Immune thrombocytopenia: a review on the pathogenetic role of immune cells.

INTRODUCTION: Immune thrombocytopenia [ITP] is a common bleeding disorder with an isolated platelet count of less than 100 × 109/L. AREAS COVERED: Relevant literature from 2003 to 2022 was retrieved and reviewed from the Google Scholar search engine and PubMed database. Antibodies produced by autoreactive B lymphocytes and the phagocytic function of macrophages are considered the most critical factors in platelet destruction. Also, macrophages present the antigen to T lymphocytes and activate them. Follicular helper T-cells [TFH] play a role in stimulating, differentiating, and activating autoreactive B cells, while cluster of differentiation [CD]-8+ T plays a role in platelet destruction through apoptosis. The classical pathway of the complement system also causes platelet destruction. By inhibiting platelet production, low levels of thrombopoietin and an immune response against megakaryocytes in the bone marrow worsen thrombocytopenia. EXPERT OPINION: T-cell subset changes and an increase in activated autoreactive B cells, in addition to the function of components of the innate immune system [the complement system, dendritic cells, and natural killer cells], play a critical role in the pathogenesis of the ITP. Accurate detection of these changes may lead to developing new therapeutic strategies and identifying better prognostic/diagnostic factors.

Bone marrow alterations in COVID-19 infection: The root of hematological problems.

INTRODUCTION: The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow. METHOD: To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms "COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia. RESULTS: Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations. CONCLUSION: To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.

Evaluation of HLA-B*05, *07, *08, *27 and *51 Allele Expression in Adults with Immune Thrombocytopenic Purpura.

Background: Immune thrombocytopenic purpura (ITP) is an immune mediated acquired disease characterized by isolated thrombocytopenia. Since there is no specific and sensitive biomarkers to guide treatment of ITP patients, this study aimed to evaluate the possible application of human leukocyte alleles HLA-B5, 7, 8, 27 and 51 and their association with patients' laboratory data and clinical findings. Methods:Thirty-one adult patients with chronic ITP were included in the present study. Human leukocyte antigen (HLA) typing was done using the standard lymphocytotoxicity HLA typing method. Moreover, patients' medical records were used to collect data about disease presentations, platelet count at diagnosis. Results:Our study included 31 patients (25 females and six males) with a mean age of 40.23±17.06 years. Among all participants, HLA-B5 (25.8%) and HLA-B51 (22.6%) alleles were the most prevalent alleles, followed by HLA-B7 (9.7%) and HLA-B8 (9.7%), HLA-B27 (3.2%). The mean platelet count significantly was lower in patients with HLA-B5 (16.13x10³/µL versus 36.63x10³/µL) (P=0.01) and HLA-B51 (14.14x10³/µL versus 36.24x10³/µL) (P=0.04). Also, epistaxis and gingival bleeding were observed in patients with 11.5x10³/µL mean platelet count (P=0.04). In addition, lymphocyte and neutrophil cell counts were significantly associated with the expression of HLA-B*05 and HLA-B*51 antigens (P <0.05). Conclusions:According to the present study results, it seems that HLA-B5 and HLA-B51 alongside complete blood count test parameters may have a positive relationship in ITP patients.

Diabetes mellitus and COVID-19: review of a lethal interaction from the cellular and molecular level to the bedside.

INTRODUCTION: While the main mode of transmission of coronavirus disease 2019 (COVID-19) is close contact with other individuals, the presence of chronic underlying diseases such as Diabetes Mellitus (DM) increases the chance of hospitalization and mortality rate due to infection. AREAS COVERED: To investigate the effects of COVID-19 infection in DM patients, we reviewed literature from Google Scholar search engine and PubMed database from '2013 to 2020' using the terms "COVID-19; SARS-CoV-2; Diabetes mellitus; obesity; Angiotensin-converting enzyme 2; ACE2; Insulin and Metformin. Evidence suggests that COVID-19 exacerbates the course of diabetes. Presence of pro-inflammatory conditions, increased expression of receptors, and more difficult control of glucose levels in diabetics COVID-19 patients are some of the problems that diabetic patients may face. Also, psychological problems caused by the COVID-19 epidemic in diabetic patients is one of the most important problems in these patients, which is less covered. EXPERT OPINION: DM is a strong and independent risk factor with a poor prognosis, which increases the risk of COVID-19 infection, the need for emergency services, the rate of hospitalization in the intensive care unit and also increases the mortality rate of COVID-19 patients.

