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Role of Leukocytes in Vaso-Occlusive Crisis in Sickle Cell Anemia

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Review Article | DOI: https://doi.org/10.31579/2639-4162/210

Role of Leukocytes in Vaso-Occlusive Crisis in Sickle Cell Anemia

  • Emmanuel Ifeanyi Obeagu

Department of Medical Laboratory Science, Kampala International University, Uganda.

*Corresponding Author: Emmanuel Ifeanyi Obeagu, Department of Medical Laboratory Science, Kampala International University, Uganda.

Citation: Emmanuel I. Obeagu, (2024), Role of Leukocytes in Vaso-Occlusive Crisis in Sickle Cell Anemia, J. General Medicine and Clinical Practice, 7(14); DOI:10.31579/2639-4162/210

Copyright: © 2024, Emmanuel Ifeanyi Obeagu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 19 July 2024 | Accepted: 16 August 2024 | Published: 24 August 2024

Keywords: sickle cell anemia; vaso-occlusive crisis; leukocytes; inflammation; adhesion

Abstract

Vaso-occlusive crisis (VOC) is a prominent and painful complication of sickle cell anemia (SCA) characterized by the obstruction of blood flow due to the interaction of sickled red blood cells (RBCs) with leukocytes and the vascular endothelium. This review highlights the multifaceted role of leukocytes in the pathophysiology of VOC, focusing on their activation, adhesion to the endothelium, interaction with sickled RBCs, and contribution to inflammation and thrombosis. The activation of leukocytes leads to the release of pro-inflammatory cytokines that exacerbate endothelial dysfunction and enhance leukocyte-endothelial adhesion, promoting the accumulation of leukocytes in the microvasculature. The interaction between leukocytes and sickled RBCs creates a feedback loop that further perpetuates inflammation and vascular obstruction. Additionally, activated leukocytes promote a pro-thrombotic state by enhancing platelet activation and increasing the risk of thrombus formation, compounding the severity of VOC. This intricate interplay underscores the critical role of leukocytes in mediating the inflammatory response associated with VOC and highlights the importance of understanding these mechanisms to develop effective therapeutic strategies. Targeting leukocyte activation and their interactions with endothelial cells and sickled RBCs presents novel therapeutic opportunities to mitigate VOC. Potential interventions may include anti-inflammatory agents, adhesion molecule inhibitors, anticoagulants, and leukocyte trafficking inhibitors. By elucidating the mechanisms underlying leukocyte involvement in VOC, this review aims to inform future research and clinical approaches to improve outcomes for individuals living with sickle cell anemia.

Introduction

Sickle cell anemia (SCA) is a genetic disorder caused by a mutation in the β-globin gene, leading to the production of abnormal hemoglobin S (HbS). Under low-oxygen conditions, HbS undergoes polymerization, resulting in the deformation of red blood cells (RBCs) into a characteristic sickle shape. This sickling process impairs the deformability of RBCs, increasing their tendency to aggregate and obstruct blood flow in the microcirculation. One of the most significant and painful complications of SCA is vaso-occlusive crisis (VOC), which occurs when sickled RBCs block blood vessels, leading to acute pain, tissue ischemia, and organ dysfunction. Understanding the underlying mechanisms that contribute to VOC is essential for developing effective therapeutic strategies to manage this debilitating condition. Leukocytes, or white blood cells, play a crucial role in the pathophysiology of VOC. They are key mediators of the inflammatory response and interact with both sickled RBCs and the endothelium of blood vessels. The activation of leukocytes in SCA is driven by a variety of factors, including chronic hemolysis, oxidative stress, and the inflammatory environment that characterizes the disease. Once activated, leukocytes undergo changes that enhance their adhesive properties and migratory capabilities, allowing them to adhere to the endothelium and accumulate in the microvasculature. This process exacerbates the obstruction of blood flow and perpetuates the cycle of inflammation and pain associated with VOC. [1-5]

