RESUMEN
INTRODUCTION: Thrombopoietin-receptor agonists (TPO-RA) are marketed for immune thrombocytopenia (ITP). They have been associated to thrombosis occurrence in randomized controlled trials. However, the characteristics of these thromboses in the real-life practice as well as their management are poorly known. The objectives of this study were to determine the risk factors, circumstances and management of thrombosis occurring during exposure to TPO-RA in ITP. METHODS: We carried out a multicentre retrospective study in France. Moreover, all cases reported to the French pharmacovigilance system were also analyzed. RESULTS: Overall, 41 thrombosis (13 arterial) in 36 ITP patients (14 males and 22 females, mean age: 59 years) were recorded between January 2009 and October 2015. Twenty patients were treated with romiplostim, 15 with eltrombopag and 1 was treated by both medications. Thirty-three (92%) of the patients had another risk factor for thrombosis. Ten (28%) had an history of thrombosis and 13 (36%) received immunoglobulin in the month preceding the thrombotic event. Three had antiphospholipid antibodies; congenital low-risk thrombophilia was found in 4 cases; 18 patients (50%) were splenectomized. Median platelet count at the time of thrombosis was 172G/l (1-1049G/l). In 22 patients (56%), a good prognosis was associated with the thrombosis and was not linked with TPO-RA withdrawal. Bleeding events occurred in 14% of the patients treated with antiplatelet or anticoagulant drug, including 5% serious events (1 death of intracranial haemorrhage, 1 death of haemorrhagic shock). CONCLUSIONS: The thrombotic risk may be carefully assessed before starting TPO-RA in ITP patients. The impact of antiphospholipid antibodies and of congenital thrombophilia remains to be defined. Thrombosis evolution seems independent of TPO-RA management. Bleeding manifestations seem rare. Poor prognosis was mainly due to ischemic sequelae.
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Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/epidemiología , Pirazoles/uso terapéutico , Receptores Fc/uso terapéutico , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Trombosis/inducido químicamente , Trombosis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Farmacovigilancia , Estudios Retrospectivos , Adulto JovenRESUMEN
The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.
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Mesilato de Imatinib/administración & dosificación , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Rituximab/administración & dosificación , Adolescente , Adulto , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
The blastic variant (BV) form of mantle cell lymphoma (MCL) is considered to be a very aggressive subtype of non-Hodgkin's lymphoma (NHL). In order to determine its clinico-biological features and response to therapy we studied 33 patients (17%) out of 187 suffering from MCL who were diagnosed with a BV of MCL. Blastic variant was diagnosed according to histopathological patterns, immunophenotyping, and bcl1 gene rearrangement and/or cyclin D1 overexpression. Three patients initially diagnosed with large cell NHL were classified as BV. Patients received front-line therapy including CHOP-like regimen or CVP (n = 29), or chlorambucil (n = 4) and CHOP or ESAP as second-line therapy. High-dose intensification with stem cell transplantation (SCT) was performed in 11 cases (autoSCT, n = 8; alloSCT, n = 3). All but two patients were in complete remission (CR) at the time of transplant (CR1, n = 5; CR2, n = 4). Clinical and biological characteristics did not differ from those of the common form of MCL. The median age was 62 years (29-80), with a sex ratio (M/F) of 2.6:1. Of the 33 patients, 66% had extranodal site involvement, 85% had an Ann Arbor stage IV, and 82% had peripheral lymphadenopathy. Circulating lymphomatous cells were seen in 48% of cases. Twelve patients (36%) entered a CR1 with a median duration of 11 months. Fifteen patients (46%) failed to respond and rapidly died of progressive disease. Second-line therapy led to a 26% (6/23) CR2 rate. Nine patients relapsed after high-dose therapy. Twenty-two of the 33 patients (66%) died of refractory or progressive disease. Median overall survival (OS) time was 14.5 months for the 33 BV patients as compared to 53 months for the 154 patients with a common form of MCL, P <0.0001. In the univariate analysis, OS was influenced by age, extranodal site involvement, circulating lymphomatous cells, and international prognosis index (IPI). In the multivariate analysis, only IPI affected OS: patients with IPI > or =2 had 8 months median OS as compared to 36 months median OS for patients with IPI <2, P = 0.003. Blastic variant is one of the worst forms of NHL. An improved recognition of BV of MCL is required, particularly in high-grade CD5+ NHL using immunophenotyping and bcl1 molecular study. Standard therapy using anthracycline or even high-dose intensification produce poor results and an alternative treatment should be proposed to such patients.
