Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Correlation Between CD133+ Stem Cells and Clinical Improvement in Patients with Autism Spectrum Disorders Treated with Intrathecal Bone Marrow-derived Mononuclear Cells.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental pathologies characterized by social and communication deficits, for which treatments are limited. Cell therapies, including intrathecal (IT) administration of bone marrow (BM) mononuclear cells (BM-MNC), improves symptoms in patients with ASD. Twenty-four patients diagnosed with ASD, according to the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR) criteria, were autologously treated with IT BM-MNC, and the clinical effect was evaluated using the Childhood Autism Rating Scale (CARS) on Days 30 (n=24) and 180 (n=14) post-treatment. IT BM-MNC improved clinical outcomes by Day 30 (p=0.0039), and those benefits remained and were further accentuated by Day 180 post-treatment (n=14; p=<0.0001). Clinical benefit at Days 30 (p=0.001; r= -0.51) and 180 (p=0.01; r= -0.60) posttreatment positively correlated with the enrichment of a putative BM stem cell population expressing the cluster of differentiation 133+ (CD133+) surface marker.

Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency in Newborns in Northeast Mexico.

OBJECTIVE: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is the most common enzymatic disease worldwide and the prevalence is not well established because of the lack of screening. This study aimed to estimate the prevalence of G6PDd in a Hispanic population from Northeast Mexico. STUDY DESIGN: In this retrospective study, a database was used to analyze the G6PDd in neonates included in the expanded newborn metabolic screening of inherited metabolic disorders during a period of 4 years through the GSP Neonatal G6 kit (PerkinElmer). RESULTS: Among 96,152 (48,462 male) neonates screened for G6PD enzyme activity, a total of 566 (0.58%) cases were deficient for G6PD. Of those 566 patients, 469 (82.8%) attended the second test and the other 97 (17.2%) patients were lost. Of those 469 who did attend, 384 (81.9%) neonates were deficient in the second test and 85 (18.1%) were normal. With the data collected, 384 neonates were confirmed with G6PDd, 348 (88.6%) were male and 36 (11.4%) patients were female. The calculated prevalence for this population was 0.72 cases per 100 male newborns. CONCLUSION: The prevalence of G6PDd in the Northeastern Mexican population is high. Since migration is increasing in the United States, pediatricians should be aware of the need to search for G6PDd in newborns and the wide clinical manifestations they can present. KEY POINTS: · The calculated prevalence of glucose-6-phosphate dehydrogenase deficiency in Northeast Mexico is 3.99 cases per 1,000 newborns.. · Glucose-6-phosphate dehydrogenase deficiency screenings should be included in all newborn metabolic screenings.. · Glucose-6-phosphate dehydrogenase deficiency is a common erythroenzymopathy that must be addressed as a public health concern. To anticipate clinical complications, target population monitoring is required..

Primary Thrombophilia XVII: A Narrative Review of Sticky Platelet Syndrome in México.

Sticky Platelet Syndrome (SPS) is a disorder characterized by platelet hyperaggregability, diagnosed by studying in vitro platelet aggregation with ADP and epinephrine. It is the second most common cause of thrombophilia in Mexican Mestizos and manifests as an autosomal dominant trait which, combined with other coagulopathies, contributes significantly to the morbidity and mortality of patients with primary thrombophilia. It is easily treatable with antiplatelet drugs; however, the methods for diagnosis are not readily available in all clinical laboratories and the disorder is often overlooked by most clinicians. Herein, we present the results of more than 20 years of Mexican experience with the study of SPS in a Mestizo population.

Stem Cell Therapy in the Treatment of Patients With Autism Spectrum Disorder: a Systematic Review and Meta-analysis.

OBJECTIVE: Assess the safety and efficacy of upcoming stem cell treatments and analyze their effects on the cognitive and behavioral impairments in patients diagnosed with autism. METHODS: We included controlled and noncontrolled, randomized and non-randomized trials evaluating stem cell therapy as a treatment in patients with autism spectrum disorder compared to placebo or without comparator. DATA SOURCES: Scopus, Web of Science, MEDLINE and EMBASE. Risk of bias was assessed using Cochrane's Risk of Bias tool and the NIH's Quality Assessment Tool for Studies With No Control Group. RESULTS: Eleven trials including 461 patients proved eligible. ABC scale meta-analysis showed a mean raw of -11.97 in the intervention groups (95 % CI -91.45 to 67.52, p < 0.01). CARS scale reported a mean raw of -9.08 (95 % CI -15.43 to -2.73, p < 0.01). VABS scale was reported by their domains: communication domain reported a mean raw of 2.69 (95 % CI 1.30 to 4.08, p = 0.92); daily living domain, 1.99 (95 % CI 0.83 to 3.15, p = 0.51); motor domain, 1.06 (95 % CI -0.37 to 2.48, p = 0.20); socialization domain, 3.09 (95 % CI 1.71 to 4.48, p = 0.61); adaptive behavior domain, 2.10 (95 % CI 1.04 to 3.16, p = 0.36). Furthermore, the most common side effects reported included fever, hyperactivity, vomit, headache, and aggressiveness; no serious adverse events were reported. CONCLUSIONS: The body of evidence suggests that stem cell therapy significantly improves scales in patients with autism spectrum disorder, hence, future studies should help us have more confidence in the results. We found no serious adverse events related to the stem cell therapy.

