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Molecular Aspects of Haemorrhagic and Thrombotic Disorders
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Molecular Aspects of Haemorrhagic and Thrombotic Disorders

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

Deadline for manuscript submissions: closed (20 May 2025) | Viewed by 13120

Special Issue Editor

Dr. Giovanni Luca Tiscia

E-Mail Website
Guest Editor
Thrombosis and Hemostasis Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
Interests: genetics; coagulation; bleeding; haemorrhage; thrombosis; mutation

Special Issue Information

Dear Colleagues,

The Special Issue “Molecular Aspects of Haemorrhagic and Trombotic Disorders” will expand the knowledge of molecular mechanisms underlying haemorrhagic diseases or favouring arterial/venous thrombosis. Although haemorrhagic and thrombotic disorders are mostly acquired, inherited cases are also described. In some cases, the identification of well-known genetic determinants or predisposing factors could fail; thus, it has been possible to find pathogenic allele variants in genes unrelated to haemostasis processes, mainly through the most recent technologies in the field of molecular biology, such as whole-exome-sequencing (WES) or next-generation-sequencing (NGS). For instance, inherited thrombocytopenia represents a haemorrhagic disorder that is most likely characterised by complex and heterogeneous signs and symptoms. As a consequence, diagnostic assessment of the inherited thrombocytopenia is quite complex. Thus, the abovementioned technologies help to define new thrombocytopenia cases, which mostly occur as syndromes. In thrombotic events, inherited thrombophilia constitutes an established predisposing risk factor. However, in some thrombosis cases, laboratory investigations evidenced no common inherited thrombophilia. Therefore, familial history, events diagnosed in young people or involving unusual sites, and recurrence raise suspicion of inherited thrombophilia. WGS and NGS could be used to describe novel genes in the mechanisms associated with inherited susceptibility for thrombosis. In an attempt to collect as much information as possible on the molecular aspects of haemorrhagic and trombotic disorders, we encourage researchers to submit papers focusing on more recent scientific achievements regarding this issue.

Dr. Giovanni Luca Tiscia
Guest Editor

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Keywords

  • next-generation sequencing
  • whole-exome sequencing
  • haemorrhagia
  • thrombosis
  • molecular biology
  • diagnosis
  • genetics
  • blood coagulation disorders
  • inherited

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Published Papers (6 papers)

