RESUMEN
Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.
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16,16-Dimetilprostaglandina E2/uso terapéutico , Síndrome de Radiación Aguda/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Plaquetas/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Trastornos Hemorrágicos/tratamiento farmacológico , Lisinopril/uso terapéutico , Megacariocitos/efectos de los fármacos , Trombocitopenia/tratamiento farmacológico , Trombopoyesis/efectos de los fármacos , Síndrome de Radiación Aguda/complicaciones , Animales , Plaquetas/efectos de la radiación , Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Proteína C-Reactiva/análisis , Radioisótopos de Cesio , Evaluación Preclínica de Medicamentos , Células Endoteliales/efectos de la radiación , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/efectos de la radiación , Femenino , Rayos gamma/efectos adversos , Trastornos Hemorrágicos/etiología , Megacariocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Selectina-P/análisis , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de la radiación , Factor Plaquetario 4/análisis , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/etiología , Trombocitopenia/etiología , Trombopoyesis/efectos de la radiación , Irradiación Corporal Total , Factor de von Willebrand/análisisRESUMEN
OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. PATIENT: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5-2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.
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Antitrombinas/uso terapéutico , Arginina/análogos & derivados , Vacunas contra la COVID-19/efectos adversos , Ácidos Pipecólicos/uso terapéutico , Sulfonamidas/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Trombosis de la Vena/tratamiento farmacológico , Arginina/uso terapéutico , Venas Cerebrales/diagnóstico por imagen , ChAdOx1 nCoV-19 , Quimioterapia Combinada , Femenino , Fondaparinux/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas , Trombocitopenia/etiología , Tomografía Computarizada por Rayos X , Trombosis de la Vena/etiología , Adulto JovenRESUMEN
Huangqi, the dried root of Radix Astragali, is an essential herb in Traditional Chinese Medicine and has been used to promote hematopoiesis for centuries. Astragalus polysaccharide (ASPS), the bioactive compound of Huangqi, serves a crucial role in hematopoiesis. The aim of the present study was to investigate the hematopoietic effects, in particular the thrombopoietic effects, and the molecular mechanisms of ASPS using an irradiationinduced myelosuppressive mouse model. Colonyforming unit assays, flow cytometric analysis of apoptosis, ELISAs, Giemsa staining and western blotting were performed to determine the hematopoietic and antiapoptotic effects of ASPS. The results demonstrated that ASPS enhanced the recovery of red blood cells at day 21 following treatment, as well as platelets and white blood cells at day 14. In addition, ASPS promoted colony formation in all lineages (megakaryocytes, granulocyte monocytes, erythroid cells and fibroblasts). The morphological study of the bone marrow demonstrated that trilineage hematopoiesis was preserved in the ASPS and thrombopoietin (TPO)treated groups compared with the control group. The overall cellularity (mean total cell count/area) of the ASPStreated group was similar to that of the TPOtreated group. Additionally, in vitro experiments indicated that treatment with 100 µg/ml ASPS exhibited the maximum effect on colony formation. ASPS attenuated cell apoptosis in megakaryocytic cells via inhibiting the mitochondrial caspase3 signaling pathway. In conclusion, ASPS promoted hematopoiesis in irradiated myelosuppressive mice possibly via enhancing hematopoietic stem/progenitor cell proliferation and inhibiting megakaryocytes apoptosis.
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Medicamentos Herbarios Chinos/química , Megacariocitos/citología , Polisacáridos/administración & dosificación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Trombocitopenia/prevención & control , Animales , Apoptosis/efectos de los fármacos , Astragalus propinquus , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hematopoyesis/efectos de los fármacos , Hematopoyesis/efectos de la radiación , Inyecciones Intraperitoneales , Masculino , Megacariocitos/efectos de los fármacos , Megacariocitos/efectos de la radiación , Ratones , Polisacáridos/farmacología , Traumatismos Experimentales por Radiación/complicaciones , Traumatismos Experimentales por Radiación/metabolismo , Trombocitopenia/etiologíaRESUMEN
Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the SLC19A2gene, which codes for a thiamine carrier protein. Oral thiamine supplementation is the main treatment. We report the case of a 19-year-old man known for TRMA, who presented in the emergency department with bicytopenia (haemoglobin 5,4 g/dL, thrombocytes 38×109/L) revealed by dyspnea and chest pain. Investigations excluded bleeding, hemolysis, coagulopathy and iron deficiencies. A recent infection and an acute coronary syndrome have also been eliminated. We later found out that thiamine treatment had been discontinued three months before, due to general confinement in Tunisia during the COVID-19 pandemic. Parenteral administration of 100 mg of thiamine daily resulted in the recovery of haematopoiesis within three weeks.
