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Molecular Researches in Pro-thrombotic Disorders

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 11035

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Special Issue Editor

Dr. Cristina Barale

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Guest Editor

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Interests: platelets; atherosclerosis; cardiovascular diseases; thrombosis; metabolic syndrome; diabetes; hypercholesterolemia; vascular smooth muscle cells; coagulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular and cerebrovascular diseases, chronic obstructive pulmonary disease, diabetes, and cancer are the leading causes of death worldwide. They share common ground in the form of inflammation that contributes to the onset of a systemic hypercoagulable state, initiating continuous crosstalk between phlogistic and thrombotic processes. In this context, vascular cells such as platelets, endothelial cells, pericytes, and inflammatory cells (i.e., neutrophils, macrophages), interact through a plethora of substances, including cytokines and chemokines that promote a prothrombotic state. The heterogeneous clinical sequelae include myocardial infarction, stroke, venous deep thrombosis and pulmonary embolisms, splanchnic thrombosis, and peripheral arterial disease. These complications worsen the prognosis and increase the mortality of any chronic disease.

This Special Issue welcomes original articles and reviews that contribute to understanding the molecular pathways involved in prothrombotic states; better comprehension of the molecular signaling that underlies such conditions could lead to the identification of new therapeutic mechanisms targets.

Dr. Cristina Barale
Guest Editor

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Keywords

inflammation
thrombosis
hypercoagulable state
coagulation cascade factors
chronic diseases
platelets
platelet activation
endothelial cells
neutrophils
macrophages

Published Papers (6 papers)

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Research

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11 pages, 3050 KiB

Open AccessArticle

Platelet Adhesion Mediated by von Willebrand Factor at High Shear Rates Is Associated with Premature Coronary Artery Disease

by Sergey Okhota, Sergey Kozlov, Yuliya Avtaeva, Ivan Melnikov, Olga Saburova, Konstantin Guria, Evgeny Matroze and Zufar Gabbasov

Biomedicines 2023, 11(7), 1916; https://doi.org/10.3390/biomedicines11071916 - 06 Jul 2023

Viewed by 793

Abstract

This study investigated von Willebrand factor (VWF)-mediated platelet adhesion at high shear rates in patients with premature coronary artery disease (CAD). The study included 84 patients with stable premature CAD and 64 patients without CAD. Whole blood samples were perfused through a microfluidic cell over a collagen-coated surface at a shear rate of 1300 s⁻¹. Measurements were performed before and after the inhibition of VWF-specific platelet GPIb receptors with an anti-GPIb monoclonal antibody (mAb). Platelet adhesion decreased by 77.0% (55.9; 84.7) in patients with premature CAD and by 29.6% (0.0; 59.7) in control patients after the inhibition of VWF–platelet interaction with anti-GPIb mAb (p < 0.001). After adjusting for traditional risk factors, the odds ratio for premature CAD per 1% decrease in GPIb-mediated platelet adhesion was 1.03 (95% CI, 1.02–1.05; p < 0.001). The optimal cut-off level value of GPIb-mediated platelet adhesion was 62.8%, with 70.2% sensitivity and 81.2% specificity for CAD. The plasma levels of VWF or antiplatelet therapy did not affect the GPIb-mediated component of platelet adhesion. Thus, the GPIb-mediated component of platelet adhesion was more pronounced in patients with premature CAD. This may indicate the possible role of excessive VWF–platelet interactions in the development of premature CAD. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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12 pages, 2297 KiB

Open AccessArticle

Hemostasis System and Plasminogen Activity in Retrochorial Hematoma in the First Trimester of Pregnancy

by Natalia B. Tikhonova, Natalya B. Kuznetsova, Andrey P. Milovanov, Eugene I. Goufman, Tatiana V. Fokina, Andrey P. Aleksankin, Valentina V. Aleksankina, Irina I. Stepanova, Alexandr A. Stepanov, Marina N. Boltovskaya and Natalia V. Nizyaeva

Biomedicines 2022, 10(9), 2284; https://doi.org/10.3390/biomedicines10092284 - 14 Sep 2022

Viewed by 1484

Abstract

(1) Background: The components of the fibrinolytic system and its main component, plasminogen, play a key role in the first months of pregnancy. The effect of autoantibodies interacting with plasminogen in the formation of retrochorial hematoma is unknown. The aim of our study was to determine the role of plasminogen and IgA, IgM, and IgG, which bind to plasminogen, in retrochorial hematoma. (2) Methods: Prothrombin time (PT), thrombin time (TT), partial activated thromboplastin time (aPTT), soluble fibrin-monomer complex (SFMC), D-dimer, plasminogen activity (%Plg), plasminogen concentration (Plg), and the levels of IgG (IgG-Plg), IgM (IgM-Plg), IgA (IgA-Plg) interacting with plasminogen were determined in plasma samples of 57 women with normal pregnancy and 16 with retrochorial hematoma. (3) Results: %Plg in plasma samples from women with retrochorial hematoma was significantly lower than in plasma samples from women with normal pregnancy. The diagnostic significance of %Plg in the ROC analysis was AUC = 0.85. A direct correlation was found between aPTT and the level of autologous IgM interacting with plasminogen. (4) Conclusions: A decrease in the activity of plasminogen in the blood serum of women in the first trimester of pregnancy may indicate disturbances in the hemostasis system and the formation of retrochorial hematoma. According to the results of the study, it is possible to recommend the determination of plasminogen activity in the management of pregnant women in gynecological practice. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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11 pages, 996 KiB

