Biallelic Deleterious Germline SH2B3 Variants Cause a Novel Clinical Syndrome of Myeloproliferation and Multi-Organ Autoimmunity
Piers BlomberyVahid PazhakhAdriana S. AlbuquerqueJesmeen MaimarisLingge TuBrenda M. BrionesFlorence EvansElla R. ThompsonBen CarpenterJulie CurtinJonathan LambertSiobhan O. BurnsGraham J. Lieschke
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Hepatosplenomegaly
Thrombocytosis
Autoimmune Hepatitis
Patients with essential thrombocythemia (ET) usually have normal thrombopoietin (TPO) concentrations because of negative feedback from thrombocytosis. TPO mutations in familial ET cases result in increased translation efficiency with excessive TPO stimulation and thrombocytosis. The authors describe an infant with a high platelet count (1300 x 103/mm3) and an elevated TPO concentration who was successfully treated with anagrelide. Sequencing of TPO revealed no genetic cause. This case may represent a case of atypical ET in which thrombocytosis results from TPO stimulation rather than clonal proliferation. Measuring TPO concentrations may be warranted for children with unexplained extreme thrombocytosis.
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Introduction: The aim of this study is to assess circulating thrombopoietin concentrations in patients with both clonal and reactive thrombocytosis (RT), which are two distinct categories of extreme platelet production circumstances. Investigation of the thrombopoietin levels in clonal versus reactive thrombocytosis may help us to understand the interactions of this key regulatory cytokine and the conditions in which abnormally increased platelet formation exist.Materials and methods: Thrombopoietin levels were measured in patients with platelet counts greater than 500 × 103 μl−1 The study population consisted of 21 patients with RT (13 with iron deficiency anemia, and 8 with rheumatoid arthritis), 24 patients with clonal thrombocytosis (six with essential thrombocytosis, three with myelofibrosis, eight with chronic myelogenous leukemia, and seven with polycythemia vera (PV)) and 16 healthy subjects were used as controls.Results: The median plasma thrombopoietin concentration was 100.5 pg ml−1 in patients with RT, 467pg ml−1 in patients with clonal thrombocytosis and 62.65pgml−1 in the control group. The thrombopoietin concentration was found to be higher in the patients with primary thrombocytosis when compared to the control group (p = 0.001), as well as in patients with RT (p = 0.002). However, there was no statistically significant difference between the patients with RT and the control group (p = 0.14). There was no correlation between thrombopoietin levels and the platelet counts in patients with clonal thrombocytosis, including essential thrombo- cythemia (ET).Conclusion: Increased levels of thrombopoietin were found in patients with clonal thrombocytosis versus patients with RT and control subjects as well. Defective clearance of thrombopoietin by megakaryocytes and platelets due to a reduced number of thrombopoietin receptors may be the causative mechanism behind this. These results indicate that plasma thrombopoietin levels may be helpful in distinguishing between clonal and reactive thrombocytosis.
Thrombocytosis
Thrombopoietin receptor
Myeloproliferative neoplasm
Mean platelet volume
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Thrombocytosis
Myeloproliferative Disorders
Thrombopoiesis
Hematology
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Objective: To investigate the relationship between platelets and serum thrombopoietin (TPO) in rheumatoid arthritis (RA) and the mechanism of RA with thrombocytosis thereof. Methods: The clinical data of 57 patients with RA were analyzed. Patients were divided into two groups by platelet count: high platelet count (300×109/L) and normal platelet count. There were 28 healthy persons as control. Serum levels of TPO and interleukin (IL)-6 were measured using enzyme-linked im- munosorbent assay(ELISA) in patients with RA and healthy controls. Results:(1)Serum TPO and IL-6 were higher in RA with thrombocytosis than those of healthy controls (P 0.05). Compared the two RA groups, the one with thrombocytosis had higher serum TPO(P 0.05). (2)The platelet count of RA with thrombocytosis did not correlate with serum level of TPO. It correlated significantly with serum level of IL-6 (r = 0.566, P 0.01) and C-reactive protein (CRP) (r = 0.401, P 0.05). (3)The serum level of TPO in RA with thrombocytosis did not correlate with serum IL-6 (r = -0.069, P 0.05). Conclusion: The serum level of TPO was significantly elevated in RA with thrombocytosis, which suggested that TPO may take part in the pathology of thrombocytosis in RA. The thrombocytosis in RA correlated with inflammatory reaction.