Effect of Helicobacter Pylori eradication on patients with ITP: a meta-analysis of studies conducted in the Middle East.

BACKGROUND: Immune thrombocytopenia (ITP) is a bleeding disorder. Helicobacter pylori is a Gram-negative bacterium that is presumed to be associated with ITP and therapeutic response of patients. To evaluate the effect of H. pylori eradication on platelet count of ITP patients, we analyzed the studies conducted on the association between H. pylori infection and response to therapy in ITP patients in Western Asia focusing on the Middle East region. METHODS: A systematic search of databases (PubMed/Medline, ISI Web of Science, Cochrane Central) and Google Scholar search engine results was conducted up until January 2020. The keywords included in the search were Helicobacter pylori and/or H. pylori, ITP and/or immune thrombocytopenia. RESULTS: Seven studies comprising a total of 228 H. pylori-infected patients (193 with successful eradication) were included in this study. The association between H. pylori eradication and ITP was expressed as odds ratios (OR) and 95% confidence intervals (CI). The findings showed that patients who received eradication treatment for H. pylori infection had significantly higher OR (OR, 8.83; 95% CI, 2.03‒38.35; P =0.004) than those in the non-eradicated group. CONCLUSION: Our results indicate a significant therapeutic effect of H. pylori eradication on the platelet count of patients with chronic ITP. Given the inherent limitations of this study, including the small number of patients, further studies with more patients are recommended.

DNA repair pathways as guardians of the genome: Therapeutic potential and possible prognostic role in hematologic neoplasms.

DNA repair pathways, which are also identified as guardians of the genome, protect cells from frequent damage that can lead to DNA breaks. The most deleterious types of damage are double-strand breaks (DSBs), which are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). Single strand breaks (SSBs) can be corrected through base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Failure to restore DNA lesions or inappropriately repaired DNA damage culminates in genomic instability and changes in the regulation of cellular functions. Intriguingly, particular mutations and translocations are accompanied by special types of leukemia. Besides, expression patterns of certain repair genes are altered in different hematologic malignancies. Moreover, analysis of mutations in key mediators of DNA damage repair (DDR) pathways, as well as investigation of their expression and function, may provide us with emerging biomarkers of response/resistance to treatment. Therefore, defective DDR pathways can offer a rational starting point for developing DNA repair-targeted drugs. In this review, we address genetic alterations and gene/protein expression changes, as well as provide an overview of DNA repair pathways.

Co-existence of mutations in myeloproliferative neoplasms and their clinical significance: a prognostic approach.

OBJECTIVE: Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders that may occur after one or more mutations in hematopoietic progenitor cells. In this study, we will review the co-existence of mutations (especially dual mutations) in MPNs and its effect on the prognosis of patients. METHODS: To find relevant published papers, we systematically searched six major international indexing databases, namely PubMed/Medline, EmBase, Cochrane central, ISI web of science, and Scopus from Feb. 2000 until Jan. 2020. We included the following keywords in the analyzes: Myeloproliferative Disorders, Mutation, Co-existence of Mutations, Acute myeloid leukemia. RESULTS: Co-existence of several mutations in MPNs is mainly associated with a poor prognosis compared with the unimutated MPN disorders. There are several effective factors such as sequence of mutations, incidence of mutations in one cell or different cells, mutation, and MPN type. CONCLUSION AND EXPERT COMMENTARY: It seems that monitoring the status of mutations in MPNs and recognizing the co-existence of mutations (especially dual mutations) in order to determine prognosis and possibility of progression to acute form of leukemia can lead to the prediction of prognosis in MPN patients as well as establishment of better and more reliable therapeutic strategies for patients.

