Prophylaxis in hemophilia

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis ­ the regular administration of therapeutic products to maintain hemostasis and prevent bleeding ­ is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs.

Hemophilia: a biography on therapeutical approaches

The history of hemophilia is ancient, with descriptions dated to the 2nd century AD. The first modern narratives appeared in 1800s, when total blood transfusion was the only available treatment and life expectancy was remarkably low. Advances occurred with the use of plasma and cryoprecipitate, but only the discovered of factor concentrates revolutionized the treatment. The implantation of prophylaxis allowed hemophilic patients to prevent bleeding and the development of chronic arthropathy, although with a significant burdensome with the regular infusions. In the past 20 years, this field has witnessed major improvements, including the development of gene therapy and other pharmacological approaches.

Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial.

Introduction: Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials. Methods: This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n = 4) received SMT plus 5 infusions of 1 × 106 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann-Whitney U test for quantitative variables. The Kaplan-Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%. Results: Nine patients with a mean Child-Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0). Conclusion: BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3.

Epidemiological characteristics of hemophilia in the pre-primary prophylaxis era: a historical cohort

Introduction: Epidemiological studies on hemophilia in the Brazilian population are historically scarce. Despite the continuous effort made by the National Program of Inherited Bleeding Disorders to map this condition, little information is available, especially on the period prior to program conception. Therefore, the present study aims to assess the epidemiological, serological, and clinical characteristics of patients with hemophilia in the state of Rio Grande do Sul, Brazil. Methods: A total of 455 patients had their medical records reviewed from January 1, 2003 to December 31, 2007. Results: We observed a remarkable prevalence of hepatitis C virus (HCV) infection in patients with both hemophilia A and B, and this prevalence significantly increased along with age (p < 0.001). No positive anti-HCV results were observed among children younger than 5 years old. There was a significant correlation between the severity of hemophilia and the number of arthropathies in all age categories. Considering the presence of inhibitors, a significant difference was observed between age groups, as older patients had higher inhibitor titers. There was a significant correlation between mean coagulation factor consumption and the number of arthropathies in patients over 5 years old. Conclusions: This profile analysis of patients with hemophilia reflects a gradual improvement in treatment safety and efficiency, as well as the need for continued investment in this population. (AU)

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

OBJECTIVE: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. METHODS: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. RESULTS: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p<0.01). Decreased overall survival was associated with advanced-phase disease (p<0.01), failure to achieve major molecular response in first-line treatment (p<0.01) and interruption of first-line treatment due to any reason (p=0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. CONCLUSION: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

Natural killer cell adoptive immunotherapy: Coming of age.

Cell therapy is a promising alternative to harsh chemotherapy and radiation therapy for cancer. Natural killer (NK) cells in particular have great potential for direct use in adoptive immunotherapy (AI) for cancer and to improve the graft-vs-leukemia (GVL) effect of hematopoietic stem cell transplants (HSCTs). NK cell number and function are associated with a strong GVL effect without inducing graft-versus-host disease in most settings. Clinical trials demonstrating the therapeutic role of NK cells in HSCT recipients or testing the safety and efficacy of AI with NK cells have been primarily directed at treating acute myeloid leukemia, although investigators have used NK cells for treatment of other hematological diseases, sarcomas, carcinomas, and brain tumors. Major challenges must be overcome in making NK cell-based therapy cost-effective, the most important being the need to collect or generate an adequate number of effector cells. In this review, we discuss protocols for isolation, expansion, and in vitro propagation of large quantities of functional NK cells that meet the criteria for clinical applications. Among the methods described are the use of bioreactors for scaling up production and expansion of NK cells in the presence of interleukins and feeder cells. We also discuss novel methodologies that optimize the generation of clinical grade NK-cell products for AI.

High prevalence of anemia in children and adult women in an urban population in southern Brazil.

This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006-2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil.

Paecilomyces variotii as an Emergent Pathogenic Agent of Pneumonia.

