Genetics and Epigenetics in Acquired Hemophilia A: From Bench to Bedside.

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of FVIII. Several factors have been associated with the activation of the auto-immunity towards FVIII. Emerging evidence implicates CD4+ T cell activation in mediating this autoimmune response, with their involvement like that observed in congenital hemophilia A. Several genes such as HLA II DRB*16, DQB1*0502, and CTLA-4 + 49 are responsible for the pathogenesis of AHA. Epigenetic modifications and mainly long-coding RNAS (lncRNAs) are potentially contributing to the pathogenesis of AHA. The treatment approach of AHA includes the management of acute bleeding events and the administration of immunosuppressive medications. This review aimed to summarize the published data on the genetics and epigenetics of AHA. The severity and the mortality of this disease are creating an emerging need for further research in the field of the genetics and epigenetics of acquired hemorrhagic disorder.

How to Manage a Patient with Haemophilia and ACS Requiring PCI: A Battle between Bleeding and Thrombosis.

We present the case of a 70-year-old man with a history of haemophilia B, who presented to our hospital with a non-ST-elevation myocardial infarction. The patient, following consultation by a haemophilia expert, was revascularized with percutaneous coronary intervention (PCI) under adequate clotting factor administration. Patients with haemophilia and acute coronary syndrome, are susceptible to periprocedural bleeding and thrombotic events during PCI, and therefore a balanced management plan should always be implemented by a multidisciplinary team.

Rivaroxaban Use in Patients with Hemoglobinopathies.

The use of rivaroxaban in patients with hemoglobinopathies and thrombotic events has not been studied extensively. Here we present eight cases of such patients, five receiving rivaroxaban for stroke and systemic embolism prevention due to non-valvular atrial fibrillation and three for deep vein thrombosis treatment. The follow-up period ranged from 6 to 34 months. During this period none of the patients experienced any thrombotic or bleeding event.There were no other adverse events reported. Further studies with larger numbers of patients with hemoglobinopathies are needed to determine the use of rivaroxaban and ensure its safety in this patient setting.

Evaluation of Mental Health and Physical Pain in Patients with ß-Thalassemia Major in Northern Greece.

ß-Thalassemia major (ß-TM) is a chronic, genetic blood disorder. Patients are considered to be vulnerable to emotional and behavioral problems. The aim of this study was to assess mental health and somatic pain of patients with homozygous ß-TM, who are systematically transfused in our unit. In this survey, 54 adult patients were studied. The general health questionnaire (GHQ-28) was used as mental health assessment model aimed at detecting mental disorders. The model of Binary was used as scoring method of GHQ-28. Overall ratings below 5 indicate no psychiatric problem, while a total score over or equal to 5 indicated the likelihood of a psychiatric disorder. The visual analogue scale (VAS) of pain was used as model for pain evaluation. One out of four examined patients who presented with a GHQ-28 score above or equal to 5 had an increased chance of being diagnosed with a psychiatric disorder. Concerning the pain, the majority of the studied patients scored between 1 and 3, meaning that they were feeling mild pain. There was no statistical significant correlation between age and GHQ-28 score. There was a statistical significant correlation between age and somatic symptoms (p = 0.026), anxiety and somatic symptoms (0.004) as well as anxiety and depression (p = 0.022). Thalassemic patients tend to be diagnosed with psychiatric disorders and it seems that they do not feel severe pain. More quantitative and comprehensive studies have to be conducted in order to estimate specific effective factors in psychosocial health.

A Retrospective Observational Study of Quality of Life in a Northern Greece Population of People with Haemophilia.

Haemophilia presents a significant challenge to the quality of life of affected individuals. Evaluating the health-related quality of life (HRQoL) of people with haemophilia (PwH) provides a valuable mean of assessing their perception of overall care outcomes, while also identifying influential factors across various age and condition severity demographics. This observational retrospective study determined the HRQoL of 100 adult PwH in Northern Greece through comprehensive analysis and interpretation of their HRQoL levels, particularly in domains concerning their physical, emotional, and mental well-being, obtained through the Haem-A-QoL index questionnaire. Disease severity and young age were significantly associated with the administration of prophylactic treatment (84.2% of patients with severe haemophilia and 65.2% of patients aged 18-30). The mean Haem-A-QoL score was 40.11 ± 17.38, with the lowest HRQoL observed in the 46-60 age group (46.16), and the highest in the ≥61 age groups (35.16). Notably, the 'Sports/Leisure' and 'Physical Health' domains exhibited the highest scores, in contrast to 'Family Planning' and 'Relationships/Sexuality'. Individuals with mild haemophilia recorded the lowest mean score (39.38), while those with a severe condition exhibited the highest (41.23). Age, disease severity, and physical activity emerged as primary determinants significantly affecting HRQoL outcomes.

