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New Advances in Thrombosis: 3rd Edition

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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 (20 May 2025) | Viewed by 3540

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Dr. Isabella Russo

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Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, 10, Orbassano, I-10043 Turin, Italy
Interests: platelets function; nitric oxide; haemostasis; thrombosis; anti-platelet drugs; platelet dysfunction in metabolic diseases
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Special Issue Information

Dear Colleagues,

Thrombosis occurs when a thrombus forms inside blood vessels, thus disrupting blood flow. It represents a major complication of cardiovascular and cerebrovascular events, such as myocardial infarction, acute ischemic stroke, or venous thromboembolism.

The components of thrombi include fibrin, red blood cells, platelets, leukocytes, and neutrophil extracellular traps, and this heterogeneous composition is deeply influenced by the specific location in which it develops and by the disease etiopathogenesis.

Furthermore, there is increasing interest in extracellular vesicles that are released by many cells through membrane shedding and that can contribute to transferring biological messages far from the triggering event, as well as be used as biomarkers of thrombo-embolic pathology.

Considering the high prevalence of the thrombotic scenarios associated with metabolic and atherosclerotic diseases, the aim of this Special Issue is to share the latest scientific achievements in the field of biological and molecular mechanisms involved in impaired coagulation, platelet reactivity, and/or fibrinolysis.

Our focus will be on studies that are related to:

Explanation of thrombosis pathogenetic mechanisms;
Searching for new biomarkers for the detection of prothrombotic risk;
The use of new research techniques on thrombus study.

Both original and review articles providing new insights into this subject are welcome.

Dr. Isabella Russo
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

thrombosis
platelets
coagulation
diabetes
obesity
insulin resistance
metabolic disease
cardiovascular diseases

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Published Papers (5 papers)

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Research

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23 pages, 17963 KiB

Open AccessArticle

A Novel KGD-Based αIIbβ3 Antagonist Prevents Arterial Thrombosis While Preserving Hemostasis and Avoiding Thrombocytopenia

by Yu-Ju Kuo, Ching-Hu Chung, Chun-Chao Chen, Ju-Chi Liu, Kuan-Rau Chiou, Joen-Rong Sheu, Woei-Jer Chuang and Tur-Fu Huang

Int. J. Mol. Sci. 2025, 26(10), 4530; https://doi.org/10.3390/ijms26104530 - 9 May 2025

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Abstract

Current αIIbβ3 antagonists are potent antithrombotic agents, their clinical use is limited by the risk of life-threatening bleeding. Emerging evidence has highlighted key mechanistic differences between thrombosis and hemostasis, opening avenues for safer antithrombotic strategies. Targeting integrin αIIbβ3 outside-in signaling has been proposed to mitigate bleeding risk; however, the short half-life of peptide-based therapeutics remains a major challenge. In this study, we developed an optimized αIIbβ3 antagonist, KGDRR—a recombinant mutant protein derived from snake venom disintegrin, incorporating an Arg55 residue within the KGD loop—through systematic structure–activity relationship (SAR) analysis. Molecular docking revealed a critical cation–π interaction between Arg55 of KGDRR and Tyr122 of the β3 subunit, stabilizing integrin αIIbβ3 in an unliganded-closed conformation. Functionally, KGDRR selectively inhibited thrombus propagation by blocking ligand binding and downstream Gα13-mediated outside-in signaling while preserving initial thrombus core formation, which is a limitation of current αIIbβ3 inhibitors. Unlike conventional antagonists, KGDRR maintained αIIbβ3 in an unliganded-closed conformation without inducing the integrin activation and conformational change that lead to immune-mediated platelet clearance and thrombocytopenia. In animal models, KGDRR effectively suppressed thrombus growth without causing thrombocytopenia or prolonging bleeding time. Furthermore, intramuscular administration of KGDRR achieved a functional half-life 3.5 times longer than that of the clinically used antithrombotic eptifibatide at equivalent antithrombotic efficacy. In conclusion, KGDRR exhibits potent antithrombotic activity with a favorable safety profile and enhanced pharmacokinetic stability. These findings position KGDRR as a promising next generation αIIbβ3 antagonist with the potential to improve clinical outcomes in antithrombotic therapy. Full article

(This article belongs to the Special Issue New Advances in Thrombosis: 3rd Edition)