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Research

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17 pages, 5266 KiB  
Article
Intrapleural Fibrinolytic Interventions for Retained Hemothoraces in Rabbits
by Christian J. De Vera, Jincy Jacob, Krishna Sarva, Sunil Christudas, Rebekah L. Emerine, Jon M. Florence, Oluwaseyi Akiode, Tanvi V. Gorthy, Torry A. Tucker, Karan P. Singh, Ali O. Azghani, Andrey A. Komissarov, Galina Florova and Steven Idell
Int. J. Mol. Sci. 2024, 25(16), 8778; https://doi.org/10.3390/ijms25168778 - 12 Aug 2024
Viewed by 1297
Abstract
Bleeding within the pleural space may result in persistent clot formation called retained hemothorax (RH). RH is prone to organization, which compromises effective drainage, leading to lung restriction and dyspnea. Intrapleural fibrinolytic therapy is used to clear the persistent organizing clot in lieu [...] Read more.
Bleeding within the pleural space may result in persistent clot formation called retained hemothorax (RH). RH is prone to organization, which compromises effective drainage, leading to lung restriction and dyspnea. Intrapleural fibrinolytic therapy is used to clear the persistent organizing clot in lieu of surgery, but fibrinolysin selection, delivery strategies, and dosing have yet to be identified. We used a recently established rabbit model of RH to test whether intrapleural delivery of single-chain urokinase (scuPA) can most effectively clear RH. scuPA, or single-chain tissue plasminogen activator (sctPA), was delivered via thoracostomy tube on day 7 as either one or two doses 8 h apart. Pleural clot dissolution was assessed using transthoracic ultrasonography, chest computed tomography, two-dimensional and clot displacement measurements, and gross analysis. Two doses of scuPA (1 mg/kg) were more effective than a bolus dose of 2 mg/kg in resolving RH and facilitating drainage of pleural fluids (PF). Red blood cell counts in the PF of scuPA, or sctPA-treated rabbits were comparable, and no gross intrapleural hemorrhage was observed. Both fibrinolysins were equally effective in clearing clots and promoting pleural drainage. Biomarkers of inflammation and organization were likewise comparable in PF from both groups. The findings suggest that single-agent therapy may be effective in clearing RH; however, the clinical advantage of intrapleural scuPA remains to be established by future clinical trials. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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18 pages, 4195 KiB  
Article
De Novo Noninversion Variants Implicated in Sporadic Hemophilia A: A Variant Origin and Timing Study
by Ming Chen, Ming-Ching Shen, Shun-Ping Chang, Gwo-Chin Ma, Dong-Jay Lee and Adeline Yan
Int. J. Mol. Sci. 2024, 25(3), 1763; https://doi.org/10.3390/ijms25031763 - 1 Feb 2024
Cited by 1 | Viewed by 2069
Abstract
Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that [...] Read more.
Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that HA-sporadic NIVs are generated as a de novo variant. Of the 125 registered families with HA, 22 were eligible for inclusion. We conducted a linkage analysis using F8 gene markers and amplification refractory mutation system–quantitative polymerase chain reaction to confirm the origin of the sporadic NIVs (~0% mutant cells) or the presence of a mosaic variant, which requires further confirmation of the origin in the parent. Nine mothers, four maternal grandmothers, and six maternal grandfathers were confirmed to be the origin of sporadic NIVs, which most likely occurred in the zygote within the first few cell divisions and in single sperm cells, respectively. Three mothers had mosaic variants, which most likely occurred early in postzygotic embryogenesis. All maternal grandparents were free from sporadic NIV. In conclusion, F8 NIVs in sporadic HA were found to be caused primarily by de novo variants. Our studies are essential for understanding the genetic pathogenesis of HA and improving current genetic counseling. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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16 pages, 2428 KiB  
Article
Whole-Exome Sequencing in a Family with an Unexplained Tendency for Venous Thromboembolism: Multicomponent Prediction of Low-Frequency Variant Deleteriousness and of Individual Protein Interaction
by Barbara Lunghi, Nicole Ziliotto, Dario Balestra, Lucrezia Rossi, Patrizia Della Valle, Pasquale Pignatelli, Mirko Pinotti, Armando D’Angelo, Giovanna Marchetti and Francesco Bernardi
Int. J. Mol. Sci. 2023, 24(18), 13809; https://doi.org/10.3390/ijms241813809 - 7 Sep 2023
Cited by 2 | Viewed by 1877
Abstract
Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented [...] Read more.
Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented VTE, filtered for MAF < 0.04 in 192 candidate genes, revealed 22 heterozygous (16 missense and six synonymous) variants in patients. Functional prediction by multi-component bioinformatics tools, implemented by a database/literature search, including ClinVar annotation and QTL analysis, prioritized 12 missense variants, three of which (CRP Leu61Pro, F2 Asn514Lys and NQO1 Arg139Trp) were present in all patients, and the frequent functional variants FGB Arg478Lys and IL1A Ala114Ser. Combinations of prioritized variants in each patient were used to infer functional protein interactions. Different interaction patterns, supported by high-quality evidence, included eight proteins intertwined in the “acute phase” (CRP, F2, SERPINA1 and IL1A) and/or in the “fibrinogen complex” (CRP, F2, PLAT, THBS1, VWF and FGB) significantly enriched terms. In a wide group of candidate genes, this approach highlighted six low-frequency variants (CRP Leu61Pro, F2 Asn514Lys, SERPINA1 Arg63Cys, THBS1 Asp901Glu, VWF Arg1399His and PLAT Arg164Trp), five of which were top ranked for predicted deleteriousness, which in different combinations may contribute to disease susceptibility in members of this family. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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15 pages, 1376 KiB  
Article
An Exploratory Study Using Next-Generation Sequencing to Identify Prothrombotic Variants in Patients with Cerebral Vein Thrombosis
by Robert Anton Kramer, Robert Zimmermann, Julian Strobel, Susanne Achenbach, Armin Michael Ströbel, Holger Hackstein, David Alexander Christian Messerer and Sabine Schneider
Int. J. Mol. Sci. 2023, 24(9), 7976; https://doi.org/10.3390/ijms24097976 - 28 Apr 2023
Cited by 1 | Viewed by 2325
Abstract
Prothrombotic hereditary risk factors for cerebral vein thrombosis (CVT) are of clinical interest to better understand the underlying pathophysiology and stratify patients for the risk of recurrence. This study explores prothrombotic risk factors in CVT patients. An initial screening in patients of the [...] Read more.
Prothrombotic hereditary risk factors for cerebral vein thrombosis (CVT) are of clinical interest to better understand the underlying pathophysiology and stratify patients for the risk of recurrence. This study explores prothrombotic risk factors in CVT patients. An initial screening in patients of the outpatient clinic of the Department of Transfusion Medicine and Hemostaseology of the University Hospital Erlangen, Germany, revealed 183 patients with a history of CVT. An initial screening identified a number of common prothrombic risk factors, including Factor V Leiden (rs6025) and Prothrombin G20210A (rs1799963). All patients without relevant findings (58 individuals) were invited to participate in a subsequent genetic analysis of 55 relevant genes using next-generation sequencing (NGS). Three intron variants (ADAMTS13: rs28446901, FN1: rs56380797, rs35343655) were identified to occur with a significantly higher frequency in the CVT patient cohort compared to the general European population. Furthermore, the combined prevalence of at least two of four potentially prothrombic variants (FGA (rs6050), F13A1 (rs5985), ITGB3 (rs5918), and PROCR (rs867186)) was significantly higher in the CVT subjects. The possible impact of the identified variants on CVT is discussed. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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Review

