RESUMEN
INTRODUCTION: Subcutaneous (SQ) vaccination has emerged as standard of care in children with severe bleeding disorders to reduce unnecessary factor exposure and avoid provoking an intramuscular bleed, but little is known about comparative immunogenicity to intramuscular (IM) vaccination. AIM: To confirm immunogenicity of Diphtheria Tetanus acellular Pertussis (DTaP) vaccines administered SQ to individuals <6 years old with haemophilia. METHODS: We performed a retrospective and prospective pilot study of tetanus and diphtheria antibody titres among patients evaluated at our Haemophilia Treatment Centre between 2015-2016. Children with haemophilia who had received three to four doses of DTaP containing vaccine administered SQ were eligible. RESULTS: Eight children met inclusion criteria. The mean age at the time of diphtheria and tetanus antibody testing was 21.1±17.8 months. All children who received SQ diphtheria and tetanus developed a positive antibody titre to both antigens. There was no statistically significant difference in distribution of titre values. The average time between the last dose of vaccine and antibody testing was 6.6±3.9 months among SQ vaccinated subjects. Minor injection site reactions were common with SQ vaccines. CONCLUSION: SQ administration of diphtheria and tetanus vaccination appears to be immunogenic in a pilot study of Haemophilia patients and supports this practice as the standard of care for this population.
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Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/inmunología , Hemofilia A/inmunología , Hemofilia B/inmunología , Vacunación/métodos , Anticuerpos Antibacterianos/inmunología , Preescolar , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Humanos , Lactante , Inyecciones Intramusculares , Inyecciones Subcutáneas , Masculino , Proyectos Piloto , Estudios Prospectivos , Estudios Retrospectivos , Literatura de Revisión como AsuntoRESUMEN
Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥ 4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥ 90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg(-1) vs. 200.0 (61.0-270.0) mcg kg(-1) for children, and 231.3 (59.3-379.7) mcg kg(-1) vs. 123.0 (81.0-289.0) mcg kg(-1) for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg(-1) ), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.
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Prescripciones de Medicamentos , Factor VIIa/uso terapéutico , Hemofilia A/tratamiento farmacológico , Isoanticuerpos/metabolismo , Médicos , Adolescente , Adulto , Niño , Preescolar , Demografía , Relación Dosis-Respuesta a Droga , Factor VIIa/administración & dosificación , Factor VIIa/efectos adversos , Directrices para la Planificación en Salud , Hemofilia A/complicaciones , Hemorragia/complicaciones , Hemorragia/terapia , Humanos , Lactante , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
Patients with congenital haemophilia with inhibitors experience acute bleeds managed with bypassing agents, such as recombinant FVIIa (rFVIIa). Home-based treatment and dosing patterns in the US remain poorly described. This study aimed to assess the prescribed and actual rFVIIa dosing in frequently bleeding inhibitor patients (≥4 bleeds in 3 months) prescribed first-line therapy with rFVIIa. Patients or caregivers recorded daily diaries, including the details of all bypassing agent infusions for 3-6 months. Median (range) initial rFVIIa dose prescribed for joint, muscle and other bleeds was 167.5 (61.0-289.0) mcg kg(-1). Additional rFVIIa doses prescribed were 90 (61-270) mcg kg(-1) at an interval of 2.5-3 (1-24) h. The actual initial rFVIIa dose reported by patients/caregivers for 158 bleeds was 212 (59-400) mcg kg(-1), with total dose per episode of 695 (74-21257) mcg kg(-1). Patient/caregiver-reported average dose per bleed was 146 (40-400) mcg kg(-1) across 5 (1-106) infusions. The initial rFVIIa dose was higher for haemarthrosis (223 [59-400] mcg kg(-1)) than muscle bleeds (148 [74-300] mcg kg(-1); P = 0.07). Initial and mean dose per day changed as treatment progressed. The DOSE study indicates that frequently bleeding inhibitor patients are prescribed and use higher rFVIIa dosing for all bleed types than recommended in the package insert (90 mcg kg(-1)). The rFVIIa dosing was highly variable within and across bleed types, with higher initial doses used for joint bleeds than muscle and other bleed types, particularly in the first days of treatment. This suggests that patients/caregivers have adopted home treatment strategies based on physician discretion and individual responses and experience.
