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Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 10709

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Prof. Tami Livnat

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Guest Editor

1. Director, Amalia Biron Research Institute of Thrombosis and Hemostasis, Faculty of Medical and Health Sciences, Tel-Aviv University Sheba Medical Center, Tel Hashomer 52621, Israel
2. Rabin Medical Centre, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Centre, Petah-Tikva 49100, Israel
Interests: procoagulant factors; anticoagulant factors; hemostasis; neuroprotection; ocular diseases
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Dr. Rima Dardik

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Guest Editor

National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
Interests: procoagulant factors; anticoagulant factors; hemostasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Normal hemostasis is highly dependent on the balance between procoagulant systems (e.g., platelets and procoagulant factors) and anticoagulant systems (e.g., protein C, protein S and antithrombin). The lack or dysfunction of a major procoagulant factor results in a bleeding disorder (e.g., factor VIII deficiency leading to hemophilia A), whereas a defect in an essential anticoagulant system (e.g. protein C deficiency) leads to a thrombotic disorder. Beyond their function in hemostasis, cell signaling pathways that are induced by procoagulant (e.g., thrombin and FVII) and anticoagulant factors (e.g., APC), mediated by specific receptors, have become the focus of increasing attention, with some of them being explored as promising therapeutic targets.

This Special Issue will focus on the genetic, functional and therapeutic aspects of procoagulant and anticoagulant systems. We invite research studies and reviews on the genetics of bleeding and thrombotic disorders annd functional and therapeutic studies of procoagulant and anticoagulant factors, as well as studies that explore their involvement in the crosstalk between hemostasis and inflammation.

Prof. Tami Livnat
Dr. Rima Dardik
Guest Editors

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Keywords

procoagulant factors
anticoagulant factors
hemostasis
inflammation
genetics
therapeutics
cell signaling

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Published Papers (8 papers)

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Research

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11 pages, 2670 KiB

Open AccessArticle

A Novel Murine Model Enabling rAAV8-PC Gene Therapy for Severe Protein C Deficiency

by Sarina Levy-Mendelovich, Einat Avishai, Benjamin J. Samelson-Jones, Rima Dardik, Tami Brutman-Barazani, Yael Nisgav, Tami Livnat and Gili Kenet

Int. J. Mol. Sci. 2024, 25(19), 10336; https://doi.org/10.3390/ijms251910336 - 26 Sep 2024

Viewed by 992

Abstract

Severe protein C deficiency (SPCD) is a rare inherited thrombotic disease associated with high morbidity and mortality. In the current study, we established a viable murine model of SPCD, enabling preclinical gene therapy studies. By creating SPCD mice with severe hemophilia A (PROC^−/−/F8⁻), the multi-month survival of SPCD mice enabled the exploration of recombinant adeno-associated viral vector-PC (rAAV8-PC) gene therapy (GT). rAAV8- PC (10¹² vg/kg of AAV8-PC) was injected via the tail vein into 6–8-week-old PROC^−/−/F8^- mice. Their plasma PC antigen levels (median of 714 ng/mL, range 166–2488 ng/mL) and activity (303.5 ± 59%) significantly increased to the normal range after GT compared to untreated control animals. PC’s presence in the liver after GT was also confirmed by immunofluorescence staining. Our translational research results provide the first proof of concept that an infusion of rAAV8-PC increases PC antigen and activity in mice and may contribute to future GT in SPCD. Further basic research of SPCD mice with prolonged survival due to the rebalancing of this disorder using severe hemophilia A may provide essential data regarding PC’s contribution to specific tissues’ development, local PC generation, and its regulation in inflammatory conditions. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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11 pages, 591 KiB

Open AccessArticle

Neutrophil Extracellular Trap Formation in Advanced Heart Failure Patients—Preliminary Report

by Tomasz Urbanowicz, Anna Olasińska-Wiśniewska, Ewelina Wojtasińska, Krzysztof J. Filipiak, Małgorzata Tomaszewska, Jędrzej Sikora, Marta Krama, Zofia Radek, Kajetan Grodecki, Aleksandra Krasińska-Płachta, Beata Krasińska, Zbigniew Krasiński, Andrzej Tykarski, Marek Jemielity and Joanna Rupa-Matysek