Application of Multicriteria Decision Analysis to Determine the Value of Prophylaxis Relative to On-Demand Treatment in Hemophilia A and Emicizumab versus Replacement Therapy in the Greek Healthcare Setting.

BACKGROUND AND OBJECTIVE: Hemophilia A (HA) is a rare disease that is characterized by congenital underproduction or dysfunction of the endogenous coagulation factor VIII (FVIII). The aim of the present study was to determine the value of prophylaxis versus on-demand treatment strategies for moderate to severe HA (MtSHA) patients and the value of emicizumab in the prophylaxis of MtSHA in Greece, compared with short half-life (SHL) FVIII and extended half-life (EHL) FVIII through multicriteria decision analysis (MCDA). METHODS: A literature review was performed to identify a set of criteria relevant to the therapeutic approaches and therapies under investigation. A performance matrix was populated by two literature reviews and meta-analyses. The criteria selected were hierarchically classified by allocating weights on a 0-100 scale. The performances of therapies were scored at the 100-point scale. The value judgments utilized for weighing and scoring were sourced via a survey among independent multidisciplinary system stakeholders. A linear additive value function was used for the calculation of total value estimates. RESULTS: The participants ranked 'annual number of bleedings per patient' and 'percentage of target joint bleeds' as the most important criteria, while the least important criterion was the 'annual treatment cost' for both assessments. Based on the weights elicited and the performance in each criterion, the overall value score was higher for prophylaxis treatment (58.27) compared with on-demand treatment (40.13). In the other comparison, the most valued treatment was emicizumab (77.05) followed by EHL FVIII (71.52) and SHL FVIII (19.88). According to the participants, the most important factors for managing MtSHA patients are those related to successful management of bleeding events given their contribution to improved quality of life (QoL) and reduced morbidity. CONCLUSIONS: This MCDA has shown that the prophylaxis strategy was perceived as a more valuable option for managing MtSHA patients when compared with the on-demand strategy. Moreover, emicizumab adds higher value and improves patient QoL compared with replacement therapy for MtSHA in Greece. Emicizumab addresses important unmet needs due to its improved efficacy and mode of administration.

Th17 and Foxp3(+) T regulatory cell dynamics and distribution in myelodysplastic syndromes.

Foxp3(+) T regulatory cells (Tregs) and Th17 cells accumulate synchronously at tumor sites during cancer progression, where their interplay is apparently affecting the efficiency of the antitumor response. In myelodysplastic syndromes, a hematopoietic malignancy of myeloid origin, Tregs are highly increased in the late stages of the disease (L-MDS), but the mechanisms driving Treg expansion and the interaction between Treg and Th17 cell dynamics are still unknown. We demonstrate that the proliferative capacity of Tregs is deficient during the early MDS stages (E-MDS), while in L-MDS it returns to normal levels. In addition, synchronously to Treg expansion, L-MDS patients exhibit increased numbers of functionally competent bone marrow IL-17(+) and FOXP3(+)/IL-17(+) cells, in contrast to E-MDS patients, where Th17 cells are significantly decreased and hypofunctional. Our findings suggest similar kinetics of Treg and Th17 cells between MDS and solid tumors, indicating a common immune pathogenetic pathway between diverse cancer types.

Successful Outcome of Severe Intra-cerebral Bleeding Associated with Acquired Factor V Inhibition: Utilization of Multiple Therapeutic Agents.

BACKGROUND: Acquired coagulation factor inhibitors are antibodies that either inhibit activity or increase the clearance of a clotting factor and lead to an increased risk of bleeding. Most of the time, the disorder is attributed to factor VIII inhibition (acquired haemophilia A); however, other coagulation factors could also be implicated. CASE REPORT: Herein, we report an interesting case of a patient who underwent coronary artery bypass grafting and received antibiotic treatment after surgery with third generation cephalosporin. A month later, he presented with extreme bleeding diathesis and cerebral haemorrhage. Following a thorough clinical and laboratory investigation, an acquired factor V inhibitor was diagnosed. The patient received treatment with corticosteroids, intravenous immunoglobulins, anti-CD20 monoclonal antibodies (rituximab), cyclophosphamide and recombinant factor VIIa. Finally, despite the poor initial prognosis, the patient managed to achieve a full recovery. CONCLUSION: As there are no clear guidelines on acquired coagulation inhibitor treatment, reports of such cases could offer insight for future therapy choices. The case was unique because the treatment regimen included a combination of multiple therapeutic agents including rituximab.

Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia.