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Coagulantes/administración & dosificación , Factor VIIa/administración & dosificación , Hemofilia A/complicaciones , Hemofilia B/complicaciones , Hemorragia/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Niño , Preescolar , Esquema de Medicación , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Hemorragia/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Estados Unidos , Adulto JovenRESUMEN
Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 µg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. SUMMARY: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 µg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 µg kg-1 dose range, with a terminal half-life of â 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 µg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.
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Coagulantes/administración & dosificación , Factor VIIa/administración & dosificación , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Administración Intravenosa , Adolescente , Adulto , Coagulantes/efectos adversos , Coagulantes/farmacocinética , Europa (Continente) , Factor VIIa/efectos adversos , Factor VIIa/farmacocinética , Hemofilia A/sangre , Hemofilia A/diagnóstico , Hemofilia B/sangre , Hemofilia B/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Índice de Severidad de la Enfermedad , Sudáfrica , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
The peptide LSARLAF causes alphaIIbeta3-dependent platelet activation exemplified by secretion, aggregation, spreading and adhesion on fibrinogen, and tyrosine phosphorylation. alphaIIIbeta3-dependent outside-in signal transduction induced by LSARLAF was investigated in variant thrombasthenic platelets which lack most of the cytoplasmic domain of the integrin beta3 subunit (alphaIIbbeta3 delta724). These studies revealed that only certain aspects of this alphaIIbbeta3-dependent outside-in signaling were affected by the beta3 truncation. Specifically, alphaIIbbeta3 delta724 supported LSARLAF-induced platelet aggregation, agglutination and secretion, but failed to trigger cytoskeletal reorganization and platelet spreading on fibrinogen, despite the fact that PMA-induced non alphaIIbbeta3 mediated signaling caused spreading of these platelets on fibrinogen. Thus, distinct domains of alphaIIbbeta3 are required to support different aspects of LSARLAF-induced platelet activation. Furthermore, these studies suggest that not all alphaIIbbeta3-dependent platelet responses require an intact beta3 cytoplasmic tail.
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Antígenos CD/genética , Codón sin Sentido , Mutación del Sistema de Lectura , Oligopéptidos/farmacología , Activación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/fisiología , Glicoproteínas de Membrana Plaquetaria/genética , Transducción de Señal/efectos de los fármacos , Trombastenia/genética , Adenosina Difosfato/farmacología , Adolescente , Alelos , Antígenos CD/química , Antígenos CD/fisiología , Epinefrina/farmacología , Trastornos Hemorrágicos/sangre , Trastornos Hemorrágicos/genética , Humanos , Integrina beta3 , Sustancias Macromoleculares , Masculino , Fosforilación/efectos de los fármacos , Activación Plaquetaria/fisiología , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/química , Glicoproteínas de Membrana Plaquetaria/química , Glicoproteínas de Membrana Plaquetaria/fisiología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/fisiología , Eliminación de Secuencia , Transducción de Señal/fisiología , Relación Estructura-Actividad , Acetato de Tetradecanoilforbol/farmacología , Trombastenia/sangre , Trombina/farmacologíaRESUMEN
Studies in adults have demonstrated that the genetic mutations C677T methylenetetrahydrofolate reductase (MTHFR), prothrombin 20210A, and the 4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene are associated with elevated plasma levels of homocysteine. prothrombin and PAI-1, respectively and with an increased risk of thrombosis. No similar data is available in children. Therefore, we assessed the relationship of plasma levels of homocysteine, prothrombin and PAI-1 with their respective mutations in 197 normal children, compared to 40 adults. By stepwise multiple regression, homocysteine was positively associated with age, PAI-1 activity was negatively associated with age, while PAI-1 antigen and prothrombin levels were associated with gender, being higher in girls than boys. When the genotypes were added to the regression model as additional explanatory variables, the MTHFR genotype accounted for 2.9% of the variance of homocysteine (p = 0.024), and the PAI-1 gene accounted for 2.7% of the variance of PAI-1 antigen levels (p = 0.023). Of children homozygous for the MTHFR mutation, 35% had homocysteine levels > or = the age-specific 95th percentile, compared to 2% heterozygotes and 5% wild type normals (p = 0.0001). The mean homocysteine level was higher in children homozygous for the MTHFR gene (8.4 micromol/1) than in heterozygotes (5.5 micromol/l), p <0.05. Of children homozygous for the 4G polymorphism of the PAI-1 gene, 19% had PAI-1 activity levels > or = the age-specific 95th percentile, compared to 2% of heterozygotes and 3% of wild type normals (p = 0.003). Studies of the incidence of the MTHFR, prothrombin, and PAI-1 4G/5G genotypes in children with thrombosis, when compared to these healthy normals, will provide evidence as to which of these genes are associated with thrombophilia.