Paecilomyces variotii is a commonly occurring species in air and food, and it is also associated with many types of human infections. Pneumonia due to Paecilomyces variotii has been rarely reported in the medical literature. The authors report a 48-year-old patient with refractory lymphoma who underwent allogenic hematopoietic cell transplantation and developed pneumonia due to Paecilomyces variotii. They also review the published case reports of pneumonia caused by this fungus.

Effectiveness of a Protective Environment implementation for cancer patients with chemotherapy-induced neutropenia on fever and mortality incidence.

In a quasiexperimental study conducted to evaluate the impact of a Protective Environment implementation, febrile neutropenia (P = .009), overall mortality (P = .001), and 30-day adjusted mortality (P = .02) were reduced in cancer patients with chemotherapy-induced neutropenia. Our study highlights the potential success of a set of prevention measures mainly designed to reduce invasive environmental fungal infections in allogeneic hematopoietic stem cell transplant patients, in reducing fever and mortality among neutropenic cancer patients.

Clinical impact of systematic nutritional care in adults submitted to allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The development of nutrition care programs for patients undergoing hematopoietic stem cell transplantation is necessity in view of the rapid and aggressive consequences frequently seen with this procedure. Patients require constant care to reduce complications and to contribute to the success of therapy. METHODS: In an attempt to ascertain the impact of systematic nutritional care on patients submitted to allogeneic hematopoietic stem cell transplantation, the present study assessed the nutritional and clinical status, use of parenteral nutrition, and complication and mortality rates in two groups of patients, who were submitted to transplantation between April 2003 and December 2004 (Non-intervention Group - NIG; n = 57) and between March 2006 and January 2008 (Intervention Group - IG; n = 34). RESULTS: There were no significant differences between groups in terms of clinical or nutritional profiles. Additionally, the length of hospital stay and complication and mortality rates were similar for both groups. However, time on parenteral nutrition during treatment was shorter for the IG [median 6.5 days (range: 1-28) for related donor recipients and 11 days (range: 1-21) for unrelated donor recipients] than for the NIG [median 20.5 days (range, 4-73) for patients submitted to myeloablative conditioning and 18.5 days (range: 11-59 days) for those submitted to nonablative conditioning]. CONCLUSION: The implementation of a nutritional follow-up and therapy protocol for adult patients submitted to hematopoietic stem cell transplantation shortens the duration of parenteral nutrition. It certainly has an impact on hospitalization costs and, potentially, on the rate of complications, even though this was not demonstrated in this study.

Clinical impact of systematic nutritional care in adults submitted to allogeneic hematopoietic stem cell transplantation

BACKGROUND: The development of nutrition care programs for patients undergoing hematopoietic stem cell transplantation is necessity in view of the rapid and aggressive consequences frequently seen with this procedure. Patients require constant care to reduce complications and to contribute to the success of therapy. METHODS: In an attempt to ascertain the impact of systematic nutritional care on patients submitted to allogeneic hematopoietic stem cell transplantation, the present study assessed the nutritional and clinical status, use of parenteral nutrition, and complication and mortality rates in two groups of patients, who were submitted to transplantation between April 2003 and December 2004 (Non-intervention Group - NIG; n = 57) and between March 2006 and January 2008 (Intervention Group - IG; n = 34). RESULTS: There were no significant differences between groups in terms of clinical or nutritional profiles. Additionally, the length of hospital stay and complication and mortality rates were similar for both groups. However, time on parenteral nutrition during treatment was shorter for the IG [median 6.5 days (range: 1-28) for related donor recipients and 11 days (range: 1-21) for unrelated donor recipients] than for the NIG [median 20.5 days (range, 4-73) for patients submitted to myeloablative conditioning and 18.5 days (range: 11-59 days) for those submitted to nonablative conditioning]. CONCLUSION: The implementation of a nutritional follow-up and therapy protocol for adult patients submitted to hematopoietic stem cell transplantation shortens the duration of parenteral nutrition. It certainly has an impact on hospitalization costs and, potentially, on the rate of complications, even though this was not demonstrated in this study.