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26 pages, 1262 KiB

Open AccessArticle

The Predictive Roles of Tumour Markers, Hemostasis Assessment, and Inflammation in the Early Detection and Prognosis of Gallbladder Adenocarcinoma and Metaplasia: A Clinical Study

by Andrei Bojan, Catalin Pricop, Maria-Cristina Vladeanu, Iris Bararu-Bojan, Codruta Olimpiada Halitchi, Simona Eliza Giusca, Oana Viola Badulescu, Manuela Ciocoiu, Dan Iliescu-Halitchi and Liliana Georgeta Foia

Int. J. Mol. Sci. 2025, 26(8), 3665; https://doi.org/10.3390/ijms26083665 - 12 Apr 2025

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Abstract

Gallbladder carcinoma (GBC) is one of the most aggressive malignancies of the biliary tract, often originating from chronic inflammation associated with gallstones and cholecystitis. Persistent inflammation plays a pivotal role in the development of preneoplastic changes, such as metaplasia, which may progress to malignancy. Despite its relatively low incidence, GBC is characterized by a poor prognosis due to late-stage diagnosis, highlighting the urgent need for improved early detection strategies. This study aimed to assess the diagnostic and prognostic significance of CA 19-9 and CEA levels in patients with gallbladder lesions, while also evaluating systemic inflammation and hemostatic dysregulation. A retrospective analysis was conducted on patients diagnosed with gallbladder lesions, with histopathological confirmation of adenocarcinoma and metaplasia. Laboratory assessments included serum levels of tumour markers, inflammatory markers such as CRP, and key hemostatic parameters, including thrombocyte count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels. A predictive scoring model was developed using the cutoff values of CA 19-9 and CEA to assess their combined diagnostic potential. Among the patients studied, 48.9% had an initial diagnosis of chronic cholecystitis, while 32.2% presented with acute cholecystitis. Adenocarcinoma was identified in 6.7% of cases after histopathological examination, predominantly in females over 65 years old with acute cholecystitis. Metaplasia was detected in 7.8% of cases, primarily in elderly females with chronic cholecystitis. Laboratory findings revealed significantly elevated levels of CA 19-9, CEA, AFP, and CA-125 in patients with adenocarcinoma. Additionally, abnormalities in hemostatic parameters, including increased fibrinogen levels and alterations in thrombocyte count, were observed in patients with malignancy. A combined predictive score using CA 19-9 and CEA demonstrated strong potential for detecting adenocarcinoma and metaplasia, improving diagnostic accuracy. Our findings emphasize the clinical importance of integrating tumour markers, inflammatory biomarkers, and hemostatic parameters in the evaluation of gallbladder lesions associated with chronic inflammation. The combined assessment of these factors enhances early detection, facilitates malignancy risk stratification, and improves prognostic evaluation, particularly in patients with metabolic and cardiovascular comorbidities. Full article

(This article belongs to the Special Issue New Advances in Thrombosis: 3rd Edition)

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11 pages, 1423 KiB

Open AccessArticle

Activation of the Mammalian Target of Rapamycin Pathway in Endothelial Cells in Antiphospholipid Antibody-Positive Patients with Leg Ulcers

by András L. Kovács, Csaba Gyömörei, Szabina Horváth, Viktória Németh, Réka Dudley, Zsuzsanna Nagy, Tímea Berki, Zsuzsanna Lengyel and Rolland Gyulai

Int. J. Mol. Sci. 2025, 26(6), 2750; https://doi.org/10.3390/ijms26062750 - 19 Mar 2025

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Abstract

Antiphospholipid antibody (aPL)-induced activation of the mTOR (mammalian target of rapamycin) signaling pathway in endothelial cells plays a role in the pathogenesis of vascular lesions in antiphospholipid syndrome (APS). However, there are no data on whether this mechanism also contributes to the development of skin ulcers commonly observed in APS. We investigated the activation of mTOR in skin specimens from aPL-positive and aPL-negative patients with leg ulcers. Patients with leg ulcers who had primary or secondary APS or no detectable aPLs were included in the study. Biopsies were taken from the ulcer edges and the adjacent non-ulcerated skin areas. Activation of mTORC1 (mTOR Complex1) and mTORC2 (mTOR Complex2) in endothelial cells was determined by immunohistochemical analysis of phosphorylated ribosomal S6 protein (pS6RP) and phosphorylated protein kinase B (pAKT), respectively. In all aPL-positive patients, regardless of whether they had primary or secondary APS, we found a positive immunohistochemical reaction to pS6RP (mTORC1 activation) in the endothelial cells of the ulcer samples. On the other hand, pS6RP could not be detected in samples from aPL-negative chronic venous ulcers. Furthermore, pS6RP was not present in samples taken from the unaffected skin adjacent to the ulcers in aPL-positive patients. The pAKT reaction (mTORC2) was negative in both aPL-positive and aPL-negative patients, both in the ulcers and in the periulcer skin. Activation of the mTOR pathway may contribute to ulcer development in APS. The mTORC1 may be a target for therapeutic modification in APS-associated skin ulcers. Full article