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Homocisteína/sangre , Mutación , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/genética , Protrombina/genética , Protrombina/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Polimorfismo GenéticoRESUMEN
A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.
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Anticoagulantes/uso terapéutico , Antitrombina III/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Insuficiencia Multiorgánica/tratamiento farmacológico , Trombofilia/tratamiento farmacológico , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Adulto , Busulfano/administración & dosificación , Busulfano/efectos adversos , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Enfermedades Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , Tablas de Vida , Masculino , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/prevención & control , Neoplasias/terapia , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Trombofilia/etiología , Resultado del TratamientoRESUMEN
Anomalies of chromosome 6q, along with other chromosomal anomalies, are described in the bone marrow cells of two patients with chronic myelogenous leukemia (CML). One patient a 14-year-old male, developed the karyotype 46,XY,t(1;6)(p36;q15),del(3)(q25), del(17)(p11),? inv(17)(q12q24) during blastic crisis of his disease. The other patient, a 24-year-old male, had the karyotype 46,XY,del(6)(q13),5(9;22)(q34;q11) during the early phase of his disease and evolution of i(17q) in the karyotype late in the disease.
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Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Cromosomas Humanos 6-12 y X , Leucemia Mieloide/genética , Adolescente , Adulto , Médula Ósea/patología , Bandeo Cromosómico , Humanos , Cariotipificación , Leucemia Mieloide/patología , MasculinoRESUMEN
Cutis marmorata telangiectatica congenita is an uncommon, congenital cutaneous condition typified by persistent cutis marmorata and other associated abnormalities. Progressive neurologic complications are generally not a feature of the disorder. A case is reported of cutis marmorata telangiectatica congenita associated with diffuse cerebrovascular infarcts at 7 months of age. Moyamoya-like vascular abnormalities were demonstrated in addition to the factor V Leiden mutation, a congenital hypercoagulable disorder. This novel case illustrates the importance of evaluating children with strokes for congenital thrombophilic disorders.
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Trastornos de la Coagulación Sanguínea/complicaciones , Infarto Cerebral/etiología , Factor V/genética , Enfermedad de Moyamoya/complicaciones , Enfermedades Cutáneas Vasculares/complicaciones , Anomalías Múltiples , Trastornos de la Coagulación Sanguínea/genética , Edema Encefálico/etiología , Angiografía Cerebral , Susceptibilidad a Enfermedades , Femenino , Heterocigoto , Luxación Congénita de la Cadera , Humanos , Lactante , Diferencia de Longitud de las Piernas , Proteína C/metabolismo , Convulsiones/etiología , Infecciones Urinarias/complicaciones , Cuerpo Vítreo/anomalíasRESUMEN
Acute hematologic-oncologic problems fall into two groups, those that require immediate assessment, diagnosis, and therapy, and those that require attention but are not life threatening if treated appropriately. Both types are considered in this article, which discusses hemorrhagic disorders; anemias, with special emphasis on patients with sickle cell disease; an approach to fever and infection in the immunocompromised child; and oncologic disorders that may be life threatening.
