thrombosis, we still do not understand the mechanisms and pathways responsible for the occurrence of observed alterations. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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26 pages, 1764 KiB

Open AccessEditor’s ChoiceReview

Thromboembolic Complications of SARS-CoV-2 and Metabolic Derangements: Suggestions from Clinical Practice Evidence to Causative Agents

by Francesco Nappi, Adelaide Iervolino and Sanjeet Singh Avtaar Singh

Metabolites 2021, 11(6), 341; https://doi.org/10.3390/metabo11060341 - 25 May 2021

Cited by 11 | Viewed by 3582

Abstract

Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a recently identified positive sense single-strand RNA (ssRNA) β-coronavirus. The viral spike proteins infect human hosts by binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2). The infection causes a systemic illness involving cell metabolism. This widespread involvement is implicated in the pathophysiology of the illness which ranges from mild to severe, requiring multi organ support, ranging from oxygen supplementation to full cardiovascular and respiratory support. Patients with multiple co-existing comorbidities are also at a higher risk. The aim of this review is to explore the exact mechanisms by which COVID-19 affects patients systemically with a primary focus on the bleeding and thrombotic complications linked with the disease. Issues surrounding the thrombotic complications following administration of the ChAdOx1 nCoV-19 (Astra-Zeneca-Oxford) vaccine have also been illustrated. Risk stratification and treatment options in these patients should be tailored according to clinical severity with input from a multidisciplinary team. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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