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Interleukin 11
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Essential thrombocythaemia (ET), a myeloproliferative disorder (MPD) manifested by excessive platelet production, lacks a specific diagnostic test to facilitate differentiation from other thrombocytoses. We studied thrombopoietin (TPO) levels in 41 patients with thrombocytosis: 25 ET patients, eight with other MPD, and eight with reactive thrombocytosis. Mean age and platelet counts for these groups were comparable. TPO levels for 96 healthy individuals provided a reference range for normal. The majority of ET patients (19/25 or 76%) had normal TPO levels. No patient with ET had a TPO level below 75 pg/ml, compared with 57% of healthy donors and 8/16 (50%) patients with other thrombocytoses ( P < 0.05). TPO levels in ET are not appropriately down‐regulated, as occurs with cytokines relevant to other MPD. In thrombocytosis, a TPO level <75 pg/ml indicates that ET is unlikely.
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Summary. To clarify the mechanisms underlying thrombocytosis secondary to infections, we longitudinally studied serum levels of thrombopoietin (TPO) and interleukin (IL)‐6 in 15 infants and young children with prominent thrombocytosis (platelets > 700 × 10 9 /l) following acute infections and 116 age‐matched controls using an enzyme‐linked immunosorbent assay. The subjects included nine patients with bacterial infections, three with viral infections and three with non‐determined pathogens. TPO values in the controls were 2·24 ± 0·87 fmol/ml (mean ± SD) with a 95% reference interval of 0·85–4·47 fmol/ml. In the first week of infection, platelet counts were normal, but TPO values increased (∼10·73 fmol/ml). TPO levels peaked on day 4 ± 2 at 6·44 ± 2·37 fmol/ml and then fell gradually. When platelet counts peaked in the second and third weeks, TPO levels were similar to the controls. IL‐6 levels in the first week rose and dropped more rapidly than TPO. Serum TPO values were significantly correlated with C‐reactive protein levels ( r = 0·688, P < 0·001) and IL‐6 levels ( r = 0·481, P = 0·027). These results suggest that TPO contributes to thrombocytosis following infections in conjunction with IL‐6, arguing for additional regulatory mechanisms of blood TPO levels.
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Abstract Familial thrombocytosis (FT) is an inherited disorder with clinical presentations similar to essential thrombocytosis (ET). In several pedigrees, overproduction of thrombopoietin (TPO) has been shown to be responsible for the disease. We report herein three cases of thrombocytosis in three successive generations. All cases had increased serum TPO levels. Sequence analysis of TPO gene and transmembrane domain of c‐MPL, known as the TPO receptor, revealed no mutations. Platelet c‐MPL expression was similar or slightly increased as compared to normal volunteers. These data suggest that altered regulation of the TPO gene might be involved in the pathogenesis of FT. Am. J. Hematol. 76:395–397, 2004. © 2004 Wiley‐Liss, Inc.
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To verify pathophysiological mechanisms underlying thrombocytosis in low-birth-weight (LBW) preterm babies, we evaluated kinetic changes in platelet counts and thrombopoietic cytokines including thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 in 24 uncomplicated preterm infants. Platelet counts in cord blood (CB) (265 +/- 64 x 10(9)/l) were similar to adult levels, increased by d 14 (473 +/- 140 x 10(9)/l), and then remained fairly constant. Thrombocytosis (> 500 x 10(9)/l) was observed in 9/24 (38%) subjects. Mean TPO level in CB was 5.11 +/- 1.51 fmol/ml, peaked at d 2 (7.64 +/- 3.28 fmol/ml), decreased at d 5 (3.93 +/- 1.67 fmol/ml), and thereafter kept fairly constant during the remaining neonatal period. Compared with term infants, mean TPO levels of preterm infants in CB and at d 2 were significantly higher (P < 0.01). There was an inverse correlation between platelet counts and TPO levels (r = 0.45, P < 0.001, n = 88). Preterm neonates with thrombocytosis had significantly higher TPO values in CB than those without thrombocytosis (P < 0.05). There was no significant relationship between platelet counts and IL-6. IL-11 was not detectable. These results suggest that an early elevation of serum TPO levels is related to the subsequent thrombocytosis in LBW preterm infants.
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Interleukin 11
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Megakaryocytopoiesis
Myeloproliferative Disorders
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Two children with hepatoblastoma, marked thrombocytosis, and extremely elevated alpha fetoproteins are reported. It is not clear from review of the literature whether hepatoblastomas or hepatocarcinomas are associated with thrombocytosis. Elevated thrombopoietin levels were found in liver tumor extract from one patient.
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