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Enfermedades Hematológicas , Anemia Hemolítica , Anemia de Células Falciformes , Infecciones Bacterianas , Transfusión Sanguínea , Niño , Preescolar , Coagulación Intravascular Diseminada , Urgencias Médicas , Fiebre , Enfermedades Hematológicas/terapia , Hemofilia A , Hemorragia/diagnóstico , Humanos , Tolerancia Inmunológica , Terapia de Inmunosupresión , Leucemia , Linfoma , Púrpura , Púrpura Trombocitopénica , Trombocitopenia , Enfermedades Vasculares , Vena Cava SuperiorRESUMEN
Anticoagulation monitoring in pediatric patients can be problematic because of the immaturity of the coagulation system in this population. In addition, the hemodilution required to place a small patient on bypass can interfere with standard monitoring methods. In this institution, the Hemochron Jr. ACT (activated clotting time)+ assay has been the standard of care for anticoagulation monitoring since 1997. This assay, with a target ACT of 400 s for initiating bypass, was compared to both the Medtronic HMS system (N = 7) and the Hemochron HiTT assay (N = 6) in pediatric patients. All three assays were then employed to monitor a pediatric Hemophilia A patient (Factor VIII <1%) with high inhibitor titer. Both the HiTT clotting time and the HMS heparin level showed statistically significant correlation to the ACT+ (HiTT, N = 24, r = 0.761; HMS, N = 31, r = 0.818). An HMS target heparin level of 1.5 mg/kg and a HiTT target clotting time of 180 s were found to be clinically equivalent to the 400-s ACT+ as indicators of the need for additional heparin. When a 7-year-old male with severe hemophilia A and high inhibitor titer required tricuspid valve replacement, all three assays were used to ensure appropriate anticoagulation management. During bypass, this patient's ACT+ remained out of range (>1005 s). The HiTT was maintained at >180 s and the HMS heparin level at >1.5 mg/kg. Heparin was administered when any single parameter was below the cutoff value. The use of the combination of three distinct monitoring assays for this patient allowed the surgical team an added level of confidence that appropriate anticoagulation had been maintained.
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Anticoagulantes/administración & dosificación , Anticoagulantes/sangre , Monitoreo de Drogas/métodos , Hemofilia A/tratamiento farmacológico , Heparina/administración & dosificación , Heparina/sangre , Inhibidores de Serina Proteinasa/sangre , Niño , Factor VIII/antagonistas & inhibidores , Implantación de Prótesis de Válvulas Cardíacas , Hemofilia A/sangre , Humanos , Masculino , Manejo de Atención al Paciente , Inhibidores de Serina Proteinasa/efectos adversos , Tiempo de Coagulación de la Sangre TotalAsunto(s)
Anemia de Células Falciformes/sangre , Plaquetas , Adenosina Difosfato/farmacología , Adolescente , Adulto , Plaquetas/efectos de los fármacos , Niño , Preescolar , Colágeno/farmacología , Epinefrina/farmacología , Femenino , Humanos , Masculino , Agregación Plaquetaria/efectos de los fármacos , Factor Plaquetario 3/análisis , Serotonina/metabolismoRESUMEN
Manifestations of pulmonary metastases were reviewed in a retrospective study of 30 patients with the autopsy diagnosis of neuroblastoma seen over a 25 year period. Seven patients with histologic evidence of pulmonary metastases are reported. Radiologic manifestations included examples of direct extension, hematogenous spread, and lymphangitic spread. Two patients with lymphangitic pulmonary metastases had clinically significant respiratory distress. Pulmonary spread in neuroblastoma represents widely disseminated metastatic diseases and is a grave prognostic sign.