The interaction between leukocytes and the endothelium is mediated by a variety of adhesion molecules. In SCA, the upregulation of these molecules on endothelial cells enhances the recruitment of leukocytes to the vascular wall. Key adhesion molecules involved in this process include E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). The binding of leukocytes to these adhesion molecules facilitates their transmigration across the endothelium, contributing to inflammation and tissue injury. The accumulation of leukocytes in the microvasculature can lead to the formation of thrombi, further complicating the pathogenesis of VOC. In addition to their role in inflammation, leukocytes can directly interact with sickled RBCs. These interactions can promote the adhesion of sickled RBCs to the endothelium, enhancing the risk of vascular occlusion. When activated, leukocytes can also release pro-inflammatory cytokines and reactive oxygen species (ROS) that exacerbate endothelial dysfunction and promote further sickling of RBCs. This interaction creates a feedback loop in which leukocyte activation leads to increased sickling, inflammation, and tissue ischemia, ultimately contributing to the severity of VOC. [6-10]

The pro-thrombotic state observed in SCA is another critical aspect of leukocyte involvement in VOC. Activated leukocytes can enhance platelet activation and aggregation through the release of pro-coagulant factors, such as tissue factor (TF) and platelet-activating factor (PAF). This pro-thrombotic environment increases the risk of thrombus formation within the microcirculation, exacerbating the obstruction of blood flow and further perpetuating the occurrence of VOC.  The inflammatory response in SCA is characterized by the overproduction of various cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines contribute to the activation of endothelial cells, leading to increased expression of adhesion molecules and further recruitment of leukocytes. This cytokine storm exacerbates the inflammatory environment and perpetuates the cycle of endothelial dysfunction, leukocyte adhesion, and vascular occlusion. The interplay between leukocytes and inflammatory cytokines underscores the complexity of the pathophysiological mechanisms underlying VOC.[11-15]

Mechanisms of Leukocyte Involvement in VOC

The involvement of leukocytes in vaso-occlusive crisis (VOC) in sickle cell anemia (SCA) is multifaceted and encompasses various mechanisms that contribute to the pathophysiology of this painful complication. The following sections outline the key mechanisms through which leukocytes influence the development and severity of VOC.

1. Activation of Leukocytes

Leukocytes in SCA are often in a state of heightened activation due to chronic inflammation and oxidative stress caused by hemolysis and sickling. Activated leukocytes, particularly neutrophils and monocytes, exhibit increased expression of adhesion molecules and enhanced migratory abilities. The activation of these immune cells leads to the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). These cytokines not only promote the inflammatory response but also contribute to the activation of the endothelium, leading to the upregulation of adhesion molecules that facilitate leukocyte adhesion to the vascular wall. The sustained activation of leukocytes is a critical factor in the initiation and perpetuation of VOC. [16-20]

2. Adhesion to Endothelial Cells

Leukocyte adhesion to the endothelium is a central event in the pathogenesis of VOC. This process is mediated by the interaction between adhesion molecules expressed on endothelial cells and ligands on leukocytes. Key adhesion molecules involved in this interaction include E-selectin, P-selectin, ICAM-1, and VCAM-1. In SCA, the inflammatory environment leads to the upregulation of these adhesion molecules on endothelial cells, enhancing the recruitment of leukocytes to the vascular wall. Once adhered, leukocytes can undergo diapedesis, migrating through the endothelium into the surrounding tissue. This accumulation of leukocytes in the microvasculature contributes to the obstruction of blood flow and exacerbates the ischemic conditions associated with VOC. [21-23]

3. Interaction with Sickled Red Blood Cells

Leukocytes can also directly interact with sickled RBCs, further complicating the pathophysiology of VOC. Activated leukocytes promote the adhesion of sickled RBCs to the endothelium through the expression of adhesion molecules such as PSGL-1 (P-selectin glycoprotein ligand-1) and LFA-1 (lymphocyte function-associated antigen-1). These interactions can lead to increased RBC aggregation and promote vaso-occlusion. Additionally, leukocytes can release inflammatory mediators, including ROS and cytokines, which exacerbate endothelial dysfunction and enhance the sickling process. This feedback loop between leukocytes and sickled RBCs perpetuates inflammation and tissue injury, contributing to the severity of VOC.[24-26]