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Anemia Megaloblástica/sangre , Betacoronavirus , Infecciones por Coronavirus/epidemiología , Diabetes Mellitus/sangre , Pérdida Auditiva Sensorineural/sangre , Pandemias , Neumonía Viral/epidemiología , Deficiencia de Tiamina/congénito , Trombocitopenia/etiología , Síndrome Coronario Agudo/diagnóstico , Anemia Megaloblástica/tratamiento farmacológico , Anemia Megaloblástica/fisiopatología , COVID-19 , Dolor en el Pecho/etiología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/fisiopatología , Diagnóstico Diferencial , Hemoglobina Glucada/análisis , Accesibilidad a los Servicios de Salud , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/fisiopatología , Hemoglobinas/análisis , Humanos , Masculino , Derrame Pericárdico/diagnóstico por imagen , Derrame Pericárdico/etiología , Recurrencia , SARS-CoV-2 , Tiamina/provisión & distribución , Tiamina/uso terapéutico , Deficiencia de Tiamina/sangre , Deficiencia de Tiamina/tratamiento farmacológico , Deficiencia de Tiamina/fisiopatología , Túnez , Adulto JovenRESUMEN
Introducción: la pseudotrombocitopenia inducida por EDTA (ácido etilendiamino tetraacético) es un fenómeno de aglutinación de plaquetas que se presenta in vitro, mediado por anticuerpos anti-plaquetarios de tipo IgG, IgA o IgM dirigidos contra el complejo glucoproteínico IIb/IIIa de la membrana plaquetaria. Caso clínico: presentamos un caso clínico de una paciente de 59 años de edad sometida a recambio valvular aórtico; clínicamente con evolución favorable durante el periodo posquirúrgico, sin embargo, en estudios de control se registra trombocitopenia severa, lo que llevo a cuestionar el uso de anticoagulantes y la necesidad de transfusión de plaquetas. Al realizar estudios complementarios se encontró agregados plaquetarios en el frotis de sangre periférica, posteriormente se realizó recuento seriado de plaquetas y comparación del histograma plaquetario, catalogando el caso como pseudotrombocitopenia. Conclusión: La trombocitopenia por agregados plaquetarios es una condición de baja incidencia (0.07% a 0.1%). Se debe a la agregación de plaquetas in vitro asociada al uso de anticoagulantes, frecuentemente etilendiaminotetraacético (EDTA), en el presente caso también se asoció al uso de citrato de sodio. Este problema no se asocia a sangrado, sin embargo su desconocimiento pudo haber llevado a realizar procedimientos diagnósticos y terapéuticos innecesarios
Introduction: EDTA (ethylenediamine tetraacetic acid) induced by pseudothrombocytopenia is a platelet agglutination phenomenon that occurs in vitro, which are mediated by anti-platelet antibodies of the IgG, IgA or IgM type directed against the glycoprotein complex IIb / IIIa of the platelet membrane . Clinical case: This is a clinical case of a 59-yearsold patient undergoing aortic valve replacement, clinically with a favorable evolution during the postoperative period, however, in control studies, severe thrombocytopenia was recorded, which led to questioning the use of anticoagulants and the need for platelet transfusion. When carrying out complementary studies, aggregated platelet were found in the peripheral blood smear, later, a serial platelet count and comparison of the platelet histogram were performed, classifying the case as pseudotrombocytopenia. Conclusion: Thrombocytopenia due to aggregated platelet is a low incidence condition (0.07% to 0.1%). It is due to the aggregation of platelets in vitro associated with the use of anticoagulants [frequently ethylenediamine tetra acetic (EDTA)]; in the present case it was also associated with the use of sodium citrate. This problem is not associated with bleeding; however its lack of knowledge leads to unnecessary diagnostic and therapeutic procedures.