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Neoplasias Pulmonares/secundario , Neuroblastoma/secundario , Niño , Preescolar , Femenino , Humanos , Lactante , Neoplasias Pulmonares/diagnóstico por imagen , Metástasis Linfática , Masculino , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/patología , Pronóstico , Radiografía , Estudios RetrospectivosRESUMEN
Infusions of factor VIII at 50-100 U/kg were administered "on demand" for bleeding episodes, or once weekly, in eight patients (aged 3-20 years) with hemophilia A and historically high titer inhibitors to factor VIII. Inhibitors were eliminated and immunologic tolerance to factor VIII occurred in five of the eight patients within 5-31 months. Four patients had minimal anamnestic responses upon starting factor VIII infusions. One patient, who continued on weekly factor VIII after appearance of the inhibitor, had a continued rise in titer for 10 weeks, followed by a gradual decrease and elimination of the inhibitor at 24 months. Three patients had marked anamnestic rises in the inhibitor levels (204-2150 BU) at the start of the factor VIII infusions, followed by a slow fall and eventual suppression of the inhibitor titers to less than 15 BU. The administration of IgG, cyclophosphamide, and prednisone was only partially successful at enhancing inhibitor suppression in two of the highest responding patients. This less intensive factor VIII infusion program appeared as effective, better tolerated, and less costly than other more intensive protocols utilizing daily factor VIII for inducing immune tolerance in hemophilia patients with inhibitors.
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Factor VIII/uso terapéutico , Hemofilia A/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Adolescente , Adulto , Niño , Preescolar , Factor VIII/antagonistas & inhibidores , Hemofilia A/tratamiento farmacológico , Humanos , MasculinoRESUMEN
Bone marrow biopsies (244) performed with a Jamshidi needle were evaluated in 53 children with leukemia or aplastic anemia. Adequate specimens were obtained in 85%. Results of cellularity estimated by biopsy were compared to the cellularity of the aspirate versus volumetric determination of the myeloid-erythroid layer (buffy coat). A wide discrepancy was noted between marrow cellularity confirmed by biopsy versus the aspirate or buffy coat. The greatest variance was seen in the hypercellular or normocellular marrows, as estimated by biopsy, in which 39% were misinterpreted as moderately or severely hypocellular by aspirate. Volumetric measurement of buffy coat was least acceptable for estimating cellularity. Thus the biopsy has proved to be an important and reliable indicator of bone marrow cellularity.
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Células de la Médula Ósea , Anemia Aplásica/patología , Biopsia con Aguja , Diferenciación Celular , Niño , Preescolar , Humanos , Leucemia Linfoide/patología , Leucemia Monocítica Aguda/patología , Leucemia Mieloide/patologíaRESUMEN
Two infants with Down syndrome had transient myeloproliferative disorder (TMD) during the neonatal period and subsequently acute nonlymphoblastic leukemia (ANLL). Histochemically, the blast cells in TMD were indistinguishable from those in ANLL. Only the constitutional chromosome (trisomy 21) was found in TMD, whereas new cytogenetic abnormalities emerged in ANLL. A mixed growth pattern in stem cell cultures during TMD suggested the existence of an abnormal clone that might be responsible for the evolution into ANLL at a later date. Serial cytogenetic studies and culture studies of peripheral blood cells may help to understand the pathophysiology and risk of ANLL in patients with TMD.
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Síndrome de Down/sangre , Leucemia/sangre , Reacción Leucemoide/sangre , Enfermedad Aguda , Recuento de Células Sanguíneas , Examen de la Médula Ósea , Ensayo de Unidades Formadoras de Colonias , Síndrome de Down/patología , Células Madre Hematopoyéticas , Humanos , Recién Nacido , Leucemia/patología , Leucemia Monocítica Aguda/sangre , Leucemia Monocítica Aguda/patología , Reacción Leucemoide/patología , MasculinoRESUMEN
A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function.
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Danazol/uso terapéutico , Pregnadienos/uso terapéutico , Deficiencia de Proteína C , Tromboflebitis/genética , Niño , Fibrinógeno/metabolismo , Heparina/uso terapéutico , Heterocigoto , Humanos , Masculino , Linaje , Proteína C/genética , Tromboflebitis/tratamiento farmacológicoRESUMEN
"Cold" lesions on bone scan have been reported in a variety of disease processes, including infection, avascular necrosis, and cysts. We present two cases of children who presented with large "cold" areas on technetium bone scans and were treated initially for septic processes. Acute childhood leukemia frequently presents with bone or joint pain, fever, and elevation of the erythrocyte sedimentation rate. Although the diagnosis may be difficult if the characteristic clinical signs and laboratory findings are absent, the presence of anemia should alert the physician to the possibility of malignancy. Bone scanning provides a sensitive method of localizing pathology, but diagnosis requires biopsy or marrow aspiration.