Osteoporosis has emerged as an important cause of morbidity in patients with thalassemia major. Studies regarding the efficacy of bisphosphonates in thalassemia-induced osteoporosis have yielded conflicting results. We performed this prospective study to evaluate the efficacy of zoledronic acid in osteoporotic patients with thalassemia major. Patients, 29, were given 1 mg zoledronic acid intravenously every 3 months for a total of four doses. Twenty age- and sex-matched healthy blood donors served as controls. Before each infusion and 3 months after the last infusion, we determined serum levels of osteoprotegerin (OPG), N-terminal cross-linking telopeptide of type I collagen (NTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1). Bone mineral density (BMD) of the lumbar spine was measured at baseline and after the treatment's completion. At baseline, OPG did not differ significantly between patients and controls (p=0.2), NTX were higher in patients although not significantly (p=0.139), whereas, OC levels were significantly higher and IGF-1 levels significantly lower in patients than in controls (p<0.001 and p<0.006, respectively). Zoledronic acid administration resulted in a significant decrease in NTX, OC and IGF-1 (p<0.05, p<0.001 and p<0.05, respectively) and in a significant increase in OPG and BMD (p<0.05 for both comparisons). The change in NTX, osteocalcin and IGF-1 became significant as early as 3 months after the first administration of zoledronic acid, while the change in OPG reached significance only after three infusions. Our study supports the effectiveness of bisphosphonates in the treatment of thalassemia-induced osteoporosis.

Expression of the activation markers Blimp1, Foxp1 and pStat3 in extranodal diffuse large B-cell lymphomas.

Different studies have suggested that the expression of biomarkers related to lymphoid cell activation may provide information on the behavior of DLBCL. Most studies have concentrated on nodal or a mixture of nodal and extranodal lymphomas. The differential expression and potential clinical impact of these markers in a homogeneous group of extranodal DLBCLs are not well defined. In this study, we investigated the expression of three activation markers, Blimp1, Foxp1 and pStat3, in a cohort of 35 extranodal DLBCLs homogeneously treated with R-CHOP. Immunohistochemical stains were evaluated using an immunoreactivity score on representative paraffin sections. Blimp1 was positive in 55% (19/35), Foxp1 in 60% (21/35), and pStat3 in 69% (24/35) of our cases. We did not observe any statistical differences in the expression of these markers in GCB and non-GCB tumors or in gastrointestinal and non-gastrointestinal tumors. Blimp1 expression was negatively correlated with overall survival (OS) (p=0.001) in the whole series and in the non-GCB group (Muris algorithm) (p=0.002). Foxp1 positivity and pStat3 positivity had no impact on the outcome of the patients in the global cohort, but they were associated with a better survival in the non-GCB subgroup (p=0.033, p=0.044 respectively). Multivariate analysis showed that Blimp1 expression but not COO was an independent negative prognostic factor for OS (HR=17.5, 95%, CI=2.2-141.1, p=0.007). Our results suggest that these markers are differentially expressed and have different impacts on outcome in extranodal DLBCLs compared to nodal tumors, emphasizing the need to evaluate separately these and probably other markers in these subsets of tumors.

A case of successful management with splenectomy of intractable ascites due to congenital dyserythropoietic anemia type II-induced cirrhosis.

The congenital dyserythropoietic anemias comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by characteristic morphological aberrations of the majority of erythroblasts in the bone marrow. Congenital dyserythropoietic anemia type II is the most frequent type. All types of congenital dyserythropoietic anemias distinctly share a high incidence of iron loading. Iron accumulation occurs even in untransfused patients and can result in heart failure and liver cirrhosis. We have reported about a patient who presented with liver cirrhosis and intractable ascites caused by congenital dyserythropoietic anemia type II. Her clinical course was further complicated by the development of autoimmune hemolytic anemia. Splenectomy was eventually performed which achieved complete resolution of ascites, increase of hemoglobin concentration and abrogation of transfusion requirements.

Understanding cardiovascular risk in hemophilia: A step towards prevention and management.

Advances in hemophilia care have led to increased life expectancy and new challenges in the management of the aging hemophilia population, including cardiovascular risk. Despite the deep knowledge into cardiovascular disease in terms of pathophysiology, risk prediction, prevention, early detection and management gained over the last decades, studies in hemophiliacs are scarce and mainly descriptive. As a growing amount of evidence points towards a similar or increased prevalence of traditional cardiovascular risk factors in hemophilia compared to the general population, the role of non-traditional, disease-related and treatment-related cardiovascular risk factors remains under investigation. Better understanding of cardiovascular risk in hemophilia is mandatory for proper cardiovascular risk prevention and management. Therefore, this review aims to summarize current knowledge on cardiovascular risk in hemophilia patients focusing on a) cardiovascular risk factors (traditional, non-traditional, disease-related and treatment-related), b) cardiovascular morbidity and mortality and c) cardiovascular prevention and management.