Int. J. Mol. Sci. 2024, 25(17), 9633; https://doi.org/10.3390/ijms25179633 - 5 Sep 2024

Viewed by 745

Abstract

In end-stage heart failure, which is characterized by persistent or progressive ventricular dysfunction despite optimal medical therapy, a left ventricular assist device (LVAD) can be beneficial. Congestive heart failure provokes inflammatory and prothrombotic activation. The aim of this study was to evaluate the serum concentration of citrullinated histone 3 (CH3) representing neutrophil extracellular trap (NET) formation in patients referred for LVAD implantation. There were 10 patients with a median age of 61 (57–65) years enrolled in a prospective single-center analysis who underwent LVAD implantation. The CH3 plasma concentration was measured preoperatively and on the 1st and 7th postoperative days, followed by control measurements on the median (Q1–3) 88th (49–143) day. The preoperative CH3 concentration strongly correlated with brain natriuretic peptide (r = 0.879, p < 0.001). Significant differences in CH3 serum concentration were observed between pre- and postoperative measurements, including an increase on the first postoperative day (p < 0.001), as well as a decrease on the seventh day (p = 0.016) and in follow-up (p < 0.001). CH3 concentration, as a marker of NET formation, decreases after LVAD implantation. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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14 pages, 758 KiB

Open AccessArticle

Association of Thymidylate Synthase (TS) Gene Polymorphisms with Incidence and Prognosis of Coronary Artery Disease

by Jung Oh Kim, Chang Soo Ryu, Jeong Yong Lee, Eun Ju Ko, Yong Hyun Ha, Jung Hoon Sung, Tae Sun Hwang, In Jai Kim and Nam Keun Kim

Int. J. Mol. Sci. 2023, 24(16), 12591; https://doi.org/10.3390/ijms241612591 - 9 Aug 2023

Cited by 2 | Viewed by 1205

Abstract

Coronary artery disease (CAD) is a prevalent cardiovascular condition characterized by the accumulation of plaque within coronary arteries. While distinct features of CAD have been reported, the association between genetic factors and CAD in terms of biomarkers was insufficient. This study aimed to investigate the connection between genetic factors and CAD, focusing on the thymidylate synthase (TS) gene, a gene involved in DNA synthesis and one-carbon metabolism. TS plays a critical role in maintaining the deoxythymidine monophosphate (dTMP) pool, which is essential for DNA replication and repair. Therefore, our research targeted single nucleotide polymorphisms that could potentially impact TS gene expression and lead to dysfunction. Our findings strongly associate the TS 1100T>C and 1170A>G genotypes with CAD susceptibility. We observed that TS 1100T>C polymorphisms increased disease susceptibility in several groups, while the TS 1170A>G polymorphism displayed a decreasing trend for disease risk when interacting with clinical factors. Furthermore, our results demonstrate the potential contribution of the TS 1100/1170 haplotypes to disease susceptibility, indicating a synergistic interaction with clinical factors in disease occurrence. Based on these findings, we propose that polymorphisms in the TS gene had the possibility of clinically useful biomarkers for the prevention, prognosis, and management of CAD in the Korean population. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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17 pages, 19070 KiB

Open AccessArticle

3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina

by Yehonatan Weinberger, Ivan Budnik, Yael Nisgav, Dahlia Palevski, Gil Ben-David, José A. Fernández, Shany Nivinsky Margalit, Sarina Levy-Mendelovich, Gili Kenet, Dov Weinberger, John H. Griffin and Tami Livnat

Int. J. Mol. Sci. 2023, 24(13), 10642; https://doi.org/10.3390/ijms241310642 - 26 Jun 2023

Cited by 4 | Viewed by 1565

Abstract

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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Review

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12 pages, 698 KiB

Open AccessReview

Concomitance of Pericardial Tamponade and Pulmonary Embolism in an Invasive Mucinous Lung Adenocarcinoma with Atypical Presentation: Diagnostic and Therapeutic Pitfalls—Case Report and Literature Review

by Nicoleta Sorina Bertici, Cristina Tudoran, Razvan Adrian Bertici, Ovidiu Fira-Mladinescu, Dragos Catalin Jianu, Caius Glad Streian, Raluca Elisabeta Staicu, Andrei Raul Manzur and Ana Lascu

