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Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications
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Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications

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 December 2022) | Viewed by 23679

Special Issue Editor

Dr. Eleni Gavriilaki

E-Mail Website
Guest Editor
Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Interests: hematologic malignancies; thrombosis; complement; cellular therapy; lymphoma; myeloma; COVID-19
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Thrombotic microangiopathies (TMAs) form a heterogeneous group of syndromes presenting with a distinct clinical triad. We currently recognize two major entities with distinct pathophysiology: thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic uremic syndrome (HUS). Beyond these, differential diagnosis also includes TMAs associated with underlying conditions, such as drugs, malignancy, infections, scleroderma-associated renal crisis, systemic lupus erythematosus (SLE), malignant hypertension, transplantation, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and disseminated intravascular coagulation (DIC). More recently, even severe COVID-19 has been postulated to share the common characteristics of TMAs. Over the last few decades, our understanding of the pathophysiology of these syndromes has led to significant molecular advances and the development of next-generation therapeutics.

Beyond TMAs, thrombotic complications include a large spectrum of arterial and venous thrombosis. Although venous thromboembolism with deep vein thrombosis and pulmonary embolism represents the most common thrombotic complication, rare complications are also interesting in terms of molecular advances and pathophysiology.

Therefore, this Special Issue aims to cover molecular advances in terms of pathophysiology, diagnosis, and treatment across the whole spectrum of thrombotic microangiopathies.

Dr. Eleni Gavriilaki
Guest Editor

Manuscript Submission Information

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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

  • thrombotic microangiopathy
  • complement
  • complement inhibitors
  • thrombotic thrombocytopenic purpura
  • complement-mediated hemolytic uremic syndrome
  • hematopoietic cell transplantation
  • COVID-19
  • arterial thrombosis
  • venous thrombosis
  • deep vein thrombosis
  • pulmonary embolism

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Published Papers (5 papers)

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Research

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9 pages, 761 KiB  
Communication
The Effect of Respiratory Viral Infections on Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria
by Ioanna Lazana, Sean Apap Mangion, Selma Babiker, Joanna Large, Roochi Trikha, Mark Zuckerman, Shreyans Gandhi and Austin G. Kulasekararaj
Int. J. Mol. Sci. 2023, 24(11), 9358; https://doi.org/10.3390/ijms24119358 - 27 May 2023
Cited by 1 | Viewed by 1816
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis and thrombosis and is associated with significant morbidity and mortality. Although complement inhibitors have significantly changed the outcomes in PNH patients, breakthrough hemolysis (BTH) may still occur as a response to stress factors such as [...] Read more.
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis and thrombosis and is associated with significant morbidity and mortality. Although complement inhibitors have significantly changed the outcomes in PNH patients, breakthrough hemolysis (BTH) may still occur as a response to stress factors such as pregnancy, surgery, and infections. Despite the well-described association between bacterial infections and hemolysis in PNH patients, little is known about the effect of respiratory viruses on triggering hemolytic episodes. This is the first study, to our knowledge, addressing this question. We retrospectively analyzed 34 patients with PNH disease between 2016 and 2018, who were on eculizumab treatment and who presented with respiratory symptoms and were subsequently tested for 10 respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus). NTS+ patients had higher inflammatory markers, with the majority requiring antibiotics. Acute hemolysis, along with a significant drop in hemoglobin, was noted in the NTS+ group, with three of them requiring a top-up transfusion and two requiring an extra dose of eculizumab. Furthermore, the time from the last eculizumab dose was longer in the NTS+ patients who had BTH, than those who did not. Our data indicate that respiratory virus infections pose a significant risk for BTH in PNH patients on complement inhibitor treatment, underlining the need for regular screening and close monitoring of patients with respiratory symptoms. Furthermore, it implies a higher risk for patients who are not established on complement inhibitors, suggesting the necessity for greater vigilance in these patients. Full article
(This article belongs to the Special Issue Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications)
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Review