The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine.

PURPOSE: Azacitidine is the mainstay of high-risk myelodysplastic syndromes (MDS) therapy, but molecular predictors of response and the mechanisms of resistance to azacitidine remain largely unidentified. Deregulation of signaling via Stat3 and Stat5 in acute myeloid leukemia (AML) is associated with aggressive disease. Numerous genes involved in cell signaling are aberrantly methylated in MDS, yet the alterations and the effect of azacitidine treatment on Stat3/5 signaling in high-risk MDS have not been explored. EXPERIMENTAL DESIGN: We assessed longitudinally constitutive and ligand-induced phospho-Stat3/5 signaling responses by multiparametric flow cytometry in 74 patients with MDS and low blast count AML undergoing azacitidine therapy. Pretreatment Stat3/5 signaling profiles in CD34(+)cells were grouped by unsupervised clustering. The differentiation stage and the molecular properties of the CD34(+)G-CSF-inducible Stat3/5 double-positive subpopulation were performed by flow cytometry and quantitative real-time PCR in isolated MDS progenitors. RESULTS: The pretreatment Stat3/5 signaling profiles in CD34(+)cells correlated strongly with response and cytogenetics and independently predicted event-free survival. We further identified a CD34(+)G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype. CONCLUSIONS: Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target.

Primary non-Hodgkin's lymphoma arising in an intramammary lymph node.

Non-Hodgkin's lymphoma (NHL) of the breast may be primary or secondary. Both are rare and there are no morphological criteria to make the differential diagnosis. Benign intramammary lymph nodes are often encountered, but the development of either primary or secondary lymphoma within an intramammary lymph node is extremely rare. We report the case of a 72-year-old woman who presented with a palpable mass in her right breast. A mammography showed a large intramammary lymph node from which a biopsy was taken. On morphological and immunohistochemical examination the tumor fulfilled the criteria of NHL originating in an intramammary lymph node. The patient received chemotherapy which led to the disappearance of the mass. A review of the literature revealed that this is the third reported case of primary NHL originating in an intramammary lymph node.

Acute large bowel pseudo-obstruction due to multiple myeloma.

Involvement of the gastrointestinal (GI) tract by multiple myeloma (MM) is extremely rare. The small intestine and stomach are the most frequent sites of spread. We report 1 case of a 61-year-old woman who presented with clinical and radiographic features of an acute large bowel pseudo-obstruction. An abdominal computerized tomography (CT) showed a large tumor of the rectum. On morphological and immunohistochemical examination the tumor fulfilled the criteria of MM. The patient received combined chemotherapy and radiotherapy which led to the disappearance of the tumor. A review of the literature revealed that this is the first reported case of MM presented as acute large bowel pseudo-obstruction due to a rectal myeloma tumor.

Treatment of recurrent gastrointestinal haemorrhage in a patient with von Willebrand's disease with administration of octreotide LAR and propranolol.

We report a patient with von Willebrand' s disease who had had recurrent and life-threatening bleeding from the gastrointestinal tract. Despite extensive investigation, no apparent cause of haemorrhage was identified. He was successfully treated with combined administration of octreotide LAR (long-acting release) and propranolol. This is the first report on the successful use of octreotide LAR in a patient with von Willebrand' s disease.

Successful Treatment of Severe Anemia using Erythropoietin in a Jehovah Witness with Non-Hodgkin Lymphoma.

Blood transfusion many times works in a life-saving way when a patient is facing a critical situation. However, some patients, such as Jehovah's Witnesses, may refuse their administration because it opposes to their religion beliefs. Thus, clinicians are forced to respect patients' preferences and seek other treatments in order to overcome the obstacle of the transfusion. In 1989, recombinant human erythropoietin (rHuEPO) was approved by the United States Food and Drug Administration (FDA) for the treatment of anemia associated with chronic renal failure. This is an amino acid glycol-protein that stimulates red blood cell production in the same manner as endogenous erythropoietin. Other treatment indications approved by the FDA include anemia due to chronic kidney disease, anemia secondary to zidovudine therapy in patients with human immunodeficiency virus infection, and anemia secondary to cancer chemotherapy. The drug also has been used for many off-label indications. Many Jehovah's Witnesses have accepted rHuEPO as a treatment option to maintain and enhance erythropoiesis. This paper reports the case of a 57-year-old Jehovah's Witness man, who was diagnosed with severe anemia due to aggressive non Hodgkin lymphoma and refused transfusion of blood; thanks to the treatment with rHuEPO he has managed to complete chemotherapy and has survived a life threatening situation.