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Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/mortalidad , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Reordenamiento Génico , Genes bcl-1 , Humanos , Inmunofenotipificación , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Monoclonal gammopathies of undetermined significance (MGUS) have been shown to be associated with an increased risk of fractures. This study describes prospectively the bone status of MGUS patients and determines the factors associated with vertebral fracture. We included prospectively 201 patients with MGUS, incidentally discovered, and with no known history of osteoporosis: mean age 66.6±12.5 years, 48.3% women, 51.7% immunoglobulin G (IgG), 33.3% IgM and 10.4% IgA. Light chain was kappa in 64.2% patients. All patients had spinal radiographs and bone mineral density measurement in addition to gammopathy assessment. At least one prevalent non-traumatic vertebral fracture was discovered in 18.4% patients and equally distributed between men and women. Fractured patients were older, had a lower bone density and had also more frequently a lambda light chain isotype. Compared with patients with κ light chain, the odds ratio of being fractured for patients with λ light chain was 4.32 (95% confidence interval 1.80-11.16; P=0.002). These results suggest a high prevalence of non-traumatic vertebral fractures in MGUS associated with lambda light chain isotype and not only explained by low bone density.
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Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Fracturas de la Columna Vertebral/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Análisis Multivariante , Prevalencia , Estudios Prospectivos , Radiografía , Factores de Riesgo , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiologíaRESUMEN
Severe veno-occlusive (VOD) disease is a major cause of morbidity and mortality in allogeneic bone marrow transplant recipients, and new approaches in managing patients who develop serious VOD is needed. In this report, we describe a patient who underwent transjugular intrahepatic portosystemic stent-shunt (TIPS) for life-threatening VOD are following allogeneic bone marrow transplantation for AML. Although the patient died of CMV-associated pneumonitis 5 weeks later, the TIPS functioned well until her death and permitted regression of the hepatic and renal symptoms. This report suggests that TIPS may be feasible and effective for managing patients with life-threatening liver dysfunction after marrow transplantation.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedad Veno-Oclusiva Hepática/terapia , Derivación Portosistémica Intrahepática Transyugular , Adulto , Femenino , Humanos , Trasplante HomólogoRESUMEN
Hodgkin's disease (HD) confined below the diaphragm accounts for less than 5% of all patients with HD. Although the major characteristics of this presentation appear established, optimal modalities of treatment still remain difficult to define. From April 1972 to October 1988, 28 patients with newly diagnosed infra-diaphragmatic HD, clinical stages I or II have been treated with 3 successive prospective protocols combining initial chemotherapy and radiotherapy (40 gy). This series of patients accounted for 4,3% of patients with HD limited to clinical stages (CS) I and II. Overall survival and freedom from relapse at 15 years were 74,4% and 73% respectively, without significant differences between clinical stages I and II, presence or absence of B symptoms or histologic subtype. There is only a trend (p < 0,10) in favour of patients younger than 40 years. In all 7 clinically staged IA patients no relapses were seen and combined treatment does not appear to be better than inverted Y irradiation alone. On the other hand initial chemotherapy seems necessary in patients with CS II A and B since 15 of our 21 patients are alive in first CR whereas the crude rate of transdiaphragmatic nodal relapses may reach up to 53% following radiotherapy alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Adolescente , Adulto , Bleomicina/administración & dosificación , Ensayos Clínicos como Asunto , Terapia Combinada , Dacarbazina/administración & dosificación , Diafragma , Doxorrubicina/administración & dosificación , Femenino , Humanos , Lomustina/administración & dosificación , Masculino , Mecloretamina/administración & dosificación , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Estudios Prospectivos , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