Cardiomyopathy in Thalassemia: Quick Review from Cellular Aspects to Diagnosis and Current Treatments.

BACKGROUND: Cardiomyopathic manifestations induced by continuous blood transfusion are the leading cause of death among patients with thalassemia major (TM). Despite introduction of chelation therapy, heart failure after cardiomyopathic manifestations is still a major threat to patients. METHODS: We performed a search of relevant English-language literature, retrieving publications from the PubMed database and the Google Scholar search engine (2005-2018). We used "thalassemia major", "cardiomyopathy", "iron overload", "cardiac magnetic resonance T2" "chelation therapy", and "iron burden" as keywords. RESULTS: The results of the studies we found suggest that cardiac hepcidin is a major regulator of iron homeostasis in cardiac tissue. Unlike previous assumptions, the heart appears to have a limited regeneration capability, originating from a small population of hypoxic cardiomyocytes. CONCLUSIONS: Oxygen levels determine cardiomyocyte gene-expression patterns. Upregulation of cardiac hepcidin in hypoxia preserves cardiomyocytes from forming out of reactive oxygen species catalyzed by free cellular iron in cardiomyocytes. Using the limited regeneration capacity of cardiac cells and gaining further understanding of the cellular aspects of cardiomyopathic manifestations may help health care professionals to develop new therapeutic strategies.

HLA-B5, 7, 8, 27, and 51 Antigens and Immune Thrombocytopenic Purpura: Is There an Association?

BACKGROUND: Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by low platelet counts in peripheral blood, impairment of thrombopoiesis in bone marrow, and risk of mild to severe bleedings. ITP can be seen among both sexes in different ages. Although definitive pathogenesis of this disorder is still ambiguous, some of risk factors for ITP are recognized, including human leukocyte antigens (HLAs). OBJECTIVE: Our goal was to evaluate the possible association between HLA-B5, 7, 8, 27, and 51 antigens with ITP for the first time. We were hoping to achieve new hypothetical diagnostic/prognostic biomarkers to introduce a new subject for further studies on HLA class I antigens as possible risk factors for ITP. MATERIALS AND METHODS: A total of 37 patients with ITP were included in this study. After confirmation of ITP diagnosis, peripheral blood samples were collected from them. The expression of each of HLA antigens was evaluated by standard lymphocytotoxicity technique. RESULTS: Compared with other studied antigens, the expression of HLA-B5 and HLA-B51 was more prevalent among our patients. According to the results, 22% of patients were positive for HLA-B5 and HLA-B51. Furthermore, no significant association was found between HLAs expressions with complete blood count parameters. CONCLUSIONS: We conclude that there is an association between HLA-B5 and HLA-B51 with ITP and that they are not likely to be used as diagnostic or prognostic biomarkers. We suggest studying the association between HLA-B antigens and ITP in large-scale studies to determine whether or not there is a significant association.

Evaluation of complete blood count parameters in cardiovascular diseases: An early indicator of prognosis?

BACKGROUND: Studies have been conducted to evaluate the correlation between complete blood count (CBC) indices and cardiovascular diseases (CVDs). Considering the dispersion of these studies as well as reports on prognostic value of CBC parameters in CVDs, we have summarized these findings as a review article for the first time. METHODS: Relevant English language literature was searched and retrieved from Google Scholar search engine and PubMed database (1996-2018). We used "Complete blood count", "Cardiovascular disease", "Red cell distribution width", and "Mean platelet volume" as keywords. RESULTS: Numerous studies indicated that red cell distribution width (RDW) is an independent prognostic biomarker in relation to CVD diseases. MPV is another considerable prognostic biomarker for CVDs. Elevations of inflammatory markers such as neutrophil to lymphocyte ratio (NLR) in CVD patients (especially in myocardial infarction and heart failure) can be considered as a factor of poor prognosis. CONCLUSIONS: RDW can be used as a valuable independent biomarker to investigate the prognosis of patients with heart failure (HF), atherosclerosis, myocardial infarction (MI), and other CVDs. Rapid and stable increase in MPV makes it a reliable prognostic/diagnostic parameter in CVDs such as MI and unstable angina. Among different inflammatory markers the evaluation of total white blood cell count, NLR, monocyte to high-density lipoprotein ratio (MHR) and platelet to lymphocyte ratio (PLR) may have a high value in predicting the prognosis of different CVDs including MI, HF and atherosclerosis in patients.