The Influence of Nutritional Status at Diagnosis of Childhood B-Cell Acute Lymphoblastic Leukemia on Survival Rates: Data from a Hispanic Cohort.

The impact of nutritional status at diagnosis of childhood acute lymphoblastic leukemia (ALL) on survival rates was assessed in a Hispanic cohort. Children <16 years with newly diagnosed ALL-B from 2011 to 2019 were studied. Overweight and obesity were classified by body mass index (BMI) and Z-score according to WHO and CDC criteria. BMI, weight percentiles for age and Z-Score were assessed using the WHO Anthro (0-5 years) and AnthroPlus (5-19 years) programs. Cox model was used to estimate risk factors for relapse and death; differences between groups were assessed with Student's T test for parametric and Mann-Whitney U test for non-parametric variables. Disease-free survival (DFS) and overall survival (OS) were determined by the Kaplan-Meier method, calculating time, status, cumulative survival and standard error with a 95% confidence interval. Equal data distribution was estimated with the log-rank test. One-hundred and seventy-two B-ALL children were studied. The overweight-obese group had a non-significant lower DFS (CDC: 54% vs. 60%, p = 0.80; WHO: 57% vs. 64%, p = 0.89) and OS rate (CDC:76% vs. 82%, p = 0.38; WHO:65% vs. 81%, p = 0.13). An association between nutritional status determined by CDC and WHO criteria at diagnosis of B-cell ALL and survival rates was not documented.

Consenso mexicano para el diagnóstico y tratamiento de la trombastenia de Glanzmann / Mexican consensus on the diagnosis and treatment of Glanzmann thrombasthenia

Resumen Las plaquetas tienen un papel central en diferentes escenarios fisiológicos, incluyendo la hemostasia; se unen unas con otras en la agregación plaquetaria, lo cual permite formar un coágulo plaquetario. Para que la agregación sea apropiada se requiere del complejo glicoproteico IIb/IIIa (GPIIb/IIIa) en la superficie plaquetaria. Toda alteración funcional plaquetaria, hereditaria o adquirida, impide la formación adecuada del coágulo y se manifiesta como hemorragia. Las enfermedades plaquetarias hereditarias son raras y, hasta recientemente, fueron ignoradas. Una de las más reconocidas y estudiadas es la trombastenia de Glanzmann (TG), entidad en la cual el número de plaquetas puede ser normal pero la función está alterada. Es un padecimiento autosómico y recesivo que causa hemorragia de diferente intensidad toda la vida y en la cual el problema radica en precisamente en la GPIIb/IIIa. Las hemorragias son típicamente mucocutáneas: equimosis, púrpura, epistaxis, gingivorragia; menos frecuentes son la hemorragia gastrointestinal, hemartrosis o en sistema nervioso central. La hiperpolimenorrea es común en las mujeres y llega a ser tan importante que amerita transfusiones en la menarca. La TG afecta a todos los grupos étnicos y su prevalencia varía entre 1/40,000 y 1/400,000. A pesar de esta información acerca de la TG en el mundo, hay pocas guías o recomendaciones basadas en la opinión de expertos y experiencias unicéntricas. En México la TG es rara y no se cuenta con una recomendación general para su diagnóstico y tratamiento. El objetivo de este documento fue establecer un consenso y hacer sugerencias generales para su diagnóstico y tratamiento.

Abstract Platelets have a central role in several physiological scenarios including hemostasis. Platelets bind each other during platelet aggregation allowing the proper formation of the clot; to be appropriate, platelet aggregation requires the glycoproteic complex IIb/IIIa (GPIIb/IIIa). Every platelet function abnormality both, congenital or acquired, impedes clot formation and favors bleeding episodes. Hereditary platelet abnormalities are rare and, until recently, they were almost ignored. Among these disorders, Glanzmann Thrombasthenia (GT) is a widely recognized abnormality in which platelet counts may be normal, but their function is affected. GT is an autosomal, recessive disease that causes life-long bleeding of different intensity. Main biochemical abnormality resides in GPIIb/IIIa. Bleeding is typically mucocutaneous: easy bruising, purpura, and nose and gum bleeds; less frequently are gastrointestinal bleeds, hemarthrosis, or intracranial. Menorrhagia and hyperpolymenorrhea are common findings in in women and may be the cause of anemia requiring blood transfusions at fertile age. GT affects all ethnic groups and its prevalence ranges between 1/40,000 to 1/400,000. Despite this worldwide information regarding GT, only a few guidelines and recommendations have been published, most of them based on expert opinions. In Mexico, GT is rare and there is not a general recommendation regarding its diagnosis and treatment. The aim of this document was to establish a consensus to suggest a general guideline for the diagnosis and treatment of GT in Mexico.

Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease.

Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10-11). Additional studies are necessary to validate these findings as hallmarks of MD.

Spinal epidural hematoma in a child with hemophilia A with high titer inhibitors and follow-up with prophylactic emicizumab: case report and literature review.

Hemorrhage in the central nervous system is the most severe and debilitating manifestation affecting patients with hemophilia A. The spinal epidural space is the most unusual and clinically challenging site of central nervous system hemorrhage in hemophilia A. These patients often show insidious neurological signs and symptoms that delay diagnosis and treatment. We share our experience treating a 4-year-old male patient with severe hemophilia A and high titer inhibitors with a spontaneous spinal epidural hematoma. The patient presented initially with intense headache and neck pain. After blood tests and imaging studies, bypassing agent therapy with recombinant-activated factor VII was used until discharge; this was later replaced with emicizumab. After 18 months, the patient is without neurological sequelae and has not experienced subsequent bleeding episodes. We review the available literature and discuss the relevance of emicizumab compared with standard therapies in the context of spontaneous spinal epidural hematoma.

Advances in gene therapy for hemophilia.

Hemophilia is a hereditary disorder that can be life-threatening in individuals who have severe spontaneous bleeding resulting from minor trauma or surgery. Although replacement therapy of the missing exogenous factor has improved patients' quality of life, it has not been possible to establish a long-term treatment. Due to the severity of the disease and the need for repetitive doses throughout the patient's life, replacement therapy has become a high-cost treatment option; therefore, the development of self-sustainable long-term therapies is critical. Hemophilia is a good candidate for gene therapy because it is a monogenic disease that can be counteracted by expression of the missing factor. In this article, we review some of the most relevant advances in gene therapy for this illness.

Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants.

INTRODUCTION: Molecular analysis in haemophilia is currently used in the diagnosis, treatment and prognosis of this disease. Hispanic populations in Latin America have been of interest to researchers due to the reportedly high prevalence of inhibitors in these patients. AIM: To perform next-generation sequencing (NGS) in a cohort of Mexican patients with HA and HB and correlate with clinical phenotypes. METHODS: Patients with Haemophilia A (HA) or haemophilia B (HB), were evaluated using NGS with an Ion AmpliSeq Custom Panel. Odds ratios (ORs) for associations between F8 variants and inhibitors were obtained. RESULTS: A total of 85 patients (60 with HA and 25 with HB) were included. Pathogenic variants in F8 were found in 93.3% of HA patients and in F9 in 96% of HB patients. Twelve novel potentially pathogenic variants were found. Inhibitors were observed in 20% of patients with severe HA. Four patients clinically diagnosed with HA were negative for F8 variants. CONCLUSION: Overall detection rate of pathogenic variants in F8 and F9 genes was 94.6%. We identified 12 non previously reported variants and pathogenic variants in other coagulation related genes. Molecular diagnosis of HA and HB permits better options for management, assessment and genetic counseling.

Prevalence of inhibitors and clinical characteristics in patients with haemophilia in a middle-income Latin American country.

INTRODUCTION: Development of inhibitors is the most serious complication in patients with haemophilia (PWH). The prevalence of inhibitors in patients with severe haemophilia A (HA) is approximately 25%-30%. Inhibitor prevalence differs among populations. Some studies report a prevalence of almost twice in Hispanic as compared to Caucasian patients. Most data available, on the prevalence of inhibitors and their predisposing factors, originate from centres in developed countries. AIM: Establish the prevalence of inhibitors of FVIII and FIX in Mexico. METHODS: This was an observational, cross-sectional and descriptive study. The records of all patients diagnosed with haemophilia A (HA) or B (HB), with and without inhibitors, were included. Clinical and demographical characteristics of patients with inhibitors were assessed. Statistical analysis was performed using IBM SPSS version 22. The Ethics Committees of the various participating institutions approved this study. RESULTS: A total of 1455 patients from the 20 participating centres were recruited, from which 1208 (83.02%) had HA and 247 (16.97%) were diagnosed with HB. The presence of inhibitors in severe HA was reported in 93/777(11.96%), and 10/162 (6.17%) in severe HB. Of them, 91.7% exhibited high titres in HA and 100% in HB. CONCLUSION: In Mexico, the general prevalence of inhibitors varies considerably among centres. This study established a basis of comparison for future development and advances in the treatment and follow-up of patients. These findings also augment our understanding of risk factors related to inhibitor development.