We report three new cases of bladder cancer occurring in patients treated by cyclophosphamide (Endoxan): two patients had Waldenström disease and were treated during 7.5 and 7 years respectively (total received dose of 220 and 190 g respectively). The third patient was treated for autoimmune erythroblastopenia and the bladder cancer occurred 5 years after treatment by cyclophosphamide (39 g during 3.3 years). Bladder cancers after cyclophosphamide treatment are generally transitional cell carcinomas. They are observed after an oral treatment, generally given for more than one year. A cumulative dose of more than 20 g is the principal risk factor, with a median interval from treatment to tumor of 7 years. No other risk factor has been identified (tobacco, age, sex, hemorrhagic cystitis). The relative risk of bladder cancer is estimated between 7 and 9, and seems proportional to the cumulative dose of cyclophosphamide. The first hypothesis to explain bladder cancer occurrence is a carcinogenic effect of one of the cyclophosphamide metabolites, acrolein, but the immunosuppressive effect of cyclophosphamide may play a role. The risk of secondary bladder cancer implies to limit the use of cyclophosphamide, particularly in non malignant disease, and to closely watch the patient especially by way of annual cystoscopy.
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Ciclofosfamida/efectos adversos , Neoplasias de la Vejiga Urinaria/inducido químicamente , Anciano , Terapia Combinada , Ciclofosfamida/administración & dosificación , Cistitis/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Hematuria/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Aplasia Pura de Células Rojas/tratamiento farmacológico , Factores de Riesgo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Macroglobulinemia de Waldenström/tratamiento farmacológicoRESUMEN
Treatment of patients with advanced-stage hematological malignancies (HM) includes frequent transfusions. Given present limited hospital budgets, administrative pressure is increasing on hematology services to limit the cost of these transfusions. An expert multidisciplinary panel involved in hematology formed a working party to draw up a series of proposals, including definitions of advanced stage disease and the indications for platelet transfusion. Their proposals included: (a) Platelet transfusions are indicated for the treatment of bleeding caused by low platelet counts; (b) Patients should receive full information, including the basic criteria for platelet transfusion; (c) Doctors should be trained to assess whether or not platelet transfusions are urgently required; and (d) The practice of home transfusions should be encouraged.
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Enfermedades de la Médula Ósea/terapia , Leucemia/terapia , Linfoma/terapia , Transfusión de Plaquetas , Enfermedades de la Médula Ósea/inducido químicamente , Toma de Decisiones , Humanos , Paris , Transfusión de Plaquetas/economía , Calidad de VidaRESUMEN
Co3(PO4)2, SrCo2(PO4)2, Co2P2O7, BaCoP2O7 and SrCoP2O7 present different geometries of five-coordinated Co(2+) (([5])Co(2+)) sites, coexisting with ([6])Co(2+) in Co3(PO4)2 and Co2P2O7, and ([4])Co(2+) in SrCo2(PO4)2. ([5])Co K-edge XANES spectra show that the intensity of the pre-edge and main-edge is intermediate between those of ([6])- and ([4])Co. Diffuse reflectance spectra show the contributions of Co(2+) in (D3h) symmetry for SrCo2(PO4)2, and (C4v) symmetry for BaCoP2O7 and SrCoP2O7. In Co3(PO4)2 and Co2P2O7 the multiple transitions observed arise from energy level splitting and may be labeled in (C2v) symmetry. Spectroscopic data confirm that (D3h) and (C4v) symmetries may be distinguished upon the intensity of the optical absorption bands and crystal field splitting values. We discuss the influence of the geometrical distortion and of the nature of the next nearest neighbors.