(This article belongs to the Special Issue New Advances in Thrombosis: 3rd Edition)

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20 pages, 2801 KiB

Open AccessArticle

A Novel Human Anti-FV mAb as a Potential Tool for Diagnostic and Coagulation Inhibitory Approaches

by Margherita Passariello, Rosa Rapuano Lembo, Lorenzo Manna, Ciro Miele, Antonello Merlino, Cristina Mazzaccara, Antonio Leonardi and Claudia De Lorenzo

Int. J. Mol. Sci. 2025, 26(6), 2721; https://doi.org/10.3390/ijms26062721 - 18 Mar 2025

Viewed by 398

Abstract

Cardiovascular diseases, including thrombosis, are the leading cause of mortality worldwide. The generation of monoclonal antibodies (mAb) targeting specific coagulation factors could provide more targeted and safer anticoagulant therapies. Factor V (FV) is a critical cofactor in the prothrombinase complex, which catalyzes the conversion of prothrombin to thrombin, a key enzyme in the coagulation cascade. We isolated a novel human antibody specific to FV by using phage display technology. The selection occurred by panning a large repertoire of phages expressing human antibody fragments (scFv) in parallel on the purified recombinant protein in its native form (FV) or activated by proteolytic maturation (Factor Va (FVa)). Through ELISA screening, we identified the clone with the highest binding affinity for both targets, and it was successfully converted into IgG1. The novel human mAb, called D9, was found capable of binding to Factor V with a low nM affinity both by ELISA and BLI assays, whereas its cross-reactivity with some other coagulation factors was found null or very poor. Furthermore, when tested in blood clotting tests, it was found able to prolong activated partial thromboplastin time (aPTT). Thus, D9 could become not only a potential therapeutic agent as a specific anticoagulant but also a precious tool for diagnostic and research applications. Full article

(This article belongs to the Special Issue New Advances in Thrombosis: 3rd Edition)

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Review

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24 pages, 1860 KiB

Open AccessReview

Exploiting the Molecular Properties of Fibrinogen to Control Bleeding Following Vascular Injury

by Tanjot Singh, Muhammad Hasan, Thembaninkosi G. Gaule and Ramzi A. Ajjan

Int. J. Mol. Sci. 2025, 26(3), 1336; https://doi.org/10.3390/ijms26031336 - 5 Feb 2025

Cited by 1 | Viewed by 1454

Abstract

The plasma protein fibrinogen is critical for haemostasis and wound healing, serving as the structural foundation of the blood clot. Through a complex interaction between coagulation factors, the soluble plasma fibrinogen is converted to insoluble fibrin networks, which form the skeleton of the blood clot, an essential step to limit blood loss after vascular trauma. This review examines the molecular mechanisms by which fibrinogen modulates bleeding, focusing on its interactions with other proteins that maintain fibrin network stability and prevent premature breakdown. Moreover, we also cover the role of fibrinogen in ensuring clot stability through the physiological interaction with platelets. We address the therapeutic applications of fibrinogen across various clinical contexts, including trauma-induced coagulopathy, postpartum haemorrhage, and cardiac surgery. Importantly, a full understanding of protein function will allow the development of new therapeutics to limit blood loss following vascular trauma, which remains a key cause of mortality worldwide. While current management strategies help with blood loss following vascular injury, they are far from perfect and future research should prioritise refining fibrinogen replacement strategies and developing novel agents to stabilise the fibrin network. Exploiting fibrinogen’s molecular properties holds significant potential for improving outcomes in trauma care, surgical interventions and obstetric haemorrhage. Full article

(This article belongs to the Special Issue New Advances in Thrombosis: 3rd Edition)

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