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13 pages, 299 KiB  
Review
Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand
by Ioanna Lazana
Int. J. Mol. Sci. 2023, 24(2), 1159; https://doi.org/10.3390/ijms24021159 - 6 Jan 2023
Cited by 9 | Viewed by 4324
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect [...] Read more.
Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect all organs. The lack of consensus diagnostic criteria, along with the common clinical features mimicking other diseases that complicate allo-HSCT, make the diagnosis of TA-TMA particularly challenging. Significant effort has been made to recognize specific risk factors predisposing to the development of TA-TMA and to identify serum biomarkers predicting the development of the disease. With regard to treatment, therapeutic plasma exchange (TPE) has been traditionally used, although with doubtful efficacy. On the other hand, the pivotal role of complement activation in the pathophysiology of TA-TMA has led to the exploration of the therapeutic potential of complement inhibitors in this setting. Eculizumab has been proposed as a first-line therapeutic agent in TA-TMA, owing to the very promising results in both pediatric and adult clinical trials. Pharmacokinetic and pharmacodynamic studies and CH50 levels are of paramount importance in the allo-HSCT setting, as a different dosing schedule (more intensive—in dose and frequency—at the beginning) seems to be required for successful outcomes. Furthermore, Narsoplimab, a MASP-2 inhibitor, recently received a Breakthrough Therapy Designation from the FDA for the treatment of TA-TMA after allo-HSCT. Finally, the decision to withdraw the CNIs, although initially advised by the Bone and Marrow Transplant Clinical Trials Network Committee, remains debatable owing to the controversial results of recent clinical trials. This review summarizes the current updates on pathophysiology, diagnosis and therapeutic approaches and emphasizes future goals and perspectives. Full article
(This article belongs to the Special Issue Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications)
27 pages, 1173 KiB  
Review
Theories and Molecular Basis of Vascular Aging: A Review of the Literature from VascAgeNet Group on Pathophysiological Mechanisms of Vascular Aging
by Eugenia Gkaliagkousi, Antonios Lazaridis, Soner Dogan, Emil Fraenkel, Bilge Guvenc Tuna, Ioana Mozos, Milica Vukicevic, Ozlem Yalcin and Kristina Gopcevic
Int. J. Mol. Sci. 2022, 23(15), 8672; https://doi.org/10.3390/ijms23158672 - 4 Aug 2022
Cited by 14 | Viewed by 6470
Abstract
Vascular aging, characterized by structural and functional alterations of the vascular wall, is a hallmark of aging and is tightly related to the development of cardiovascular mortality and age-associated vascular pathologies. Over the last years, extensive and ongoing research has highlighted several sophisticated [...] Read more.
Vascular aging, characterized by structural and functional alterations of the vascular wall, is a hallmark of aging and is tightly related to the development of cardiovascular mortality and age-associated vascular pathologies. Over the last years, extensive and ongoing research has highlighted several sophisticated molecular mechanisms that are involved in the pathophysiology of vascular aging. A more thorough understanding of these mechanisms could help to provide a new insight into the complex biology of this non-reversible vascular process and direct future interventions to improve longevity. In this review, we discuss the role of the most important molecular pathways involved in vascular ageing including oxidative stress, vascular inflammation, extracellular matrix metalloproteinases activity, epigenetic regulation, telomere shortening, senescence and autophagy. Full article
(This article belongs to the Special Issue Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications)
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16 pages, 2941 KiB  
Review
Novel Insights into Factor D Inhibition
by Eleni Gavriilaki, Anna Papakonstantinou and Konstantinos A. Agrios
Int. J. Mol. Sci. 2022, 23(13), 7216; https://doi.org/10.3390/ijms23137216 - 29 Jun 2022
Cited by 13 | Viewed by 3213
Abstract
Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle [...] Read more.
Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle of complement inhibitors as “orphan drugs” has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies. Efficacy has been significantly improved by upstream inhibition in patients with PNH. Different molecules may exert diverse characteristics in vitro and in vivo. Further studies remain to show safety and efficacy of upstream inhibition in other complementopathies. In addition, cost and availability issues are major drawbacks of current treatments. Therefore, further developments are warranted to address the unmet clinical needs in the field of complementopathies. This state-of-the-art narrative review aims to delineate novel insights into factor D inhibition as a promising target for complementopathies. Full article
(This article belongs to the Special Issue Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications)
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14 pages, 699 KiB  
Review
Molecular Advances in Preeclampsia and HELLP Syndrome
by Angeliki Gardikioti, Theodora-Maria Venou, Eleni Gavriilaki, Evangelia Vetsiou, Ioulia Mavrikou, Konstantinos Dinas, Angelos Daniilidis and Efthymia Vlachaki
Int. J. Mol. Sci. 2022, 23(7), 3851; https://doi.org/10.3390/ijms23073851 - 31 Mar 2022
Cited by 16 | Viewed by 6743
Abstract
Preeclampsia (PE) constitutes one of the principal reasons for maternal and perinatal morbidity and mortality worldwide. The circumstance typically implicates formerly healthful normotensive women, after 20 weeks of gestation, typically withinside the third trimester, without regarded threat elements or past deliveries. PE can [...] Read more.
Preeclampsia (PE) constitutes one of the principal reasons for maternal and perinatal morbidity and mortality worldwide. The circumstance typically implicates formerly healthful normotensive women, after 20 weeks of gestation, typically withinside the third trimester, without regarded threat elements or past deliveries. PE can be further complicated with hemolysis and thrombocytopenia, leading to the emergence of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low platelets). Both conditions are classified as hypertensive diseases of pregnancy (HDP), and their pathogenesis has been linked to an excessive maternal inflammatory response, accompanied by enhanced endothelial activation. Several studies have found that in pregnancies affected by PE/HELLP, von Willebrand factor (vWF) antigen levels (vWF:Ag) are significantly elevated, while its cleaving protease (ADAMTS-13, A Disintegrin-like and Metalloprotease with Thrombospondin type 1 motif, member 13) activity is normal to decreased. Furthermore, the higher urine excretion of the terminal complement complex C5b-9, as well as its greater deposition in the placental surface in preeclamptic women, imply that the utero-placental unit’s distinctive deficits are intimately tied to disproportionate complement activation. The goal of this updated evaluation is to provide the most up-to-date molecular advances in the pathophysiology of PE/HELLP syndromes. Recent medical data on vWF:Ag levels in patients with PE, ADAMTS-13, and dysregulation of the complement system, are highlighted and evaluated. Furthermore, we discuss the relationship between those entities and the progression of the disease, as well as their significance in the diagnostic process. Finally, considering the difficulties in analyzing and controlling those symptoms in pregnant women, we can provide a current diagnostic and therapeutic algorithm. Full article
(This article belongs to the Special Issue Molecular Advances in Thrombotic Microangiopathy and Thrombotic Complications)
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