Int. J. Mol. Sci. 2024, 25(15), 8413; https://doi.org/10.3390/ijms25158413 - 1 Aug 2024

Viewed by 1019

Abstract

The invasive mucinous adenocarcinoma of the lungs (LIMA) is an uncommon histological subtype of the mucinous adenocarcinoma. In this article, we present the case of a patient with a very high cardiovascular risk profile, diagnosed with LIMA, pericardial tamponade due to secondary dissemination, and pulmonary embolism, whose management rouses many challenges. Despite receiving the correct anticoagulant and antiaggregant therapy, our patient developed repeated acute major cardiovascular events leading to a fatal outcome. To gather additional information on LIMA and the above cluster of pathologies, we performed the first research of the international medical literature for scientific articles published in the last eight years on PubMed, ResearchGate, Clarivate, and Google Scholar. As the first literature research failed to identify any case similar to our patient, we performed a second study of the same databases for subjects with lung adenocarcinoma instead of LIMA and the same comorbidities, and we found 10 cases. LIMA is a less frequent type of adenocarcinoma, with polymorphic radiologic appearances on the chest computed tomography, frequently mimicking pneumonia, and thus delaying the diagnosis and therapy. It has a worse prognosis and higher mortality than the common adenocarcinoma, but information on its secondary dissemination and complications is still required. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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27 pages, 1338 KiB

Open AccessReview

Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function

by Juan Fernando Padín, José Manuel Pérez-Ortiz and Francisco Javier Redondo-Calvo

Int. J. Mol. Sci. 2024, 25(14), 7553; https://doi.org/10.3390/ijms25147553 - 10 Jul 2024

Cited by 1 | Viewed by 1278

Abstract

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin–kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin–angiotensin–aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled “Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions”, we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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36 pages, 2102 KiB

Open AccessReview

Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions

by Juan-Fernando Padín, José Manuel Pérez-Ortiz and Francisco Javier Redondo-Calvo

Int. J. Mol. Sci. 2024, 25(13), 7209; https://doi.org/10.3390/ijms25137209 - 29 Jun 2024

Cited by 3 | Viewed by 1428

Abstract

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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20 pages, 4013 KiB

Open AccessReview

Could Cyclosiversioside F Serve as a Dietary Supplement to Prevent Obesity and Relevant Disorders?

by Siqi Qin, Junren Chen, Kexin Zhong, Dan Li and Cheng Peng

Int. J. Mol. Sci. 2023, 24(18), 13762; https://doi.org/10.3390/ijms241813762 - 6 Sep 2023

Cited by 2 | Viewed by 1766

Abstract

Obesity is the basis of numerous metabolic diseases and has become a major public health issue due to its rapidly increasing prevalence. Nevertheless, current obesity therapeutic strategies are not sufficiently effective, so there is an urgent need to develop novel anti-obesity agents. Naturally occurring saponins with outstanding bio-activities have been considered promising drug leads and templates for human diseases. Cyclosiversioside F (CSF) is a paramount multi-functional saponin separated from the roots of the food-medicinal herb Astragali Radix, which possesses a broad spectrum of bioactivities, including lowering blood lipid and glucose, alleviating insulin resistance, relieving adipocytes inflammation, and anti-apoptosis. Recently, the therapeutic potential of CSF in obesity and relevant disorders has been gradually explored and has become a hot research topic. This review highlights the role of CSF in treating obesity and obesity-induced complications, such as diabetes mellitus, diabetic nephropathy, cardiovascular and cerebrovascular diseases, and non-alcoholic fatty liver disease. Remarkably, the underlying molecular mechanisms associated with CSF in disease therapy have been partially elucidated, especially PI3K/Akt, NF-κB, MAPK, apoptotic pathway, TGF-β, NLRP3, Nrf-2, and AMPK, with the aim of promoting the development of CSF as a functional food and providing references for its clinical application in obesity-related disorders therapy. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors 2.0)

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