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Humanos , Femenino , Persona de Mediana Edad , Trombocitopenia/diagnóstico , Trombocitopenia/etiología , Trombocitopenia/sangre , Agregación Plaquetaria/efectos de los fármacos , Ácido Edético/efectos adversos , Citrato de Sodio/efectos adversos , Anticoagulantes/efectos adversosRESUMEN
A 53-year-old woman presented at our hospital due to nasal bleeding and petechiae with profound thrombocytopenia (0.4×109/L). Her platelet count returned to the normal range immediately following a platelet transfusion. In this case, tea brewed from Taxus yunnanensis was the only suspected agent ingested prior to the onset of thrombocytopenia while all other etiologies for thrombocytopenia were excluded. A re-exposure test to Taxus yunnanensis resulted in the recurrence of acute thrombocytopenia. The association of thrombocytopenia with substances other than drugs has so far only been rarely described and to the best of our knowledge, this is the first reported case of thrombocytopenia caused by Taxus yunnanensis.
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Bebidas/efectos adversos , Extractos Vegetales/efectos adversos , Taxus/efectos adversos , Trombocitopenia/etiología , Femenino , Humanos , Persona de Mediana Edad , Recuento de Plaquetas , Transfusión de Plaquetas , Trombocitopenia/terapiaRESUMEN
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.
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Terapia por Quelación , Transfusión de Eritrocitos/efectos adversos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/prevención & control , Síndromes Mielodisplásicos/terapia , Anemia/tratamiento farmacológico , Anemia/etiología , Transfusión Sanguínea/métodos , Terapia por Quelación/métodos , Transfusión de Eritrocitos/métodos , Humanos , Hierro/sangre , Sobrecarga de Hierro/etiología , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología , Reacción a la Transfusión/sangre , Reacción a la Transfusión/prevención & controlRESUMEN
BACKGROUND: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING: Onxeo.
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Antibióticos Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Doxorrubicina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Anciano , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos/efectos adversos , Astenia/etiología , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas , Neutropenia/etiología , Sorafenib/efectos adversos , Trombocitopenia/etiología , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Dengue is an emerging threat to public health. At present, no clear modalities are available for the prevention and management of thrombocytopenia due to dengue. This article reports the clinical outcomes of integrative homeopathic care in a hospital setting during a severe outbreak of dengue in New Delhi, India, during the period September to December 2015. METHODS: Based on preference, 138 patients received a homeopathic medicine along with usual care (H+UC), and 145 patients received usual care (UC) alone. Assessment of thrombocytopenia (platelet count < 100,000/mm3) was the main outcome measure. Kaplan-Meier analysis enabled comparison of the time taken to reach a platelet count of 100,000/mm3. RESULTS: There was a statistically significantly greater rise in platelet count on day 1 of follow-up in the H+UC group compared with UC alone (mean difference = 12,337; 95% confidence interval [CI], 5,421 to 19,252; p = 0.001). This trend persisted until day 5 (mean difference = 14,809; 95% CI, 1,615 to 28,004; p = 0.02). The time taken to reach a platelet count of 100,000/mm3 was nearly 2 days earlier in the H+UC group compared with UC alone (H+UC: 3.44 days ± standard error of the mean [SEM] 0.18; 95% CI, 3.08 to 3.80; UC: 5.28 days ± SEM 0.29; 95% CI, 4.71 to 5.86; p < 0.001). CONCLUSION: These results suggest a positive role of adjuvant homeopathy in thrombocytopenia due to dengue. Randomized controlled trials may be conducted to obtain more insight into the comparative effectiveness of this integrative approach.
