Infused factor VIII-expressing platelets or megakaryocytes as a novel therapeutic strategy for hemophilia A.

B-domainless factor VIII (FVIII) ectopically expressed in megakaryocytes (MKs) is stored in α granules of platelets (pFVIII) and is capable of restoring hemostasis in FVIIInull mice, even in the presence of circulating inhibitors. However, our prior studies have shown that this ectopically expressed pFVIII can injure developing MKs. Moreover, the known risks of prolonged thrombocytopenia after bone marrow transplantation are significant challenges to the use of this strategy to treat individuals with severe hemophilia A and particularly those with intractable clinically relevant inhibitors. Because of these limitations, we now propose the alternative therapeutic pFVIII strategy of infusing pFVIII-expressing MKs or platelets derived from induced pluripotent stem cells (iPSCs). pFVIII-expressing iPSC-derived MKs, termed iMKs, release platelets that can contribute to improved hemostasis in problematic inhibitor patients with hemophilia A. As proof of principle, we demonstrate that hemostasis can be achieved in vitro and in vivo with pFVIII-expressing platelets and show prolonged efficacy. Notably, pFVIII-expressing platelets are also effective in the presence of inhibitors, and their effect was enhanced with recombinant FVIIa. Human pFVIII-expressing iMKs improved hemostasis in vitro, and derived platelets from infused human pFVIII-expressing iMKs improved hemostasis in FVIIInull mice. These studies indicate the potential therapeutic use of recurrent pFVIII-expressing MK or platelet infusions with prolonged hemostatic coverage that may be additive with bypassing agents in hemophilia A patients with neutralizing inhibitors.

Mortality of patients with haemophilia in Brazil: First report.

INTRODUCTION: Brazil has the fourth largest world population of patients with haemophilia. However, mortality rates in this population are unknown. AIM: To analyse mortality and its causes in Brazilian patients with haemophilia from 2000 to 2014. METHODS: The number of deceased patients with haemophilia and causes of death were obtained from the Brazilian National Mortality Information System (SIM), according to the 10th International Classification of Diseases (ICD-10). Standardized mortality ratios (SMR) were calculated to estimate the rate of overall death of patients with haemophilia relative to that of the Brazilian general male population. RESULTS: A total of 784 deaths were identified in the period of 15 years. Mortality of patients with haemophilia was 13% higher when compared with the general male population (SMR 1.13, 95% CI: 1.01-1.16). Haemorrhage was the main cause of death (n = 254; 32.4%) of which 137 (54%) was intracranial haemorrhage. The total number of deaths due to HIV decreased over the years, and an increase in deaths due to cancer and cardiovascular disease was observed. A total of 129 deaths (16.5%) were related to hepatitis infection, of whom, 109 (86.5%) patients also presented with cirrhosis and hepatocellular carcinoma or other liver diseases. CONCLUSION: Mortality rate of Brazilian patients with haemophilia decreased over the evaluated period. Intracranial haemorrhage is still an important cause of death in these patients, which requires major effort for prevention. Death due to age-related cardiovascular disease and cancer has increased over the years, following the same tendency observed in developed countries.

Hemophilia Liver Transplantation Observational Study.

Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation. Whether transplant outcomes are worse in hemophilic (H) rather than nonhemophilic (NH) candidates is unknown. In order to determine rates and predictors of pretransplant and posttransplant survival, we conducted a retrospective observational study using United Network for Organ Sharing national transplant registry data, comparing HCV+ H and NH candidates. We identified 2502 HCV+ liver transplant candidates from 8 US university-based transplant centers, between January 1, 2004 to December 31, 2010, including 144 HIV+ (6%) and 2358 HIV-; 36 H (1%) and 2466 NH; 1213 (48%) transplanted and 1289 not transplanted. Other than male predominance and younger age, each were P < 0.001. Baseline data were comparable between H and NH. In univariate analysis, 90-day pretransplant mortality was associated with higher baseline Model for End-Stage Liver Disease (MELD; hazard ratio [HR] = 1.15; P < 0.001), lower baseline platelet count (HR = 0.9 per 25,000/µL; P = 0.04), and having HIV/HCV+ hemophilia (P = 0.003). In multivariate analysis, pretransplant mortality was associated with higher MELD (P < 0.001) and was significantly greater in HIV+ than HIV- groups (P = 0.001). However, it did not differ between HIV+ H and NH (HR = 1.7; P = 0.36). Among HIV/HCV+, posttransplant mortality was similar between H and NH, despite lower CD4 in H (P = 0.04). In conclusion, this observational study confirms that hemophilia per se does not have a specific influence on transplant outcomes and that HIV infection increases the risk of mortality in both H and NH patients. Liver Transplantation 23 762-768 2017 AASLD.