4. Promotion of Thrombosis

Leukocytes also play a significant role in the pro-thrombotic state observed in SCA. Activated leukocytes release pro-coagulant factors such as tissue factor (TF), which initiates the extrinsic pathway of the coagulation cascade, and platelet-activating factor (PAF), which promotes platelet activation and aggregation. The interaction between activated leukocytes and platelets can lead to the formation of thrombi in the microvasculature, further obstructing blood flow and worsening ischemia. This thrombotic environment is compounded by the presence of sickled RBCs, creating a vicious cycle that exacerbates the risk of VOC. [27-30]

5. Inflammatory Cytokine Release

The release of inflammatory cytokines from activated leukocytes contributes to the pathogenesis of VOC by promoting endothelial activation and dysfunction. Cytokines such as TNF-α and IL-6 can increase the expression of adhesion molecules on endothelial cells, further enhancing leukocyte recruitment and adhesion. Additionally, these cytokines can induce a state of endothelial dysfunction characterized by increased permeability and reduced vasodilation, which exacerbates the conditions leading to VOC. The inflammatory milieu generated by leukocytes can also activate other immune cells, perpetuating the cycle of inflammation and further driving the pathogenesis of VOC. [31-34]

6. Reactive Oxygen Species (ROS) Production

Leukocytes produce reactive oxygen species (ROS) as part of their immune response to pathogens and tissue injury. In SCA, the excessive generation of ROS contributes to oxidative stress and endothelial damage. Elevated ROS levels can lead to the oxidation of lipids, proteins, and DNA, impairing endothelial function and promoting inflammation. ROS can also react with nitric oxide (NO), reducing its bioavailability and further contributing to endothelial dysfunction. The interplay between leukocyte-derived ROS and endothelial cells is critical in the pathogenesis of VOC, as it exacerbates the inflammatory response and promotes vascular obstruction. [35-38]

7. Impact on Hemolysis and Inflammation

The chronic hemolysis observed in SCA leads to the release of free hemoglobin into circulation, which can scavenge nitric oxide (NO) and further contribute to endothelial dysfunction. Inflammatory cytokines released by activated leukocytes can also enhance the rate of hemolysis, creating a feedback loop that perpetuates the cycle of inflammation and vaso-occlusion. This relationship underscores the interconnectedness of hemolysis, inflammation, and leukocyte activation in the pathophysiology of VOC. [39-42]

8. Role of Monocytes and Macrophages

Monocytes and macrophages play a significant role in the inflammatory response in SCA. Upon activation, these cells can produce a variety of pro-inflammatory cytokines and chemokines that attract additional leukocytes to the site of inflammation. Macrophages can also contribute to tissue injury through the release of proteolytic enzymes and ROS. The presence of activated monocytes and macrophages in the microvasculature during VOC can exacerbate tissue damage and enhance the inflammatory response, further promoting the severity of VOC. [43-45]

Therapeutic Implications

Targeted interventions can address the activation, adhesion, and inflammatory processes mediated by leukocytes, as well as their interactions with sickled red blood cells (RBCs) and the vascular endothelium. The following therapeutic implications highlight potential strategies to improve patient outcomes in SCA. Given the pivotal role of inflammation in the pathogenesis of VOC, the use of anti-inflammatory agents represents a promising therapeutic strategy. Medications such as corticosteroids can be employed to reduce the overall inflammatory response during acute VOC episodes. Corticosteroids help to decrease the levels of inflammatory cytokines, thereby reducing leukocyte activation and adhesion to the endothelium. Clinical studies exploring the efficacy of corticosteroids in SCA patients experiencing VOC are warranted to establish optimal dosing and timing for intervention. Targeting the adhesion molecules that facilitate leukocyte-endothelial interactions may provide a means to prevent leukocyte recruitment and accumulation in the microvasculature. Potential interventions could include monoclonal antibodies or small molecule inhibitors that block the interactions between leukocytes and endothelial cells. For example, inhibitors targeting E-selectin, P-selectin, or integrins such as LFA-1 may effectively reduce leukocyte adhesion and, consequently, the incidence of VOC. Research into these adhesion molecule inhibitors is critical for assessing their safety and efficacy in SCA patients. [46-50]