Open AccessArticle

Circulating Microvesicles in Association with the NLRP3 Inflammasome in Coronary Thrombi from STEMI Patients

by Vibeke Bratseth, Jostein Nordeng, Ragnhild Helseth, Svein Solheim, Sissel Åkra, Harald Arnesen, Gemma Chiva-Blanch and Ingebjørg Seljeflot

Biomedicines 2022, 10(9), 2196; https://doi.org/10.3390/biomedicines10092196 - 05 Sep 2022

Viewed by 1537

Abstract

Microvesicles (MVs) are actively secreted by cells. The NLRP3-inflammasome and the interleukin 6 (IL-6)-pathways are central in cardiovascular disease. Knowledge of how the inflammasome influences the MVs is limited. In a cross-sectional study, we assessed whether MVs in plasma associate with genes encoding inflammasome signalling in coronary thrombi. Moreover, any relationships between inflammasome activation and phosphatidylserine (PS) externalization, determined through Annexin V (AV⁺) labelling, and myocardial injury, assessed by cardiac troponin T (cTnT), were analysed. Intracoronary thrombi and blood samples from STEMI patients (n = 33) were investigated. mRNA of NLRP3, caspase-1, interleukin-1β (IL-1β), interleukin-18 (IL-18), IL-6, soluble IL-6-receptor (sIL-6R), and glycoprotein-130 (gp130) were isolated from the thrombi and relatively quantified by RT-PCR. MVs were analysed by flow cytometry. Total AV⁺ MVs, mainly reflecting hypercoagulability, correlated positively to NLRP3 gene expression (r = 0.545, p = 0.009). A similar pattern was seen for platelet, endothelial and leukocyte derived MVs, separately. The majority of the MVs were AV⁻ (96%). Total and AV⁻ MVs correlated inversely with IL-1β (r = −0.399 and −0.438, respectively, p < 0.05, both) and gp130 (r = −0.457 and −0.502, respectively, p < 0.05, both). No correlations between MVs and cTnT were observed. Our findings indicate an association between NLRP3-inflammasome in coronary thrombi and procoagulant AV⁺ MVs in STEMI patients. The inverse relationships between AV⁻ MVs and the gene expression of inflammasome activation may indicate an immuno-dampening role of this subpopulation. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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19 pages, 4224 KiB

Open AccessArticle

Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients

by Michael Hultström, Karin Fromell, Anders Larsson, Barbro Persson, Bo Nilsson, Susan E. Quaggin, Christer Betsholtz, Robert Frithiof, Miklos Lipcsey and Marie Jeansson

Biomedicines 2022, 10(6), 1333; https://doi.org/10.3390/biomedicines10061333 - 06 Jun 2022

Cited by 10 | Viewed by 2798

Abstract

Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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Review

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35 pages, 5286 KiB

Open AccessReview

Fibrinaloid Microclots and Atrial Fibrillation

by Douglas B. Kell, Gregory Y. H. Lip and Etheresia Pretorius

Biomedicines 2024, 12(4), 891; https://doi.org/10.3390/biomedicines12040891 - 17 Apr 2024

Viewed by 606

Abstract

Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known consequence of atrial fibrillation. We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known ‘risk factors’ for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF. Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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23 pages, 2692 KiB

Open AccessReview

Association between COVID-19 Diagnosis and Coronary Artery Thrombosis: A Narrative Review

by Francesco Nappi, Omar Giacinto, Omar Ellouze, Antonio Nenna, Sanjeet Singh Avtaar Singh, Massimo Chello, Assine Bouzguenda and Xavier Copie

Biomedicines 2022, 10(3), 702; https://doi.org/10.3390/biomedicines10030702 - 18 Mar 2022

Cited by 13 | Viewed by 2843

Abstract

Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The aim of this review is to assess the association between COVID-19 and its thrombotic complications, specifically related to the cardiovascular system. The role of neutrophil extracellular traps (NETs) is explored in the pathogenesis of the disease. The structure and anatomy of the virus are pivotal to its virulence in comparison to other α and β Coronaviridae (HCoV-229E, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1). In particular, the host interaction and response may explain the variability of severity in patients. Angio tensin-converting enzyme 2 (ACE2) activation may be implicated in the cardiovascular and throm bogenic potential of the disease. The virus may also have direct effects on the endothelial lining affecting hemostasis and resulting in thrombosis through several mechanisms. Dipyridamole may have a therapeutic benefit in NET suppression. Therapeutic avenues should be concentrated on the different pathophysiological steps involving the virus and the host. Full article

(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)

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