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Bario/química , Cobalto/química , Complejos de Coordinación/química , Fosfatos/química , Estroncio/química , Espectroscopía de Absorción de Rayos X , Tecnología de Fibra Óptica , Modelos QuímicosRESUMEN
A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy+Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36±4%, respectively. Disease status (relapse <12 months, including refractory patients), FLT3-ITD-positive status and high-risk cytogenetics were the three strongest independent adverse prognostic factors for OS and EFS in this series. We then defined three subgroups with striking different outcomes at 2 years: no adverse factor (favourable, N=36): OS 58%, EFS 45%; one adverse factor (intermediate, N=54): OS 37%, EFS 31%; two or three adverse factors (poor, N=43): OS 12%, EFS 12% (P<10(-4), P=0.001). This new simplified Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.
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Leucemia Mieloide Aguda/patología , Pronóstico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Supervivencia sin Enfermedad , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/diagnóstico , Persona de Mediana Edad , Recurrencia , Terapia Recuperativa/métodos , Resultado del TratamientoRESUMEN
This was a retrospective multicenter study including 44 acute leukaemia patients who have received allogeneic haematopoietic SCT (allo-HSCT) after prior exposure to Gemtuzumab Ozogamicin (GO) + chemotherapy. Median interval between last administration of GO and allo-HSCT was 4.2 (range, 0.8-26.3) months. At time of allo-HSCT, 33 patients were in CR. The majority of patients (n=36) received a reduced-intensity conditioning (RIC) regimen before allo-HSCT. All but one patient received low-dose heparin for veno-occlusive disease (VOD) prophylaxis. With a median follow-up of 15 (range, 1.1-63) months, overall survival and disease-free survival after allo-HSCT were 45% (95% confidence interval (CI), 30-61%) and 38% (95% CI, 24-54%) at 2 years, respectively. The cumulative incidence of grade 3-4 hyperbilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (< or =3.5 months) GO-allo-HSCT interval (n=4/19) vs 8% in all others (P=NS). Overall, the cumulative incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (< or =3.5 months) vs 4% (n=1/25) for all others (P=NS), and 5.5% (n=2/36) in patients receiving an RIC regimen vs 12.5% for the others (n=1/8) (P=NS). These results suggest that GO-based chemotherapy before allo-HSCT is feasible and does not result in an excessive rate of liver toxicity, especially VOD, after allo-HSCT.
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Aminoglicósidos/efectos adversos , Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Veno-Oclusiva Hepática/etiología , Leucemia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Niño , Preescolar , Terapia Combinada , Femenino , Gemtuzumab , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Heparina/uso terapéutico , Enfermedad Veno-Oclusiva Hepática/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Daunorrubicina/administración & dosificación , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Inducción de Remisión , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Femenino , Gemtuzumab , Humanos , Cariotipificación , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia/genética , Nucleofosmina , Pronóstico , Terapia Recuperativa , Secuencias Repetidas en Tándem , Resultado del Tratamiento , Adulto JovenRESUMEN
Factor VII deficiency is a rare autosomal bleeding disorder with a highly variable hemorrhagic predisposition. Severe bleeding, including hemarthroses, may be encountered when plasma factor VII levels are below 1%. Patients have prolonged prothrombin times, and the final diagnosis is established by quantitative factor VII assays. Some patients have true deficiencies, that is, very low factor VII activity and low factor VII antigen (cross-reacting material) levels (CRM-); others have normal antigen levels but low activity (CRM+). Still others have reduced antigen levels (CRMR). There is a rather poor correlation between clinical symptoms and factor VII activity levels in plasma. Treatment of these patients consists of fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII (rFVIIa) is a very useful alternative, and several patients have been treated successfully. Because of the short half-life of factor VIIa, repeated doses have to be administered, and continuous infusion may be even better. Antibodies to factor VII have been reported but seem to be rather rare. From the available data it appears that rFVIIa is a safe and effective treatment modality for patients with congenital factor VII deficiency.