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18 pages, 3016 KiB  
Review
The Cellular and Protein Arms of Coagulation in Diabetes: Established and Potential Targets for the Reduction of Thrombotic Risk
by Nawaz Z. Safdar, Noppadol Kietsiriroje and Ramzi A. Ajjan
Int. J. Mol. Sci. 2023, 24(20), 15328; https://doi.org/10.3390/ijms242015328 - 18 Oct 2023
Cited by 6 | Viewed by 2889
Abstract
Diabetes is a metabolic condition with a rising global prevalence and is characterised by abnormally high blood glucose levels. Cardiovascular disease (CVD) accounts for the majority of deaths in diabetes and, despite improvements in therapy, mortality and hospitalisations in this cohort remain disproportionally [...] Read more.
Diabetes is a metabolic condition with a rising global prevalence and is characterised by abnormally high blood glucose levels. Cardiovascular disease (CVD) accounts for the majority of deaths in diabetes and, despite improvements in therapy, mortality and hospitalisations in this cohort remain disproportionally higher compared to individuals with normal glucose metabolism. One mechanism for increased CVD risk is enhanced thrombosis potential, due to altered function of the cellular and acellular arms of coagulation. Different mechanisms have been identified that mediate disordered blood clot formation and breakdown in diabetes, including dysglycaemia, insulin resistance, and metabolic co-morbidities. Collectively, these induce platelet/endothelial dysfunction and impair the fibrinolytic process, thus creating a prothrombotic milieu. Despite these abnormalities, current antithrombotic therapies are largely similar in diabetes compared to those without this condition, which explains the high proportion of patients experiencing treatment failure while also displaying an increased risk of bleeding events. In this narrative review, we aimed to summarise the physiological functioning of haemostasis followed by the pathological effects of diabetes mellitus on platelets and the fibrin network. Moreover, we carefully reviewed the literature to describe the current and future therapeutic targets to lower the thrombosis risk and improve vascular outcomes in diabetes. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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Other

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8 pages, 1033 KiB  
Case Report
SARS-CoV-2 Vaccine Improved Hemostasis of a Patient with Protein S Deficiency: A Case Report
by Mohammad A. Mohammad, Alaa Malik, Lekha Thangada, Diana Polanía-Villanueva, Jovanny Zabaleta and Rinku Majumder
Int. J. Mol. Sci. 2024, 25(19), 10717; https://doi.org/10.3390/ijms251910717 - 5 Oct 2024
Viewed by 1442
Abstract
A 16-year-old patient, while an infant, incurred right-sided hemiparesis and had difficulty breast feeding. She was later diagnosed with a neonatal stroke and her genetic testing showed a missense mutation in her PROS1 (Protein S) gene. Both her grandfather and father, but not [...] Read more.
A 16-year-old patient, while an infant, incurred right-sided hemiparesis and had difficulty breast feeding. She was later diagnosed with a neonatal stroke and her genetic testing showed a missense mutation in her PROS1 (Protein S) gene. Both her grandfather and father, but not her mother, had hereditary Protein S (PS) deficiency. The patient was not prescribed any mediation due to her young age but was frequently checked by her physician. The patient’s plasma was first collected at the age of 13, and the isolated plasma from the patient and her father were analyzed by aPTT, thrombin generation, and enzyme-linked immunosorbent assays. These analyses showed low PS activity and clotting time associated with the missense mutation in the PROS1 gene. During the COVID-19 pandemic, the patient received her first Pfizer vaccination dose in 2021, followed by a booster dose in 2022. The plasma samples were collected 8 weeks post-immunization, after which her clotting parameters had improved for up to 6 months following vaccination. The patient’s plasma showed a significant reduction in thrombin generation and an improved aPTT clotting time. Mass spectrometry analysis revealed that her antithrombin-III level was significantly higher post-vaccination, and both thrombin and FXII levels were significantly lowered compared with her father. To our knowledge, this is the first report to document that COVID-19 vaccination can lower the risk of thrombosis in a patient with inherited thrombophilia. Although the effect was observed on a single mutation, it would be interesting to investigate the effect of COVID-19 vaccinations on other thrombophilia. Full article
(This article belongs to the Special Issue Molecular Aspects of Haemorrhagic and Thrombotic Disorders)
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