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Dengue/complicaciones , Homeopatía/normas , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología , Adolescente , Adulto , Quimioterapia Adyuvante/métodos , Estudios de Cohortes , Dengue/tratamiento farmacológico , Femenino , Homeopatía/métodos , Homeopatía/estadística & datos numéricos , Humanos , India , Masculino , Materia Medica/normas , Materia Medica/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. METHODS: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, nâ¯=â¯169) or in combination with cTACE on demand (Arm C, nâ¯=â¯170). Sorafenib was started within 3â¯days and cTACE within 7-21â¯days of randomization. The primary endpoint was overall survival (OS). RESULTS: For Arms C and S, the median OS was 12.8 vs. 10.8â¯months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; pâ¯=â¯0.290); median time to progression, 5.3 vs. 3.5â¯months (HR 0.67; 90% CI 0.53-0.85; pâ¯=â¯0.003); median progression-free survival, 5.2 vs. 3.6â¯months (HR 0.73; 90% CI 0.59-0.91; pâ¯=â¯0.01); and tumor response rate, 60.6% vs. 47.3% (pâ¯=â¯0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (pâ¯=â¯0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8â¯months; HR 0.58; 95% CI 0.40-0.82; pâ¯=â¯0.006). CONCLUSION: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. LAY SUMMARY: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , Anciano , Alanina Transaminasa/sangre , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ascitis/etiología , Quimioembolización Terapéutica/efectos adversos , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hiperbilirrubinemia/etiología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Sorafenib/administración & dosificación , Sorafenib/efectos adversos , Trombocitopenia/etiologíaRESUMEN
Extracorporeal circulation causes many deleterious effects on blood cells. Low-level light therapy (LLLT) in the red/near-infrared spectral range is known for its cytoprotective properties but its use during cardiopulmonary bypass (CPB) has not yet been studied. We aimed to assess whether LLLT protects platelets during CPB. 24 pigs were connected to 1-hour-CPB and observed for the next 23 hours. In 12 animals, blood circulating through the oxygenator was treated with LLLT. Platelet count and function were monitored throughout the experiment. The decrease in platelet count was greater in the control group, especially during CPB and after 24 hours. In LLLT group CD62P expression remained quite stable up to the 12th hour of the experiment, whereas in the control group it continuously decreased till the end of observation. Platelets in the control group were more prone to aggregation in the postoperative period than at the beginning of the experiment, whereas platelets in the LLLT group aggregated similarly or less intense. Limitation of platelet loss, pattern of aggregation and CD62P expression suggest that LLLT may stabilize platelet function during CPB and diminish the negative effects associated with the interaction of cells with an artificial surface.
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Puente Cardiopulmonar/métodos , Circulación Extracorporea/métodos , Terapia por Luz de Baja Intensidad/métodos , Trombocitopenia/radioterapia , Animales , Plaquetas/metabolismo , Plaquetas/efectos de la radiación , Puente Cardiopulmonar/efectos adversos , Circulación Extracorporea/efectos adversos , Humanos , Selectina-P/metabolismo , Agregación Plaquetaria/efectos de la radiación , Recuento de Plaquetas , Porcinos , Trombocitopenia/etiologíaRESUMEN
INTRODUCTION: Treatment with ruxolitinib, a selective JAK1/2 inhibitor, has significantly improved the lives of patients with myelofibrosis. Unfortunately, this treatment is frequently limited by cytopenias, precluding a high-risk group characterized by baseline thrombocytopenia. Additionally, there are no approved treatments for patients who have progressed while receiving ruxolitinib. Pacritinib is a novel JAK2/FLT3 inhibitor associated with less treatment-related myelosuppression that has the potential to fill these unmet treatment needs. Areas covered: This review will describe the preclinical rationale for JAK2/FLT3 inhibition, review the pharmacology of pacritinib, and detail available clinical data for pacritinib treatment of myelofibrosis. The circumstances surrounding the full clinical hold temporarily placed on pacritinib will also be explored. Expert commentary: Pacritinib has demonstrated promising results in patients with myelofibrosis and thrombocytopenia. Improvements in splenomegaly and symptom burden were observed with the 200 mg twice-daily dose in PERSIST-2, including those with platelet counts <50,000 mm. Safety concerns pertaining to cardiovascular events and bleeding that arose in an early analysis of PERSIST-2 were likely related to the advanced disease state enrolled rather than clear attribution to pacritinib. The results of an ongoing dose-finding, phase II study are eagerly awaited in order to move this promising myelofibrosis therapy forward.
