ABSTRACT
Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.
Subject(s)
MicroRNAs/genetics , Myeloproliferative Disorders/genetics , Primary Myelofibrosis/genetics , Aged , Alleles , Animals , Cytokines/genetics , Disease Progression , Female , Genotype , Humans , Inflammation/genetics , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Mutation/genetics , Myeloproliferative Disorders/pathology , NF-kappa B/genetics , Polycythemia Vera/genetics , Polycythemia Vera/pathology , Signal Transduction/genetics , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/pathologySubject(s)
Polycythemia Vera/pathology , Primary Myelofibrosis/pathology , Thrombocythemia, Essential/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prognosis , RegistriesABSTRACT
Platelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombocytopenia, that induces activation and aggregation of autologous or allogeneic platelets via interaction with platelet glycoprotein (GP)VI. Patient temperature-dependent pseudothrombocytopenia was EDTA-independent, but was prevented by integrin αIIbß3 blockade. Unstimulated patient platelets revealed elevated levels of bound IgM, increased expression of activation markers (P-selectin and CD63), low GPVI levels and abnormally high thromboxane (TX)A2 production. Patient serum induced temperature- and αIIbß3-dependent decrease of platelet count in allogeneic donor citrated platelet-rich plasma (PRP), but not in PRP from Glanzmann's thrombasthenia or afibrinogenaemia patients. In allogeneic platelets, patient plasma induced shape change, P-selectin and CD63 expression, (14)C-serotonin release, and TXA2 production. Activation was not inhibited by aspirin, cangrelor or blocking anti-Fc receptor (FcγRIIA) antibody, but was abrogated by inhibitors of Src and Syk, and by a soluble GPVI-Fc fusion protein. GPVI-deficient platelets were not activated by patient plasma. These data provide the first evidence for an IgM PCA causing platelet activation/aggregation via GPVI. The PCA activity persisted over a five-year follow-up period, supporting a causative role in patient chronic thrombocytopenia and bleeding.
Subject(s)
Hemorrhagic Disorders/immunology , Immunoglobulin M/immunology , Platelet Aggregation/immunology , Platelet Membrane Glycoproteins/physiology , Thrombocytopenia/immunology , Adult , Afibrinogenemia/blood , Autoantibodies/blood , Biomarkers/blood , Cold Temperature/adverse effects , Cryoglobulins/pharmacology , Female , Humans , Platelet Activation/immunology , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/physiology , Protein-Tyrosine Kinases/blood , Thrombasthenia/blood , Thrombocytopenia/bloodABSTRACT
Somatic mutations in the CALR gene were recently discovered in a substantial proportion of Philadelphia-negative chronic myeloproliferative neoplasm (cMPN) patients lacking JAK2 and MPL mutations. Somatically acquired defects are not the only pathogenic mechanism involved in these disorders. Since germline JAK2 46/1 haplotype predisposes to cMPN-associated mutations, including JAK2V617F and MPLW515K7L, we evaluated whether the 46/1 haplotype also confers susceptibility to CALR-mutated cMPN, both in sporadic and familial cases. The single-nucleotide polymorphism rs10974944, which tags 46/1, was investigated in 155 sporadic MPN patients and 270 unrelated controls, as well as in 11 familial cMPN cases and 36 unaffected relative controls. As described elsewhere, the 46/1 haplotype was overrepresented, both in sporadic and familial cMPN. In sporadic cMPN, the JAK2 46/1 haplotype was closely associated with JAK2V617F (p = 0.0003) but not with JAK2-nonmutated cases. Analysis of CALR-mutated sporadic cMPN (n = 22) showed no association between CALR mutations and 46/1 haplotype (p = 0.87). Regarding the familial cMPN, the prevalence of carriers of the G allele was higher in familial (81.8%) than in sporadic (62%) cMPN, but it did not differ significantly (p = 0.3). Although we described a family with carriers of both JAK2V617F and CALR mutations, due to the low number of CALR-mutated familial cases, we could not determinate whether the JAK2 46/1 haplotype predisposes or does not to CALR-mutated familial cMPN. We conclude, for the first time, that the 46/1 haplotype, unlike JAK2V617F and MPLW515K7L, is not associated with CALR-mutated cMPN.