Asunto(s)
Deficiencia del Factor VII/tratamiento farmacológico , Factor VII/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Deficiencia del Factor VII/congénito , Factor VIIa , HumanosRESUMEN
We investigated a Sephardic Jewish patient with a mild bleeding diathesis whose plasma levels of factor VII coagulant activity and factor VII antigen were 7% and 9% of normal, respectively. Sequencing demonstrated homozygosity for the Ala244Val mutation and the Arg353Gln polymorphism, which is associated with a modest decrease in factor VII levels. To elucidate the mechanism by which Ala244Val reduced factor VII levels in this patient, transient transfections were performed in COS-1 cells with wild type and mutant factor VII cDNAs and factor VII antigen levels in cell lysates and conditioned media were measured. The secretion of the mutant protein (FVII244V) into the media was 20% of wild type (FVIIwt), and intracellular levels of FVII244V were 60% of FVIIwt. A construct encoding Ala244Val along with the Arg353Gln polymorphism decreased the factor VII level in the media to that observed in the patient's plasma. Pulse-chase experiments demonstrated that FVII244V did not accumulate intracellularly and that low levels of the abnormal protein were maintained throughout the chase. To test the hypothesis that FVII244V results in an unstable molecule, amino acids with smaller (Gly) or larger (Phe) side chains were substituted for Val244 by site-directed mutagenesis. Transient transfection assays with these constructs demonstrated that the side chain of amino acid 244 is crucial in maintaining a proper conformation of the molecule. We conclude that Ala244Val results in a factor VII molecule that is unstable and is probably degraded intracellularly.
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Deficiencia del Factor VII/genética , Mutación Missense/genética , Alanina/genética , Factor VII/biosíntesis , Deficiencia del Factor VII/etnología , Femenino , Homocigoto , Humanos , Judíos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético , Valina/genéticaRESUMEN
Acute respiratory failure developed in two patients with hyperleukocytic acute myelomonocytic leukemia with abnormal marrow eosinophils within 1 to 3 days after the beginning of high-dose induction chemotherapy. The presence of moderate pulmonary leukostasis before chemotherapy initiation, the simultaneous occurrence of an acute tumor lysis syndrome, the lack of evidence of any other cause of respiratory distress, and the clinical evolution lead the authors to attribute pulmonary injury to lysis of resident leukemic cells. The responsibility of eosinophilic cellular constituents for the diffuse alveolar damage is discussed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Médula Ósea/patología , Eosinófilos/patología , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Síndrome de Lisis Tumoral/etiología , Enfermedad Aguda , Adulto , Tos/etiología , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Hipoxia/etiología , Leucemia Mielomonocítica Aguda/patologíaRESUMEN
Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10,976 resulting in Arg353Gln and a decanucleotide insert at position -323 in the 5'-flanking region of the factor VII gene, have been associated with a 20% to 25% reduction in plasma factor VII levels. However Arg353Gln almost always segregates on alleles containing the insert in UK and Italian populations, thereby making it impossible to independently evaluate the impact of Arg353Gln on factor VII levels in these ethnic groups. We have evaluated the influence of genotype on factor VII levels in 99 healthy Polish blood donors and observed that Arg353Gln frequently occurs in the absence of the insert. In univariate analysis, the mean levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) were significantly lower in 16 people who were heterozygous for Arg353Gln and the insert compared with 72 normal subjects who had neither Arg353Gln nor the insert (88.8% of normal and 83.1% versus 102% and 100%, P = .019 and P = .0003, respectively). In nine subjects heterozygous for Arg353Gln alone, VII:C and VII:Ag were significantly decreased compared with the normal subjects (81.9% and 83%, respectively, P = .007 and P = .004). In multivariate analysis, Arg353Gln but not the insert significantly reduced VII:C and VII:Ag after adjustment for age and plasma triglycerides (P < .05 and P = .02, respectively). To evaluate the mechanism responsible for reduced factor VII levels in individuals with Arg353Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gln353 and wild-type factor VII cDNA in COS-1 cells. The levels of VII:Ag in the cell lysates were similar, but the amino acid substitution significantly reduced factor VII secretion into the media to 74.9% of wild-type (P = .0001). Based on these in vivo and in vitro studies, we conclude that the Arg353Gln polymorphism alone can decrease plasma factor VII levels.