Intervenciones de enfermería en la atención pediátrica de la hemofilia / Nursing interventions in pediatric hemophilia care

Introducción: La hemofilia es una enfermedad crónica, específicamente un trastorno de la coagulación de la sangre que causa hemartrosis y sangrado prolongado espontáneo (Murillo, 2008). La patología requiere un abordaje integral en donde el papel del profesional de enfermería es satisfacer las necesidades biopsicosociales del paciente pediátrico con este problema de salud. Método: La búsqueda sistemática de información se enfocó a documentos obtenidos acerca de la temática de intervenciones de enfermería y hemofilia en pacientes pediátricos. Se utilizaron 22 documentos para la elaboración de esta guía. Resultados: Las principales intervenciones de enfermería en el paciente pediátrico con hemofilia son: ministración del Factor VIII o IX según prescripción, control de la hemorragia, manejo del dolor, inmovilización, aplicación de frio, identificación de riesgos, monitorización de extremidades inferiores, apoyo emocional y enseñanza de los procedimientos y tratamientos. Conclusiones: La valoración de enfermería en pacientes con hemofilia se centra en las respuestas humanas (Dolor, limitación del movimiento, temor, angustia y ansiedad) y en las respuestas fisiológicas (Edema, hematomas, hemorragias internas y externas)

Background: Hemophilia is a chronic disease, specifically a disorder of blood clotting and prolonged bleeding hemarthrosis cause spontaneous (Murillo, 2008). The disease requires a comprehensive approach where the role of the nurse is to meet the biopsychosocial needs of pediatric patients with this health problem.Method: A systematic search of information obtained documents focused on the theme of nursing interventions and pediatric hemophilia patients. 22 documents for the development of this guide were used.Results: The main nursing interventions in pediatric patients with hemophilia are: ministry of Factor VIII or IX as prescribed, control of bleeding, pain management, immobilization, application of cold, risk identification, monitoring lower extremities, emotional support and teaching procedures and treatments.Conclusions: Nursing assessment in patients with hemophilia focuses on human responses (pain, limitation of movement, fear, anguish and anxiety) and physiological responses (edema, bruising, internal and external bleeding).

Introdução: A hemofilia é uma doença crônica, especificamente um distúrbio da coagulação do sangue, que causa hemartrose e sangramento prolongado espontâneo (Murillo, 2008). A doença requer uma abordagem integral onde o papel do enfermeiro é satisfazer as necessidades biopsicossociais do paciente pediátrico com este problema de saúde.Método: A pesquisa sistemática de informação foi enfocada em documentos obtidos sobre o tema das intervenções de enfermagem e hemofilia em pacientes pediátricos. Foram utilizados 22 documentos para o desenvolvimento deste guia.Resultados: As principais intervenções de enfermagem no paciente pediátrico com hemofilia são: ministração de Fator VIII ou IX, conforme prescrito, controle da hemorragia e dor, imobilização, aplicação de frio, identificação de riscos, monitoramento de extremidades inferiores, apoio emocional e ensino de procedimentos e tratamentos.Conclusões: A avaliação de enfermagem em pacientes com hemofilia concentra-se nas respostas humanas (dor, limitação de movimento, medo, angústia e ansiedade) e nas respostas fisiológicas (edema, hematomas, hemorragias internas e externas).

Evaluation of the host response to endotoxemia of FVIII and FIX deficient mice.