Subject(s)
Haplotypes/genetics , Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Aged , Alleles , Female , Humans , Male , Middle Aged , Mutation , Philadelphia ChromosomeABSTRACT
BACKGROUND AND OBJECTIVES: Inaccuracy of fingerstick haemoglobin compromises donor's health and losses blood donations. We evaluated the benefit of double haemoglobin screening with HemoCue. STUDY DESIGN AND METHODS: Blood donors underwent fingerstick screening by HemoCue and were driven for donation if capillary haemoglobin was within the regulatory range. Those failing were drawn venous blood and donated if their venous haemoglobin determined with HemoCue was acceptable. RESULTS: Of 276 605 donor clinic visits, 10 011 (3·6%) were assessed by two-step haemoglobin screening using HemoCue, because of low (n = 9444) or high (n = 567) capillary haemoglobin. Among these, 2561 (25·6%) were deemed eligible [recovered donations]. The recovery rate was 23·8% and 55·0% among donors presenting with low and high capillary haemoglobin, respectively. In both categories of attempted donations, capillary and venous haemoglobin with HemoCue correlated significantly in recovered donors (R(2) ≈ 0·5-0·7) but not in deferred visits (R(2) < 0·15). Venous haemoglobin with HemoCue and by haematological analyzer significantly correlated in all donations attempts (R(2) ≈ 0·7). Donors presenting with low capillary haemoglobin showed small bias between capillary and venous haemoglobin by HemoCue (-2·4 ± 6·2 g/l), fingerstick haemoglobin and venous haemoglobin with counter (1·3 ± 7·3 g/l), and venous haemoglobin with HemoCue and counter (3·7 ± 3·9 g/l). This bias was slightly greater in donors with high capillary haemoglobin (-7·5 ± 7·8, 13·7 ± 7·5, and 6·2 ± 7·5, respectively). Double haemoglobin screening by HemoCue reached an accuracy of 87·3% for qualifying donors presenting with low fingerstick haemoglobin. CONCLUSIONS: Double haemoglobin measurement with HemoCue [fingerstick and venous blood if required] is feasible and allows a significant recovery of blood donations.
Subject(s)
Blood Specimen Collection/methods , Hemoglobinometry , Hemoglobins/analysis , Adult , Aged , Blood Donors , Blood Specimen Collection/instrumentation , Donor Selection , Female , Hemoglobinometry/instrumentation , Humans , Male , Odds RatioABSTRACT
BACKGROUND: Thrombocytopenia is frequent among neonates, and 20-25% of affected infants are treated with platelet transfusions. These are frequently given for mild thrombocytopenia (platelets: 50-100 × 10(9) L(-1)), largely because of the known hyporeactivity of neonatal platelets. In tests of primary hemostasis, however, neonates have shorter bleeding and closure times (CTs) than adults. This has been attributed to their higher hematocrits, higher von Willebrand factor (VWF) concentrations, and predominance of longer VWF polymers. OBJECTIVE: To determine whether the 'transfusion' of adult (relatively hyperreactive) platelets into neonatal blood results in a hypercoagulable profile. METHODS: Cord blood (CB) and adult peripheral blood (PB) were separated (with a modified buffy coat method) to generate miniaturized platelet concentrates (PCs) and thrombocytopenic blood. PB-derived and CB-derived PCs (n = 7 per group) were then 'transfused'in vitro into thrombocytopenic CB and PB. The effects of autologous vs. allogeneic (developmentally mismatched) 'transfusions' were evaluated with whole blood aggregometry, a platelet function analyzer (PFA-100), and thromboelastography (TEG). RESULTS: Adult platelets aggregated significantly better than neonatal platelets in response to thrombin receptor-activating peptide, ADP, and collagen, regardless of the blood into which they were transfused. The 'transfusion' of adult platelets into thrombocytopenic CB resulted in shorter CTs-EPI (PFA-100) and higher clot strength and firmness (TEG) than 'transfusion' of neonatal autologous platelets. CONCLUSIONS: In vitro'transfusion' of adult platelets into neonatal blood results in shorter CTs than 'transfusion' with neonatal platelets. Our findings should raise awareness of the differences between the neonatal and adult hemostatic system and the potential 'developmental mismatch' associated with platelet transfusions for neonatal hemostasis.