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Antineoplásicos/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología , Animales , Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/efectos adversos , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresAsunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/fisiopatología , Nerium/envenenamiento , Hojas de la Planta/envenenamiento , Intoxicación por Plantas/fisiopatología , Trombocitopenia/fisiopatología , Adulto , Femenino , Humanos , Nerium/química , Hojas de la Planta/química , Trombocitopenia/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study was to evaluate effects of Shen-Cao granules for the prevention of thrombocytopenia caused by anticancer chemotherapy. METHODS: In this prospective study, a total of 200 patients with various malignant tumors were enrolled and evenly divided into a Shen-Cao granule treatment (nâ=â100) and a control group (nâ=â100). After 2 cycles chemotherapy with any combination of platinum-based drugs (cisplatin, carboplatin, and nedaplatin), the blood platelet (PLT) counts, levels of the PLT production regulator thrombopoietin (TPO), PLT aggregation rates, and the PLT activation marker CD62P expressions were monitored for 2 weeks. RESULTS: During 2 weeks of post-chemotherapy, the mean values of the minimum PLT count were 49.65â±â7.35 × 10/L in the treatment group and 31.56â±â9.32 × 10/L in the control group. The PLT count in the treatment group reached the lowest value 1.8 days later and recovered to a concentration ≥100â×â10/L 3 days earlier than in the control group. The concentrations of the TPO were 71.43â±â1.74 and 87.24â±â0.92âng/mL in the treatment group and 65.75â±â1.39 and 67.75â±â0.67âng/mL in the control group at 7 and 14 days post-chemotherapy, respectively. The maximum PLT aggregation rate declined after chemotherapy in the treatment group from 58.14â±â11.46% to 52.89â±â10.52%, while it increased in the control group from 56.94â±â10.55% to 61.75â±â12.26%. Coordinately, the expression of CD62P in the treatment group decreased from 6.17â±â0.59% to 4.89â±â0.72%, while it increased from 6.09â±â0.75% to 7.75â±â0.67% in the control group. CONCLUSION: Our study demonstrated that Shen-Cao granule treatment alleviated thrombocytopenia after chemotherapy, and reduced tumor-induced PLT activation and aggregation.
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Antineoplásicos/efectos adversos , Medicina Tradicional China , Neoplasias/tratamiento farmacológico , Compuestos de Platino/efectos adversos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Enfermedades de la Médula Ósea/tratamiento farmacológico , Enfermedades de la Médula Ósea/etiología , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Compuestos de Platino/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología , Adulto JovenRESUMEN
BACKGROUND/AIMS: Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. RESULTS: The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively (P=0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014) and Child-Pugh class B (HR=1.856, P=0.008). CONCLUSIONS: MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Esquema de Medicación , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Hiperbilirrubinemia/etiología , Hígado/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Estudios Retrospectivos , Sorafenib , Trombocitopenia/etiología , Resultado del Tratamiento , Trombosis de la Vena/complicaciones , Trombosis de la Vena/diagnóstico , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND/AIMS: It has been shown, both experimentally and clinically, that water-pipe smoke (WPS) exposure adversely affects the cardiovascular system (CVS) through the generation of oxidative stress and inflammation. Betaine, a naturally occurring compound in common foods, has antioxidant and anti-inflammatory actions. However, its potential to mitigate the adverse effect of WPS on the CVS has never been reported before. This is the subject of this study in mice. METHODS: Mice were exposed daily for 30 min to either normal air (control), or to WPS for two consecutive weeks. Betaine was administered daily by gavage at a dose of 10mg/kg, 1h before either air or WPS exposure. RESULTS: Betaine mitigated the in vivo prothrombotic effect of WPS in pial arterioles and venules. Moreover, it reversed the WPS-induced decrease in circulating platelets. Likewise, betaine alleviated platelet aggregation in vitro, and the shortening of activated partial thromboplastin time and prothrombin time induced by WPS. Betaine reduced the increase of plasminogen activator inhibitor-1 and fibrinogen concentrations in plasma induced by WPS. Betaine also diminished the WPS-induced increase of plasma concentrations of interleukin 6 and tumor necrosis factor α, and attenuated the increase of lipid peroxidation and superoxide dismutase. Immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome C by cardiomyocytes of the WPS-exposed mice. These effects were averted by betaine. CONCLUSION: Our findings suggest that betaine treatment significantly mitigated WPS-induced hypercoagulability, and inflammation, as well as systemic and cardiac oxidative stress.