Proteomic tools and new insights for the study of B-cell precursor acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a hematological malignancy of immature B-cell precursors, affecting children more often than adults. The etiology of BCP-ALL is still unknown, but environmental factors, sex, race or ethnicity, and genomic alterations influence the development of the disease. Tools based on protein detection, such as flow cytometry, mass spectrometry, mass cytometry and reverse phase protein array, represent an opportunity to investigate BCP-ALL pathogenesis and to identify new biomarkers of disease. This review aims to document the recent advancements with respect to applications of proteomic technologies to study mechanisms of leukemogenesis, how this information could be used in the discovery of biological targets, and finally we describe the challenges of application of proteomic tools for the approach of BCP-ALL.

How Does Comprehensive Care Impact Life of Pediatric Patients With Hemophilia? Results From a Center in a Developing Country.

BACKGROUND: Quality of life (QoL) has been included as a marker of treatment effectiveness in pediatric patients with chronic diseases. We believe that frequent multidisciplinary interventions and patient education could lead to an improvement in QoL. AIMS: Determine the QoL and economic impact of monthly interventions in multidisciplinary treatment. MATERIALS AND METHODS: The Haemo-QoL questionnaire was applied to patients who attended the hemophilia center of the University Hospital "Dr. José Eleuterio González," Monterrey, Mexico, at the time of enrollment and 1 year later. RESULTS: Male patients between 4 and 16 years diagnosed with hemophilia were included. The score results presented are based on Haemo-QoL versions that classify patients by their age group: group 1 (4 to 7 y) and group 2 (8 to 12 y). Statistical significant improvement was observed in the overall score (sociodemographic, psychosocial, etc.) after 1 year of follow-up in both groups (P<0.05). CONCLUSIONS: Impact on the QoL of patients receiving this approach was favorable. Improvement was observed regardless of severity and in those who were already in prophylaxis, suggesting that this type of approach could be causing the improvement. Results support the application of multidisciplinary treatment as the gold standard, and it should be considered in all centers including those with limited resources.

The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis.

AIM: Management of osteoarthritis (OA) is basically symptomatic. Recently, stem cells (SC) have been used in the search for an optimum treatment. We decided to conduct a controlled clinical trial to determine if a single intra-articular injection of in vivo stimulated bone marrow SC could lead to an improvement in pain management and quality of life in patients with knee OA. METHOD: This was a prospective, open-label, phase I/II clinical trial to assess the safety and efficacy of a single intra-articular injection of autologous stimulated bone marrow stem cells (BM-SC) in patients with knee OA. Individuals of both genders older than 30 years with confirmed diagnosis of OA who signed informed consent were included in two groups: SC group received in vivo BM stimulation with subcutaneous administration of granulocyte colony stimulating factor (G-CSF). SC were obtained by BM aspiration and administered in a single intra-articular injection. The control group received exclusively oral acetaminophen. Visual analogue scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were performed at 1 week, 1 month and 6 months in both groups. This trial was registered in ClinialTrials.gov NCT01485198. RESULTS: A total of 61 patients were included. Socio-demographic characteristics, OA grades and initial scores were similar in both groups. The BM-SC group showed significant improvement in knee pain and quality of life during the 6-month follow-up. CONCLUSION: The study demonstrates feasibility and supports efficacy of a completely ambulatory procedure in treatment of knee OA.

Adding Multiple Adipokines into the Model do not Improve Weight Gain Prediction by Leptin Levels in Newborns.

OBJECTIVE: Most adipose tissue programming is realized in early life. Also, the postnatal three months, rather than the later phases of infancy, may be more relevant in the development of an adverse cardiometabolic risk profile. The adipokines phenotype, as a predictor of early-life weight gain, has been recently explored in cord blood. To determine whether in addition to leptin levels in cord samples, adiponectin, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), resistin, plasminogen activator inhibitor-1 (PAI-1), and tumor necrosis factor alpha (TNF-α) levels improve weight gain prediction during the first three months of life. METHODS: Adiponectin, IL-6, MCP-1, leptin, resistin, PAI-1, and TNF-α were measured by multiplex immunoassay in a subsample of 86 healthy term newborns. RESULTS: Leptin levels significantly predicted weight gain at 3 months of follow-up (r2=0.09, p=0.006). In the multivariate analysis, including additional adipokines in the model, stepwise or all at once, did not increase the prediction of weight gain after the first three months of life. CONCLUSION: Adding adiponectin, IL-6, MCP-1, resistin, PAI-1, and TNF-α to the prediction model of weight gain in healthy newborns did not prove to be useful. It is probable that their relative contribution to weight gain is not important. Only leptin was relevant as a predictor of weight gain at the 3-month endpoint.