Asunto(s)
Huesos/diagnóstico por imagen , Leucemia Linfoide/diagnóstico por imagen , Compuestos de Tecnecio , Artritis Infecciosa/diagnóstico por imagen , Médula Ósea/patología , Preescolar , Diagnóstico Diferencial , Difosfonatos , Humanos , Lactante , Leucemia Linfoide/patología , Masculino , Osteomielitis/diagnóstico por imagen , Cintigrafía , TecnecioRESUMEN
Recently reported data suggest the possibility of differences in clinical efficacy between full-length factor VIII (FL-FVIII) and B-domain deleted recombinant factor VIII (BDD-rFVIII). To address this question, we conducted a meta-analysis of studies reporting the incidence of bleeding under prophylaxis, as well as studies of FL-FVIII and BDD-rFVIII half-life. The pooled cumulative weekly prophylactic dose of BDD-rFVIII (81.3 +/- 13.8 IU kg(-1) week(-1)) was greater by 36% (P = 0.11) than that of FL-FVIII (60.0 +/- 5.9 IU kg(-1) week(-1)). The pooled incidence of bleeding in BDD-rFVIII recipients [16.8 bleeds per patient year; confidence interval (CI), 9.5-24.2 bleeds per patient year] was more than 2.5-fold larger (P < 0.0005) than that in patients receiving FL-FVIII (6.6 bleeds per patient year; CI, 4.7-8.5 bleeds per patient year). In a multivariate analysis, the incidence rate ratio was 2.10 (CI, 1.98-2.24), indicating that breakthrough bleeding under prophylaxis was more than twice as likely with BDD-rFVIII than FL-FVIII at equivalent doses and ages. The pooled half-life for plasma-derived FL-FVIII (13.7 h; CI, 12.8-14.6 h) was closely similar to that for recombinant FL-FVIII (14.3 h; CI, 13.3-15.4 h). By contrast, the pooled half-life for BDD-rFVIII (11.3 h; CI, 9.9-12.7 h) was shorter by approximately 3 h compared with FL-FVIII. Although the results of the meta-analysis need to be interpreted with caution, the pooled data suggest that breakthrough bleeding under prophylaxis may occur more frequently in patients receiving BDD-rFVIII than FL-FVIII and may at least partly reflect a more abbreviated half-life of BDD-rFVIII. Several biochemical differences between BDD-rFVIII and FL-FVIII may underlie the observed disparities in bleeding incidence and half-life. This meta-analysis should be confirmed by further studies.
Asunto(s)
Factor VIII/uso terapéutico , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológico , Adolescente , Niño , Preescolar , Factor VIII/farmacocinética , Semivida , Hemartrosis/etiología , Hemofilia A/sangre , Hemofilia A/complicaciones , Humanos , Lactante , Masculino , Análisis Multivariante , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/uso terapéuticoRESUMEN
Yield stress is a sensitive index of blood fluidity at low shear stress. Using a method that measured the stress required to cause motion of a thin sedimenting layer of red cells, we found significant elevations of yield stress in patients with homozygous sickle cell anemia during clinical steady state. Mixing studies of sickle cells in normal plasma and buffered saline and of normal red cells in sickle plasma showed (1) that the increased yield stress of sickle blood was not due to differences between sickle and normal plasma factors and (2) that yield stress of sickle cells was not increased in the absence of plasma proteins. Multivariate regression analysis was performed to determine the dependence of sickle blood yield stress on several red cell and plasma factors. The yield stress measurements were normalized for differences in plasma fibrinogen concentration. Other factors studied included cell density, fetal hemoglobin concentration, alpha globin genotype, cell deformability as measured by high shear viscosity, and fibronectin and von Willebrand factor concentrations. Cell density was the primary determinant of yield stress. Measurements of yield stress on density fractionated sickle cells confirmed that the increased yield stress of sickle blood was due to the dense sickle erythrocyte. We conclude that the increased yield stress of sickle blood during clinical steady state was due to an abnormal interaction between the dense sickle cell membrane and plasma protein(s).