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Antioxidantes/farmacología , Betaína/farmacología , Fumar/efectos adversos , Trombocitopenia/prevención & control , Trombosis/prevención & control , Administración Oral , Animales , Plaquetas/citología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Fibrinógeno/genética , Fibrinógeno/metabolismo , Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tiempo de Tromboplastina Parcial , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Tiempo de Protrombina , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Trombocitopenia/etiología , Trombocitopenia/metabolismo , Trombocitopenia/patología , Trombosis/etiología , Trombosis/metabolismo , Trombosis/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Constitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.
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Trombocitopenia/etiología , Trombocitopenia/metabolismo , Animales , Autoantígenos/metabolismo , Síndrome de Bernard-Soulier/etiología , Síndrome de Bernard-Soulier/metabolismo , Plaquetas/metabolismo , Diferenciación Celular/genética , Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Yoduro Peroxidasa/metabolismo , Proteínas de Unión a Hierro/metabolismo , Megacariocitos/citología , Megacariocitos/metabolismo , Ratones , Receptores de Trombopoyetina/metabolismo , Transducción de Señal , Trombocitopenia/diagnóstico , Trombopoyesis , Factores de Transcripción/metabolismo , Síndrome de Wiskott-Aldrich/etiología , Síndrome de Wiskott-Aldrich/metabolismoRESUMEN
Waldenström macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 × 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenström macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/análogos & derivados , Anemia/etiología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Clorhidrato de Bendamustina/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Dexametasona/administración & dosificación , Doxorrubicina/uso terapéutico , Humanos , Inmunoglobulina M/inmunología , Lenalidomida , Enfermedades Linfáticas/etiología , Recurrencia Local de Neoplasia , Piperidinas , Prednisona/uso terapéutico , Pronóstico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Inducción de Remisión , Rituximab/administración & dosificación , Esplenomegalia/etiología , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Trombocitopenia/etiología , Vincristina/uso terapéutico , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/inmunologíaRESUMEN
PURPOSE/OBJECTIVE(S): To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS: We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS: During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS: Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.
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Antineoplásicos/efectos adversos , Enfermedades de la Médula Ósea/etiología , Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Quimioradioterapia/efectos adversos , Neoplasias del Recto/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Ilion/efectos de la radiación , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucopenia/etiología , Modelos Logísticos , Vértebras Lumbares/efectos de la radiación , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Huesos Pélvicos/efectos de la radiación , Cuidados Preoperatorios , Curva ROC , Neoplasias del Recto/patología , Estudios Retrospectivos , Sacro/efectos de la radiación , Estadísticas no Paramétricas , Trombocitopenia/etiologíaRESUMEN
Malignant infantile osteopetrosis is a rare genetic disease characterized by increased bone density due to osteoclastic dysfunction. We report on the case of a 3-month-old girl who was referred to our hospital by the ENT department for severe anemia in the context of bilateral choanal atresia. Clinical examination showed failure to thrive, anemia, respiratory distress, bilateral choanal atresia, and chest deformation. The abdomen was soft with large hepatosplenomegaly. We noted a lack of eye tracking, no optical-visual reflexes, and left nerve facial paralysis. The blood count showed normocytic normochromic anemia with severe thrombocytopenia. The infectious work-up and blood smears were negative. The skeleton X-ray showed diffuse bone densification of the skull, long bones, pelvis, vertebrae, and ribs. The facial bone CT confirmed membranous choanal atresia. The molecular biology search for the TCIRG1 gene mutation was not available. The patient had supportive treatment (transfusion, oral steroid, vitamin D, oxygen, nutrition). Bone marrow transplantation was indicated but not available. She died at 6 months in a context of severe anemia and bleeding. Malignant infantile osteopetrosis is rare and symptoms are nonspecific. Diagnosis should be considered in young infants presenting refractory anemia, particularly in the context of choanal atresia. Bone marrow transplantation remains the only curative treatment.