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Congenital and Acquired Platelet Disease
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Congenital and Acquired Platelet Disease

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 2021) | Viewed by 34695

Special Issue Editors

Dr. José Rivera

E-Mail Website
Guest Editor
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, 30003 Murcia, Spain
Interests: platelets; pharmacology; platelet aggregation; coagulation; hematology; blood coagulation; blood; hemostasis; cardiology; thrombosis
Dr. José María Bastida

E-Mail Website
Guest Editor
Department of Hematology, Instituto de Investigación Biomédica de Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca (CAUSA), Universidad de Salamanca (USAL), 37007 Salamanca, Spain
Interests: hematology; human genetics; bleeding disorders; blood platelet disorders; molecular diagnostics

Special Issue Information

Dear Colleagues,

The primary and well established function of platelets is to stop blood loss after vascular trauma and exposure of the subendothelial matrix. Accordingly, it has been known for some time that defects in the number of platelet in the circulation and/or in the function of these pseudo blood cells increases the bleeding risk of the affected individuals. In most cases, these defects are acquired, i.e., associated to other systemic/hematologic diseases, or secondary to the use of certain drugs or medical treatments. However, there are also patients affected from rare inherited platelet disorders (IPD), caused by genetic changes affecting either the platelet number (inherited thrombocytopenia, IT) or the platelet function (inherited platelet function disorders, IPFD). In some IPD, the platelet defect associates with additional disease affecting, severely in many cases, other organs and tissue. Moreover, in some IPD, the genotype (gene and type of molecular alteration) influences the severity of the disease. Consequently, precise and early in life diagnosis of these platelet defects, either acquired or congenital, including genetic, is fundamental for the appropriate clinical management of the patients, their survival, and quality of life.    

The frontier between hemostasis and pathological thrombosis is very narrow, and it is also well established that platelets are critical elements in atherothrombosis. In fact, antiplatelet therapy is fundamental in clinical management of cardiovascular disease. There is current recognition that the profile of platelet reactivity can influence/predict the response of patients to this therapy and the occurrence of thrombotic and bleeding complications.

Lastly, in recent years, there has been increasing evidence of the relevant role of platelets in other processes or diseases, such as cancer, immunity, and inflammation.

Contributions on the above and related topics, either review or original research, are welcome in this Special Issue of the International Journal of Molecular Sciences, entitled “Congenital and Acquired Platelet Disease”.

Dr. José Rivera
Dr. José María Bastida
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Platelets
  • Inherited thrombocytopenia
  • Inherited platelet function disorders
  • Acquired platelet disorder
  • Immune thrombocytopenia purpura
  • Thrombopoietin receptor agonist
  • Antiplatelet drugs
  • Atherothrombosis
  • Cardiovascular disease
  • Cancer
  • Infection
  • Inflammation

Published Papers (7 papers)

