RNA sequencing suggests that non-coding RNAs play a role in the development of acquired haemophilia.

Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.

Current therapeutic approaches in the management of hemophilia-a consensus view by the Romanian Society of Hematology.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

Mobile Health Technology for the Personalized Therapy of Hemophilia.

The management of patients with hemophilia has evolved significantly since the first treatment attempts were made in the late 1930s. Since then, each new step in the treatment of patients with hemophilia has brought important advancements, as well as its unique set of challenges. Today, a patient-centered, individualized comprehensive approach is the new paradigm, moving away from the traditional "one size-fits-all" approach, to provide the best possible care for each patient with a bleeding disorder. As part of this complex task, mobile health applications might have the capacity to play an important role in reaching that goal. However, the use of new electronic technologies as part of a comprehensive treatment approach for patients with hemophilia simultaneously presents a new set of challenges that needs consideration. In the first section, currently available treatment of hemophilia patients will be revised, while in the second part the role of IT software in the treatment monitoring of hemophilia patients will be discussed.

The Possible Non-Mutational Causes of FVIII Deficiency: Non-Coding RNAs and Acquired Hemophilia A.

Hemophilia type A (HA) is the most common type of blood coagulation disorder. While the vast majority of cases are inherited and caused by mutations in the F8 gene, recent data raises new questions regarding the non-heritability of this disease, as well as how other molecular mechanisms might lead to the development of HA or increase the severity of the disease. Some data suggest that miRNAs may affect the severity of HA, but for some patients, miRNA-based interference might cause HA, in the absence of an F8 mutation. A mechanism in HA installation that is also worth investigating and which could be identified in the future is the epigenetic silencing of the F8 gene that might be only temporarily. Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified.

A narrative review of central nervous system involvement in acute leukemias.

Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia.

The Influence of Methylating Mutations on Acute Myeloid Leukemia: Preliminary Analysis on 56 Patients.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by abnormal proliferation and a lack of differentiation of myeloid blasts. Considering the dismal prognosis this disease presents, several efforts have been made to better classify it and offer a tailored treatment to each subtype. This has been formally done by the World Health Organization (WHO) with the AML classification schemes from 2008 and 2016. Nonetheless, there are still mutations that are not currently included in the WHO AML classification, as in the case of some mutations that influence methylation. In this regard, the present study aimed to determine if some of the mutations that influence DNA methylation can be clustered together regarding methylation, expression, and clinical profile. Data from the TCGA LAML cohort were downloaded via cBioPortal. The analysis was performed using R 3.5.2, and the necessary packages for classical statistics, dimensionality reduction, and machine learning. We included only patients that presented mutations in DNMT3A, TET2, IDH1/2, ASXL1, WT1, and KMT2A. Afterwards, mutations that were present in too few patients were removed from the analysis, thus including a total of 57 AML patients. We observed that regarding expression, methylation, and clinical profile, patients with mutated TET2, IDH1/2, and WT1 presented a high degree of similarity, indicating the equivalence that these mutations present between themselves. Nonetheless, we did not observe this similarity between DNMT3A- and KMT2A-mutated AML. Moreover, when comparing the hypermethylating group with the hypomethylating one, we also observed important differences regarding expression, methylation, and clinical profile. In the current manuscript we offer additional arguments for the similarity of the studied hypermethylating mutations and suggest that those should be clustered together in further classifications. The hypermethylating and hypomethylating groups formed above were shown to be different from each other considering overall survival, methylation profile, expression profile, and clinical characteristics. In this manuscript, we present additional arguments for the similarity of the effect generated by TET2, IDH1/2, and WT1 mutations in AML patients. Thus, we hypothesize that hypermethylating mutations skew the AML cells to a similar phenotype with a possible sensitivity to hypermethylating agents.