HLAs in Autoimmune Diseases: Dependable Diagnostic Biomarkers?

BACKGROUND: The process of antigen presentation to immune cells is an undeniable contributor to the pathogenesis of autoimmune diseases. Different studies have indicated several factors that are related to autoimmunity. Human Leukocyte Antigens (HLAs) are among such factors, which have a key role in autoimmunity because of their involvement in antigen presentation process. METHODS: Relevant English language literature was searched and retrieved from Google Scholar search engine and PubMed database (1996-2018). The following keywords were used: "Human leukocyte antigen", "Behcet's syndrome", "Rheumatoid arthritis", "Systemic lupus erythematosus", "Type 1 diabetes", "Celiac Disease" and "Autoimmunity". RESULTS: There is a strong association between HLA alleles and autoimmune diseases. For instance, HLA-B alleles and Behcet's syndrome are strongly correlated, and systemic lupus erythematosus and Type 1 diabetes are related to HLA-DQA1 and HLA-DQB1, respectively. CONCLUSION: Association between numerous HLA alleles and autoimmune diseases may justify and rationalize their use as biomarkers as well as possible diagnostic laboratory parameters.

The Association Between Human Leukocyte Antigens and ITP, TTP, and HIT.

BACKGROUND: Autoimmune thrombocytopenia in immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and heparin-induced thrombocytopenia (HIT) is associated with immunologic degradation of platelets and reduced platelet counts in patients, leading to bleeding risk in patients. Considering the role of human leukocyte antigens (HLA) in the development of immune response, in this review, we examine the relationship between HLA and pathogenesis of the above-mentioned diseases. METHODS: Relevant English-language literature was searched and retrieved from Google Scholar search engine and PubMed database (1979 to 2018). The following keywords were used: "Immune Thrombocytopenic purpura," "Thrombotic Thrombocytopenic Purpura," Human Leukocyte Antigen," and "Heparin-induced thrombocytopenia." RESULTS: In autoimmune thrombocytopenia, HLA molecule presents self-antigens or foreign antigens similar to self-antigens, provoking an immune response against platelets that results in the degradation of platelets in peripheral blood and possible bleeding in the patient. For example, HLA-DRB1 *11 presents the self-antigen and induces an immune response against ADAMTS13, which is associated with thrombocytopenia in TTP patients. CONCLUSIONS: HLA alleles can be used as prognostic biomarkers for immunologic disorders of platelet such as ITP, TTP, and HIT. Different DRB1 alleles enable the assessment of resistance to common ITP treatments as well as disease prognosis. Due to the genetic association between HLA-DR1 and HLA-DQ1 alleles and the role of HLA-DRB1 *11 in TTP, the HLA-DQB1 *02: 02 allele may also play a role in TTP pathogenesis.

Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias.

Several factors such as chromosomal translocations, gene mutations, and polymorphisms are involved in the pathogenesis of leukemia/lymphoma. Recently, the role of vitamin D (VD) and vitamin D receptor (VDR) polymorphisms in hematologic malignancies has been considered. In this review, we examine the possible role of VD levels, as well as VDR polymorphisms as prognostic biomarkers in leukemia/lymphoma. Relevant English language literature were searched and retrieved from Google Scholar search engine (1985-2017). The following keywords were used: vitamin D, vitamin D receptor, leukemia, lymphoma, and polymorphism. Increased serum levels of VD in patients with leukemia are associated with a better prognosis. However, low VD levels are associated with a poor prognosis, and VDR polymorphisms in various leukemias can have prognostic value. VD biomarker can be regarded as a potential prognostic factor for a number of leukemias, including acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL). There is a significant relationship between different polymorphisms of VDR (including Taq I and Fok I) with several leukemia types such as ALL and AML, which may have prognostic value.