Subject(s)
Platelet Transfusion/methods , Thrombocytopenia/therapy , Adult , Bleeding Time , Blood Coagulation , Blood Platelets/cytology , Fetal Blood/cytology , Hematocrit , Hemostasis , Humans , In Vitro Techniques , Infant, Newborn , Platelet Aggregation , Platelet Count , Platelet Function Tests , Thrombelastography/methodsABSTRACT
The Food and Drug Administration recently approved two novel thrombopoiesis-stimulating agents, Romiplostim (AMG-531, Nplate) and Eltrombopag (Promacta), for the treatment of adults with immune thrombocytopenic purpura. For physicians taking care of critically ill neonates, this offers the opportunity of decreasing platelet transfusions and potentially improving the outcomes of neonates with severe and prolonged thrombocytopenia. However, several developmental factors need to be taken into consideration. First, the population of thrombocytopenic neonates likely to benefit from these agents needs to be carefully selected. Second, the mechanisms underlying neonatal and adult thrombocytopenia differ from each other and are incompletely understood, and pre-clinical evidence suggests that the response of neonates to thrombopoietic factors might be different from that of adults. Finally, the potential non-hematopoietic effects of thrombopoietin have not been well established. Here, we will discuss these issues in detail, and will highlight the critical developmental differences between neonates and adults that need to be considered as we think about introducing these agents into neonatal care.
Subject(s)
Benzoates/therapeutic use , Hydrazines/therapeutic use , Platelet Transfusion , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Pyrazoles/therapeutic use , Receptors, Fc/therapeutic use , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/therapeutic use , Thrombocytopenia, Neonatal Alloimmune/drug therapy , Thrombopoiesis/drug effects , Thrombopoietin/therapeutic use , Adult , Age Factors , Apoptosis/drug effects , Benzoates/adverse effects , Brain/drug effects , Dose-Response Relationship, Drug , Drug Approval , Humans , Hydrazines/adverse effects , Infant, Newborn , Neurons/drug effects , Patient Selection , Purpura, Thrombocytopenic, Idiopathic/blood , Pyrazoles/adverse effects , Recombinant Fusion Proteins/adverse effects , Thrombocytopenia, Neonatal Alloimmune/blood , Thrombopoietin/adverse effects , United States , United States Food and Drug AdministrationABSTRACT
El linfoma pulmonar primario (LPP) es una patologíainfrecuente que engloba un amplio espectro deentidades clínico-patológicas, la gran mayoría de lascuales corresponde a linfomas de baja malignidadtipo BALT (linfoma asociado al tejido linfoidebronquial).Presentamos el caso de una paciente con un linfomalinfocítico B de células pequeñas, primario depulmón, de bajo grado de malignidad, con la excepcionalidadde no ser encuadrable dentro del subtipoBALT. Discutimos aquí el diagnóstico diferencialhistológico entre ambos tipos de linfomas, así comolos hallazgos clínico-radiológicos, el pronóstico y larespuesta al tratamiento
Primary lung lymphomas show a broad clinicaland cytological spectrum. The most commonhistological subtypes are low-grade lymphomasfrom bronchus-associated lymphoid tissue (BALT).We report a case of non-BALT low-grade lunglymphoma: a primary small B-cell lymphocyticlymphoma. We discuss the histological differentialdiagnosis, the clinical and radiological findings,prognosis and response to treatment
Subject(s)
Female , Adult , Humans , Lung Neoplasms/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Diagnosis, Differential , Lung Neoplasms/drug therapyABSTRACT
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