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Research

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17 pages, 1916 KiB  
Article
Morphometric and Nanomechanical Features of Platelets from Women with Early Pregnancy Loss Provide New Evidence of the Impact of Inherited Thrombophilia
by Tonya Andreeva, Regina Komsa-Penkova, Ariana Langari, Sashka Krumova, Georgi Golemanov, Galya B. Georgieva, Stefka G. Taneva, Ina Giosheva, Nikolina Mihaylova, Andrey Tchorbanov and Svetla Todinova
Int. J. Mol. Sci. 2021, 22(15), 7778; https://doi.org/10.3390/ijms22157778 - 21 Jul 2021
Cited by 3 | Viewed by 2823
Abstract
Pregnancy is associated with hypercoagulation states and increased thrombotic risk, especially in women with thrombophilia. We combine atomic force microscopy (AFM) and flow cytometry to examine the morphology and nanomechanics of platelets derived from women with early pregnancy loss (EPL) and control pregnant [...] Read more.
Pregnancy is associated with hypercoagulation states and increased thrombotic risk, especially in women with thrombophilia. We combine atomic force microscopy (AFM) and flow cytometry to examine the morphology and nanomechanics of platelets derived from women with early pregnancy loss (EPL) and control pregnant (CP) and non-pregnant (CNP) women. Both control groups exhibit similar morphometric parameters (height and surface roughness) and membrane stiffness of platelets. EPL patients’ platelets, on the other hand, are more activated than the control groups, with prominent cytoskeletal rearrangement. In particular, reduced membrane roughness (22.9 ± 6 nm vs. 39.1 ± 8 nm) (p < 0.05) and height (692 ± 128 nm vs. 1090 ± 131 nm) (p < 0.05), strong alteration in the membrane Young modulus, increased production of platelets’ microparticles, and higher expression of procoagulant surface markers, as well as increased occurrence of thrombophilia (FVL, FII20210A, PLA1/A2, MTHFR C677T or 4G/5G PAI-1) polymorphisms were found. We suggest that the carriage of thrombophilic mutations triggers structural and nanomechanical abnormalities in platelets, resulting in their increased activation. The activation state of platelets can be well characterized by AFM, and the morphometric and nanomechanical characteristics might serve as a new criterion for evaluation of the cause of miscarriage and offer the prospect of an innovative approach serving for diagnostic purposes. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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16 pages, 1991 KiB  
Article
Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach
by Maria L. Lozano, Cristina Segú-Vergés, Mireia Coma, María T. Álvarez-Roman, José R. González-Porras, Laura Gutiérrez, David Valcárcel and Nora Butta
Int. J. Mol. Sci. 2021, 22(13), 6907; https://doi.org/10.3390/ijms22136907 - 27 Jun 2021
Cited by 10 | Viewed by 5035
Abstract
Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an [...] Read more.
Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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16 pages, 1673 KiB  
Article
Characterization of Procoagulant COAT Platelets in Patients with Glanzmann Thrombasthenia
by Alessandro Aliotta, Manuel Krüsi, Debora Bertaggia Calderara, Maxime G. Zermatten, Francisco J. Gomez, Ana P. Batista Mesquita Sauvage and Lorenzo Alberio
Int. J. Mol. Sci. 2020, 21(24), 9515; https://doi.org/10.3390/ijms21249515 - 14 Dec 2020
Cited by 4 | Viewed by 2215
Abstract
Patients affected by the rare Glanzmann thrombasthenia (GT) suffer from defective or low levels of the platelet-associated glycoprotein (GP) IIb/IIIa, which acts as a fibrinogen receptor, and have therefore an impaired ability to aggregate platelets. Because the procoagulant activity is a dichotomous facet [...] Read more.
Patients affected by the rare Glanzmann thrombasthenia (GT) suffer from defective or low levels of the platelet-associated glycoprotein (GP) IIb/IIIa, which acts as a fibrinogen receptor, and have therefore an impaired ability to aggregate platelets. Because the procoagulant activity is a dichotomous facet of platelet activation, diverging from the aggregation endpoint, we were interested in characterizing the ability to generate procoagulant platelets in GT patients. Therefore, we investigated, by flow cytometry analysis, platelet functions in three GT patients as well as their ability to generate procoagulant collagen-and-thrombin (COAT) platelets upon combined activation with convulxin-plus-thrombin. In addition, we further characterized intracellular ion fluxes during the procoagulant response, using specific probes to monitor by flow cytometry kinetics of cytosolic calcium, sodium, and potassium ion fluxes. GT patients generated higher percentages of procoagulant COAT platelets compared to healthy donors. Moreover, they were able to mobilize higher levels of cytosolic calcium following convulxin-plus-thrombin activation, which is congruent with the greater procoagulant activity. Further investigations will dissect the role of GPIIb/IIIa outside-in signalling possibly implicated in the regulation of platelet procoagulant activity. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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Review

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13 pages, 325 KiB  
Review
Primary Immune Thrombocytopenia and Essential Thrombocythemia: So Different and yet Somehow Similar—Cases Series and a Review of the Literature
by Marta Sobas, Maria Podolak-Dawidziak, Krzysztof Lewandowski, Michał Bator and Tomasz Wróbel
Int. J. Mol. Sci. 2021, 22(20), 10918; https://doi.org/10.3390/ijms222010918 - 09 Oct 2021
Cited by 5 | Viewed by 2713
Abstract
This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse [...] Read more.
This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
13 pages, 2574 KiB  
Review
Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation
by José Miguel Rivera-Caravaca, Anny Camelo-Castillo, Inmaculada Ramírez-Macías, Pablo Gil-Pérez, Cecilia López-García, María Asunción Esteve-Pastor, Esteban Orenes-Piñero, Antonio Tello-Montoliu and Francisco Marín
Int. J. Mol. Sci. 2021, 22(13), 7113; https://doi.org/10.3390/ijms22137113 - 01 Jul 2021
Cited by 7 | Viewed by 5504
Abstract
Peripheral artery disease (PAD) is a major cause of morbidity and mortality but it is usually underdiagnosed and undertreated. Patients with PAD present dysregulated procoagulant, anticoagulant, and fibrinolytic pathways leading to arterial and venous thrombosis. The risk of several ischemic-related complications could be [...] Read more.
Peripheral artery disease (PAD) is a major cause of morbidity and mortality but it is usually underdiagnosed and undertreated. Patients with PAD present dysregulated procoagulant, anticoagulant, and fibrinolytic pathways leading to arterial and venous thrombosis. The risk of several ischemic-related complications could be mitigated with appropriate antithrombotic therapy, which plays a central role in all types of PAD. For years, antiplatelets have been indicated in patients with symptomatic PAD or those who have undergone revascularization. Unfortunately, a non-negligible proportion of patients with PAD will suffer from adverse events during the follow-up, even despite proper medical therapies for the prevention of PAD complications. Thus, there is room for improving clinical outcomes in these patients. Given the implication of both, primary and secondary hemostasis in arterial thrombosis and the pathophysiology of PAD, the combination of antiplatelets and anticoagulants has emerged as a potential antithrombotic alternative to antiplatelets alone. In this narrative review article, we have highlighted the most recent evidence about antithrombotic therapy in PAD patients, with a special focus on oral anticoagulation. Certainly, COMPASS and VOYAGER PAD trials have shown promising results. Thus, rivaroxaban in combination with aspirin seem to reduce cardiovascular outcomes with a similar bleeding risk compared to aspirin alone. Nevertheless, results from real-world studies are needed to confirm these observations, and other trials will provide novel evidence about the safety and efficacy of emerging anticoagulant agents. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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31 pages, 2858 KiB  
Review
Inherited Platelet Disorders: An Updated Overview
by Verónica Palma-Barqueros, Nuria Revilla, Ana Sánchez, Ana Zamora Cánovas, Agustín Rodriguez-Alén, Ana Marín-Quílez, José Ramón González-Porras, Vicente Vicente, María Luisa Lozano, José María Bastida and José Rivera
Int. J. Mol. Sci. 2021, 22(9), 4521; https://doi.org/10.3390/ijms22094521 - 26 Apr 2021
Cited by 42 | Viewed by 12264
Abstract
Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either [...] Read more.
Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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21 pages, 846 KiB  
Review
Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia
by José María Bastida, José Ramón Gonzalez-Porras, José Rivera and María Luisa Lozano
Int. J. Mol. Sci. 2021, 22(9), 4330; https://doi.org/10.3390/ijms22094330 - 21 Apr 2021
Cited by 12 | Viewed by 3088
Abstract
In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. [...] Read more.
In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott–Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs. Full article
(This article belongs to the Special Issue Congenital and Acquired Platelet Disease)
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