The production of reactive oxygen species (ROS) by activated leukocytes contributes to oxidative stress and endothelial dysfunction in SCA. Antioxidant therapies aimed at reducing oxidative stress may therefore offer therapeutic benefits. Agents such as N-acetylcysteine (NAC), which replenishes intracellular glutathione levels, and vitamin E, a potent lipid-soluble antioxidant, could help mitigate oxidative damage to endothelial cells. Clinical trials investigating the efficacy of these antioxidants in reducing VOC frequency and severity are needed to determine their potential role in SCA management. Strategies aimed at inhibiting leukocyte trafficking may help prevent the migration of activated leukocytes to sites of injury. These interventions could involve the use of chemokine receptor antagonists or small molecules that disrupt leukocyte signaling pathways involved in adhesion and migration. By preventing leukocyte recruitment to the endothelium, these therapies could reduce the inflammatory response and subsequent vascular obstruction associated with VOC. Given the pro-thrombotic state associated with leukocyte activation in SCA, the use of anticoagulant therapies may be beneficial in managing VOC. Low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) can help reduce thrombus formation and improve blood flow during VOC episodes. Research into the appropriate use of anticoagulants in SCA patients is essential to determine their safety and efficacy, particularly in the context of VOC. [51-55]

Hydroxyurea is a cornerstone treatment for SCA, primarily due to its ability to increase fetal hemoglobin levels and reduce leukocyte counts. By decreasing the overall number of circulating leukocytes, hydroxyurea may help mitigate the inflammatory response and reduce the frequency of VOC. Additionally, hydroxyurea has been shown to reduce the expression of adhesion molecules on endothelial cells, further decreasing leukocyte recruitment. Ongoing studies continue to elucidate the full benefits of hydroxyurea in managing SCA complications. Biologic agents that target specific inflammatory cytokines involved in the pathogenesis of VOC may provide another therapeutic avenue. Monoclonal antibodies that inhibit cytokines such as TNF-α or IL-6 could help reduce the inflammatory response and subsequent leukocyte activation. The development of these targeted therapies requires careful evaluation through clinical trials to determine their safety and efficacy in SCA patients. Advancements in gene therapy hold promise for the future of SCA treatment. Approaches aimed at correcting the underlying genetic mutation responsible for sickle hemoglobin production or enhancing the production of fetal hemoglobin could significantly alter the disease course. Gene editing technologies, such as CRISPR/Cas9, offer the potential to directly modify the β-globin gene, potentially reducing the incidence of VOC by addressing the root cause of the disease. [56-60] A multidisciplinary approach to managing SCA can optimize patient outcomes and reduce the frequency of VOC. Comprehensive care strategies should include regular monitoring for signs of VOC, patient education on recognizing early symptoms, and adherence to treatment regimens. Coordination among hematologists, primary care providers, and supportive care specialists is essential to ensure that patients receive comprehensive and individualized care.[61]

Conclusion

Vaso-occlusive crisis (VOC) remains one of the most challenging complications of sickle cell anemia (SCA), characterized by acute pain and significant morbidity. Leukocytes play a central role in the pathophysiology of VOC through their involvement in inflammation, adhesion to the endothelium, and interaction with sickled red blood cells (RBCs). The activation of leukocytes leads to a cascade of events that exacerbates endothelial dysfunction, promotes vascular occlusion, and contributes to the overall inflammatory milieu associated with VOC. Understanding these mechanisms provide valuable insights into the intricate interplay between leukocytes and other components of the blood, paving the way for targeted therapeutic strategies. The potential for developing interventions aimed at modulating leukocyte activity, reducing inflammation, and preventing thrombus formation offers hope for improved management of VOC in SCA patients. Therapeutic approaches, including anti-inflammatory agents, adhesion molecule inhibitors, antioxidant therapies, and anticoagulants, hold promise for alleviating the burden of VOC. Additionally, advancements in gene therapy and comprehensive care strategies may further enhance treatment outcomes for individuals living with sickle cell anemia.

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Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

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Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

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Delcio G Silva Junior

Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

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Ziemlé Clément Méda

Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

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Mina Sherif Soliman Georgy

We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

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Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

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Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

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Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

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Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

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Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

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Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner