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1.
Pediatr Blood Cancer ; 71(5): e30931, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38433307

RESUMEN

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Niño , Azacitidina/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnóstico , Resultado del Tratamiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos
2.
Proc Natl Acad Sci U S A ; 115(30): 7777-7782, 2018 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-29987015

RESUMEN

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.


Asunto(s)
Alelos , Enfermedades de la Médula Ósea/metabolismo , ADN Helicasas/metabolismo , Reparación del ADN , Enfermedades Genéticas Congénitas/metabolismo , Inestabilidad Genómica , Transcripción Genética , Células A549 , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , ADN Helicasas/genética , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/metabolismo , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Células HeLa , Humanos , Masculino , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Síndrome
5.
Eur J Haematol ; 102(4): 319-330, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30664257

RESUMEN

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the ß-globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell-derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA-approved therapy to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L-glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.


Asunto(s)
Anemia de Células Falciformes/etiología , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/metabolismo , Animales , Antidrepanocíticos/farmacología , Antidrepanocíticos/uso terapéutico , Biomarcadores , Coagulación Sanguínea , Moléculas de Adhesión Celular/metabolismo , Micropartículas Derivadas de Células/metabolismo , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Membrana Eritrocítica/metabolismo , Eritrocitos Anormales/metabolismo , Genotipo , Hemoglobina Falciforme/genética , Hemólisis , Humanos , Hidroxiurea/farmacología , Hidroxiurea/uso terapéutico , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Mutación , Óxido Nítrico/metabolismo , Globinas beta/genética
6.
Blood ; 127(9): 1192-201, 2016 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-26511133

RESUMEN

Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF(-/-) C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF(-/-) mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF(-/-) and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood-brain barrier permeability was significantly attenuated in VWF(-/-) mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.


Asunto(s)
Malaria Cerebral/etiología , Malaria Cerebral/metabolismo , Factor de von Willebrand/metabolismo , Animales , Antígenos/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Células Endoteliales/metabolismo , Humanos , Malaria Cerebral/parasitología , Malaria Cerebral/prevención & control , Ratones Endogámicos C57BL , Modelos Biológicos , Péptidos/metabolismo , Permeabilidad , Plasmodium berghei , Multimerización de Proteína , Trombocitopenia/sangre , Trombocitopenia/complicaciones
7.
Blood ; 127(11): 1387-97; quiz 1518, 2016 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-26702063

RESUMEN

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.


Asunto(s)
Factor de Transcripción GATA2/deficiencia , Síndromes Mielodisplásicos/genética , Adolescente , Edad de Inicio , Niño , Preescolar , Aberraciones Cromosómicas , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Ensayos Clínicos Fase III como Asunto , Análisis Mutacional de ADN , Sordera/genética , Femenino , Factor de Transcripción GATA2/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Síndromes de Inmunodeficiencia/genética , Estimación de Kaplan-Meier , Masculino , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/patología , Fenotipo , Prevalencia , Pronóstico , Estudios Prospectivos , Sesgo de Selección , Adulto Joven
9.
Blood ; 126(7): 915-9, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26084674

RESUMEN

Activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. In this study, a recombinant APC variant (APC(N329Q)) mimicking the naturally occurring APC-ß plasma glycoform was found to exhibit superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling. APC(N329Q) also enhanced integrin αMß2-dependent PAR1 proteolysis to exert significantly improved antiinflammatory activity on macrophages compared with wild-type APC. Recent therapeutic applications of recombinant APC in ischemic stroke models have used APC variants with limited anticoagulant activity to negate potential bleeding side effects. Using a mouse model of ischemic stroke and late t-PA intervention, the neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPC(PS)) was compared with an identical APC variant except for the absence of glycosylation at the APC-ß sequon (mAPC(PS/N329Q)). Remarkably, mAPC(PS/N329Q) limited cerebral ischemic injury and reduced brain lesion volume significantly more effectively than mAPC(PS). Collectively, this study reveals the importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC and demonstrates the potential of novel APC variants with superior cytoprotective signaling function as enhanced therapeutic agents for the treatment of ischemic stroke.


Asunto(s)
Isquemia Encefálica/metabolismo , Proteína C/metabolismo , Receptor PAR-1/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Isquemia Encefálica/terapia , Catepsinas/genética , Catepsinas/metabolismo , Modelos Animales de Enfermedad , Receptor de Proteína C Endotelial , Variación Genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Oligosacáridos , Proteína C/genética , Proteína C/uso terapéutico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapéutico , Proteolisis , Receptor PAR-1/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Transducción de Señal
11.
Br J Haematol ; 172(6): 930-6, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26766110

RESUMEN

Low-dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2-30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non-toxic option in palliative situations to prolong survival.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adolescente , Adulto , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Niño , Preescolar , Esquema de Medicación , Evaluación de Medicamentos/métodos , Femenino , Humanos , Masculino , Neutropenia/inducido químicamente , Cuidados Paliativos/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
12.
Pediatr Transplant ; 20(3): 432-7, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26841203

RESUMEN

G-CSF post-allogeneic HSCT accelerates neutrophil engraftment, but evidence that it impacts on cost-related outcomes is lacking. We performed a retrospective child and adolescent single-center cohort study examining G-CSF administration from Day +6 of allogeneic HSCT vs. ad hoc G-CSF use where clinically indicated. Forty consecutive children and adolescents undergoing allogeneic HSCT were included. End-points were as follows: time to engraftment; incidence of acute and chronic GvHD; number of patients alive at Day +100; 180-day TRM; post-transplant days in hospital; and cost of antimicrobials, TPN, and G-CSF usage. Neutrophil engraftment occurred earlier in the group that received G-CSF from Day +6. There was no difference between groups in any of the other end-points with the following exception: the cost of GCSF was significantly higher in the D + 6 G-CSF group. However, median G-CSF cost in this group amounted to only €280. There was a trend towards reduced cost of antimicrobials in the D + 6 G-CSF group, although this did not reach significance (p = 0.13). The median cost per patient of antimicrobial agents between groups differed by €1116. This study demonstrated the administration of G-CSF on Day +6 in pediatric HSCT to be safe. A further study using a larger cohort of patients is warranted to ascertain its true clinico-economic value.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Costos de la Atención en Salud , Trasplante de Células Madre Hematopoyéticas/métodos , Neutrófilos/citología , Adolescente , Antiinfecciosos/química , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped , Factor Estimulante de Colonias de Granulocitos/economía , Trasplante de Células Madre Hematopoyéticas/economía , Humanos , Lactante , Masculino , Pediatría/métodos , Complicaciones Posoperatorias , Estudios Retrospectivos , Factores de Tiempo , Trasplante Homólogo/economía , Trasplante Homólogo/métodos
13.
Pediatr Int ; 58(4): 304-7, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26670157

RESUMEN

Non-Hodgkin's lymphoma (NHL) is a relatively common childhood cancer that can present in a myriad of ways. It is essential that NHL is included in the differential diagnosis of children presenting with an abdominal complaint, especially those with unexplained or prolonged symptoms. We describe three acute pediatric presentations of abdominal NHL, two of which presented as acute abdomen (the first mimicking intussusception and the second appendicitis), and the third involving lower limb edema. This case series illustrates the array of presentations of abdominal NHL and the diagnostic challenges that they can provide.


Asunto(s)
Neoplasias Abdominales/diagnóstico , Linfoma no Hodgkin/diagnóstico , Adolescente , Biopsia , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Rayos X
14.
Br J Haematol ; 171(1): 38-51, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26123689

RESUMEN

Kasabach-Merritt Phenomenon (KMP) refers to the clinical constellation of thrombocytopenia, consumptive coagulopathy and purpura associated with Kaposiform haemangioedothelioma or tufted angioma, but not the more common infantile haemangioma. It shows a variable and unpredictable response to traditional pharmacological agents, such as steroids, vincristine or interferon alpha 2a or 2b. More recently, the interaction between platelets and endothelial cells and the proangiogenic phenotype that results has been recognized to underly the pathogenesis of this disorder. Recent efforts have attempted to target the platelet by using antiplatelet agents and by the withholding of platelet transfusions even in those patients who have significant thrombocytopenia and laboratory evidence of coagulopathy. Excellent response rates and prompt results have been achieved by combining antiplatelet therapy with vincristine, without the need for steroid use. This synergistic approach moves away from the conventional wisdom of treating the underlying lesion to control the coagulopathy. Sirolimus, which is directed against the PI3/AKT/mTOR downstream signalling pathway involved in lymphangiogenesis, has also shown promising results, although further study is needed.


Asunto(s)
Síndrome de Kasabach-Merritt/metabolismo , Síndrome de Kasabach-Merritt/fisiopatología , Síndrome de Kasabach-Merritt/terapia , Humanos , Transducción de Señal , Trombocitopenia/patología , Trombocitopenia/fisiopatología , Trombocitopenia/terapia
15.
Haematologica ; 100(1): 17-22, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25552679

RESUMEN

Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.


Asunto(s)
Ensayos Clínicos como Asunto/normas , Leucemia Mielomonocítica Juvenil/mortalidad , Leucemia Mielomonocítica Juvenil/terapia , Recurrencia Local de Neoplasia/prevención & control , Guías de Práctica Clínica como Asunto/normas , Niño , Terapia Combinada , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Pronóstico , Tasa de Supervivencia
16.
Haematologica ; 99(9): 1472-8, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24763401

RESUMEN

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6-10%, 11-20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Células de la Médula Ósea/efectos de los fármacos , Daunorrubicina/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Células de la Médula Ósea/patología , Niño , Preescolar , Monitoreo de Drogas , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Pronóstico , Recurrencia , Inducción de Remisión , Análisis de Supervivencia
17.
Haematologica ; 99(4): 656-63, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24162791

RESUMEN

Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090).


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Pancitopenia/tratamiento farmacológico , Adolescente , Animales , Suero Antilinfocítico/administración & dosificación , Niño , Preescolar , Femenino , Caballos , Humanos , Inmunosupresores/administración & dosificación , Lactante , Masculino , Pancitopenia/diagnóstico , Conejos , Recurrencia , Factores de Riesgo , Resultado del Tratamiento
18.
J Pediatr Hematol Oncol ; 36(5): 404-6, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24136025

RESUMEN

A 6-year-old girl presented with presumed relapse of childhood immune thrombocytopenia. Investigations revealed deranged coagulation parameters, abnormal small bowel thickening, and splenomegaly. A clinically significant bleeding diathesis emerged which was refractory to most hemostatic interventions. Laparatomy revealed a composite diagnosis of splenic hemangiomatosis and small bowel lymphangiomatosis. Splenectomy resulted in complete resolution of the coagulopathy. The diagnosis and management of these conditions is inherently complex and without clear guidance. We discuss our perioperative management of the bleeding diathesis. There is a need for long-term follow-up of the underlying pathologies particularly as potentially useful therapeutic agents have emerged.


Asunto(s)
Hemangioma/complicaciones , Trastornos Hemorrágicos/etiología , Intestino Delgado/patología , Linfangioma/complicaciones , Neoplasias del Bazo/complicaciones , Trombocitopenia/etiología , Niño , Femenino , Hemangioma/diagnóstico , Trastornos Hemorrágicos/cirugía , Humanos , Laparotomía , Linfangioma/diagnóstico , Pronóstico , Esplenectomía , Neoplasias del Bazo/diagnóstico , Trombocitopenia/cirugía
20.
Thromb Res ; 233: 101-108, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38039722

RESUMEN

OBJECTIVE: A high platelet turnover rate may produce a population of platelets that confers an inadequate response to aspirin. We aimed to investigate the relationship between residual platelet aggregation and platelet turnover in paediatric cardiology patients on aspirin monotherapy by evaluating the fraction of immature platelets as a marker for turnover and secondly to test the predictive value of the immature platelet fraction (IPF) to classify patients as responsive or non-responsive to aspirin. METHODS: Sixty patients divided into two age categories (≤90 days, >90 days of age) were included in this prospective observational study. Patients were then stratified into tertiles using their IPF level. Platelet studies included thromboelastography with platelet mapping (TEGPM). RESULTS: The overall incidence of 'inadequate response to aspirin' was 38 % in our patient cohort recently post-cardiac surgery a consequence that warrants further study. The frequency of inadequate response to aspirin was higher in the upper tertile of IPF when compared to the lower tertile, (88 %) versus (4 %) respectively (p < 0.05). The 'cut off' for IPF was determined to be 3.9 % with a sensitivity of 95.7 %, and a specificity of 92.9 % (area under the curve of 0.955 [CI 0.896-1.014, p < 0.05]). CONCLUSION: This study demonstrates that inadequate response to aspirin occurs in approximately 38 % of patients undergoing specific high-risk congenital cardiac procedures using the dosing practice of a national centre. This study supports the hypothesis that an elevated platelet turnover may result in aspirin being less effective in patients who are recently post cardiac surgery. These data are of direct translational relevance.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Cardiopatías Congénitas , Niño , Humanos , Lactante , Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Plaquetas/fisiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Cardiopatías Congénitas/cirugía
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