Sobrevida de pacientes submetidos a transplante alogênico de medula óssea / Survival of patients submittes to allogeneic boné marrow transplantation

Introdução: O transplante de células-tronco hematopoiéticas (TCTH) alogênico é um procedimento que oferece um potencial de cura para doenças hematológicas malignas e benignas. O benefício da técnica está especialmente relacionado ao aumento da sobrevida em pacientes com doadores HLA-compatíveis em cujos casos o tratamento quimioterápico mostrou-se insuficiente ou ineficaz. Objetivos: Analisar a sobrevida de pacientes que receberam TCTH alogênico aparentado no Serviço de Hematologia Clínica e Transplante de Medula Óssea (SHCTMO) do Hospital de Clínicas de Porto Alegre (HCPA). Métodos: Estudo de coorte prospectiva com análise de sobrevida de pacientes transplantados entre 1994 e 2003. Resultados: Foram analisados 133 pacientes com idade média de 30,8±14,8 anos com um tempo médio de 26,8 meses entre o diagnóstico e o TCTH. Cinco anos após o transplante, 71 pacientes (53,4%) estavam vivos, 22 pacientes tinham leucemia mieloide aguda (LMA), 54, leucemia mieloide crônica (LMC), e seis padeciam de síndrome mielodisplásica (SMD), sendo que, em 5 anos, a sobrevida foi de 52, 50 e 33%, respectivamente. Dos 26 pacientes transplantados por anemia aplásica (AA), 66,7% tinham idade inferior a 20 anos, e 61,5% dos que tinham mais de 20 anos estavam vivos. Conclusão: Embora, no nosso estudo, o tempo médio entre o diagnóstico e o transplante tenha sido superior a 2 anos, e embora nossa análise tenha sido apenas estratificada pelo tipo da doença, independentemente do regime de condicionamento ou da fase da doença no momento do TCTH, nossos resultados são superponíveis aos descritos na literatura mundial.

Background: Hematopoietic stem cell transplantation (HSCT) represents a curative alternative for malignant and benign hematological diseases. The benefits of the technique are especially related to an increase in the survival of patients with HLA-compatible hematopoietic stem cell donors when chemotherapy or clinical therapy has resulted ineffective. Objectives: To analyze the survival of patients submitted to allogeneic HSCT at the Hematology and Bone Marrow Transplant Service of Hospital de Clínicas de Porto Alegre. Methods: A prospective cohort of all patients submitted to transplantation between 1994 and 2003 was analyzed for overall survival. Results: A total of 133 patients were submitted to transplantation in the study period, with a mean age of 30.8±14.8 years; mean time elapsed between diagnosis and transplant was 26.8 months. Five years after the procedure, 71 patients (53.4%) were alive, 22 patients had acute and 54 had chronic myeloid leukemia, and six patients presented myelodysplastic syndrome; the 5 year overall survival was 52, 50, and 33%, respectively. Of the 26 patients transplanted for aplastic anemia, 66.7% had 20 or less years of age, and 61.5% of the patients older than 20 years were alive. Conclusion: Although the mean time elapsed between diagnosis and transplantation was over 2 years and although our results were stratified by type of disease only, the findings herein reported are similar to those found in the literature, independently of conditioning regimen or disease stage at the time of transplant.

Aplicação do D-dímero na investigação de distúrbios tromboembólicos / D-dimer testing in the investigation of thromboembolic disorders

A hemostasia requer um interessante equilíbrio entre a coagulação e a fibrinólise. Durante a formação de um trombo, os polímeros as fibrina são degradados pela plasmina e passam a dar origem a produtos de degradação de diferentes pesos moleculares. O menor e melhor caracterizado destes produtos é o D-dímero. Embora baixos níveis de D-dímero possam ser detectados na circulação de indivíduos saudáveis, seus níveis aumentam significativamente nos pacientes com trombose venosa profunda (TVP), embolia pulmonar (EP), coagulação intravascular disseminada, infarto do miocárdio, câncer, sepse, entre outros. O D-dímero é reconhecido atualmente como o mais específico indicador de ativação da coagulação e de fibrinólise. Os ensaios para a detecção de D-dímero são utilizados em muitos laboratórios na investigação de distúrbios hemostáticos associados com a ativação do sistema fibrirnolítico, incluindo os eventos tromboembólicos. A sua principal aplicação clínica diz respeito à possibilidade de exclusão diagnóstica de distúrbios tromboembólicos quando os seus níveis estão normais.

[Screening for hemoglobinopathies in blood donors from Caxias do Sul, Rio Grande do Sul, Brazil: prevalence in an Italian colony]. / Triagem de hemoglobinopatias em doadores de sangue de Caxias do Sul, Rio Grande do Sul, Brasil: prevalência em área de colonização italiana.

The high prevalence of beta thalassemia among Italians and their participation in the ethnic formation of Caxias do Sul, Rio Grande do Sul State, Brazil, and neighboring cities prompted us to investigate hemoglobinopathies in 608 blood donors at the Caxias do Sul Regional Blood Center. Despite the ethnic influence, abnormal hemoglobin levels were found in only 1.81% of the donors (0.16% Hb AC, 0.99% Hb AS, and 0.66% Hb AH), similar to the levels observed in a study on qualitative disorders conducted in the rural area of Rio Grande do Sul. In our setting, the most commonly used screening tests for thalassemia, combined with DNA sequencing, were unable to detect quantitative hemoglobin synthesis disorders. This may be attributable to still-unknown genetic disorders, technical limitations, or simply to miscegenation.

Triagem de hemoglobinopatias em doadores de sangue de Caxias do Sul, Rio Grande do Sul, Brasil: prevalência em área de colonização italiana / Screening for hemoglobinopathies in blood donors from Caxias do Sul, Rio Grande do Sul, Brazil: prevalence in an Italian colony

A alta prevalência de beta-talassemia em italianos e a participação dos mesmos na formação étnica da cidade de Caxias do Sul e arredores, Rio Grande do Sul, Brasil, conduziram-nos à investigação de hemoglobinopatias em uma amostra de 608 doadores de sangue do Hemocentro Regional de Caxias do Sul. Apesar da influência étnica, encontramos 1,81 por cento de hemoglobinas anormais (0,16 por cento Hb AC, 0,99 por cento, Hb AS e 0,66 por cento Hb AH), um padrão similar com o estudo do interior do Estado do Rio Grande do Sul para alterações qualitativas. Para as talassemias, as técnicas mais comuns, cruzadas com seqüenciamento de DNA, em nossas mãos, não foram capazes de esclarecer anormalidades quantitativas da hemoglobina. Esse resultado pode ser atribuído a alterações genéticas ainda não conhecidas, a limitações técnicas ou, mais simplesmente, à miscigenação.

[Neonatal screening for hemoglobinopathies: a pilot study in Porto Alegre, Rio Grande do Sul, Brazil]. / Triagem neonatal para hemoglobinopatias: um estudo piloto em Porto Alegre, Rio Grande do Sul, Brasil.

This study was conducted to establish the frequency of hemoglobinopathies among newborns undergoing screening tests for metabolic diseases at the University Hospital (Hospital de Clínicas) in Porto Alegre, Rio Grande do Sul, Brazil. Testing for abnormal hemoglobins was performed by isoelectric focusing electrophoresis on agarose gel with blood obtained by heel stick and applied to filter paper. For confirmatory testing of abnormal neonatal screening, a venopuncture blood sample was obtained from the infant and parents and then submitted to hemoglobin electrophoresis on cellulose acetate at pH 8.6 and citrate agar at pH 6.2. A total of 1,615 subjects were studied: 20 samples showed the Hb S pattern and six samples showed Hb C. Thus, frequency of the sickle cell gene was 1.2% and that of the Hb C gene was 0.4%, regardless of race or origin. These data suggest that the inclusion of universal neonatal screening for hemoglobinopathies in the ongoing projects for the detection of phenylketonuria and congenital hypothyroidism has many advantages and should be considered in health programs.