For several years, coagulation has been implicated in the pathogenesis of sepsis. However, results from clinical trials with natural anticoagulants, as well as studies with knock-out mice for specific coagulation factors yielded conflicting results on the role of coagulation in the pathogenesis of sepsis. The aim of this study was to evaluate the impact of severe The factor VIII:C (FVIII:C) and factor IX:C (FIX:C) deficiency on a lipopolysaccharide (LPS)-induced murine model of sepsis. FVIII:C and FIX:C deficient mice, and their haemostatic normal littermate controls were challenged with LPS, and several parameters of the host response were evaluated: seven-day survival experiments were performed using two dose levels of LPS; biochemical and histological markers of tissue damage, coagulation parameters, and pro-inflammatory cytokines were evaluated at baseline and after 3 h and 6 h after an injection of LPS. Severe FVIII and FIX deficiency were compatible with normal survival in experimental sepsis. In addition, LPS-induced tissue damage and coagulation activation were similar in FVIII or FIX deficient mice compared to their respective controls. A lower release of pro-inflammatory cytokines was observed in FIX but not in FVIII deficient mice. Severe FIX or FVIII deficiency does not protect mice from mortality or from tissue damage in the endotoxemia model, supporting the hypothesis that FVIII and FIX are not critical to the pathogenesis of experimental sepsis.

Prevalence and geographic distribution of haemophilia in Costa Rica.

Haemophilia is the most frequent hereditary haemorrhagic illness and it is due to the deficiency of coagulation factors VIII (haemophilia A, HA) or IX (haemophilia B, HB). The prevalence of this disease varies according to the country, those having better survival rates having also higher prevalences. Specifically in Costa Rica, there are around 130 HA and 30 HB families. This study reports the prevalence and a spatial distribution analysis of both types of the disease in this country. The prevalence of haemophilia in this country is 7 cases per 100000 men, for HA it is 6 cases per 100000 and for HB it is 1 case per 100000 male inhabitants. The prevalence of this disease is low when compared with other populations. This low prevalence could be due to the many patients that have died because of infection with human immunodeficiency virus during the 1980s. The prevalence of haemophilia in Costa Rica is almost one half of that present in developed countries. Nevertheless, the ratio between HA and HB follows world tendency: 5:1. In this study, nationwide geographical distribution maps were drawn in order to visualize the origin of severe cases and how this influences the pattern of distribution for both types of haemophilia. By means of these maps, it was possible to state that there is no association between the sites of maximum prevalence of mutated alleles and ethnicity. With this study, haemophilia prevalence distribution maps can be used to improve efforts for the establishment of hemophilia clinics or specialized health centers in those areas which hold the highest prevalences in this country. Also, this knowledge can be applied to improve treatment skills and offer the possibility of developing focused genetic counseling for these populations.

A genetic and demographic study of hemophilia A in Brazil.

A genetic and demographic study was made of patients with hemophilia A in Rio Grande do Sul, Brazil, during a 15-year period. The study comprised 104 patients belonging to 70 pedigrees. Life expectancy at birth increased from 32.2 to 44.5 years, mean age of death from 11.1 to 14.6 years, and survival to maturity from 33 to 38%. However, fertility decreased from an average number of 1.6 to 0.8 children. Among the normal brothers, the average number of offspring was decreased from 2.2 to 1.5 children. The fitness of patients in this population, in spite of the increase of the average life expectancy, was decreased due to the decrease of fertility, from 0.47 to 0.43 using the normal brother as control, and from 0.35 to 0.20 using the general population as control.

Genetic characteristics of hemophilia A in Chile.

A genetic and demographic study of 40 kindreds (113 cases) with hemophilia A, representing one quarter of all Chilean cases is reported. Only 10 sporadic cases were found. Segregation analysis of progeny from matings Aa X AY showed p = 0.2206 +/- 0.043. Fertility of 59 obligatory carriers was 3.88 children per mother with a mean age of 49.9 years, a figure higher than the mean of a control population, 3.36. The fertility of hemophiliacs was found to be 2.3 compared with their normal sibs with 3.15 children per couple. Life expectancy at birth in hemophiliacs was 22.4 years, compared with 28.1 for their normal brothers, 34.4 for their sisters and 58.5 and 64.6 for males and females in the general population. Mean relative fitness was calculated as 0.45 and the prevalence of hemophilia A in Chile as 1 case among 13,500 males. A preliminary estimate of the mutation rate was 1.35 X 10-5, within expected ranges. During the last 10 years, family planning and modern treatment with cryoprecipitates have increased the mean age of living hemophiliacs from 12.7 up to 22.7 years, and life expectancy from 15.6 to 22.4 years. Probably relaxation of natural selection will account for a possible increase of new cases of hemophilia A in the near future.