Absence Of Thrombocytosis Research Articles

Classification of Philadelphia-Negative MPN As Low Risk and High Risk MPN Based on Peripheral Blood Values and Molecular Genetics Only

Background: Philadelphia-negative myeloproliferative neoplasms (Ph -MPN) are characterized by overproduction of differentiated hematopoietic cells mediated in the majority of cases by mutations in JAK2, MPL or CALR (MPN driver genes). Ph - MPN include polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and MPN, unclassifiable (MPN-U) which differ in clinical presentation, prognosis, fibrosis and leukemic transformation rate as well as therapeutic options. However, WHO based classification requires experienced pathologists, in particular to diagnose prefibrotic PMF as high risk MPN, and thus remains observer dependent. Aim: Observer independent classification of Ph - MPN solely based on molecular genetics and peripheral blood (PB) parameters. Patients and Methods: We analyzed 267 Ph - MPN cases diagnosed as ET (n=76), PV (n=74), PMF (n=68) or MPN-U (n=49) following the WHO4R classification including only patients with an MPN driver mutation (median age: 68 years [22-91]; female: 41%; median follow-up: 5 years). All samples were analyzed by cytomorphology and whole genome sequencing (median coverage 100x). Mutation status of 20 genes associated with myeloid malignancies were analyzed in detail. Results: Genomic landscape of the MPN cohort showed mutations in JAK2 in 222 (83%) (n=132: single mutation; n=90: either mutation and copy neutral loss of heterozygosity or mutation and 9p gain), in CALR in 36 (14%), and in MPL in 9 (3%) patients. The median number of mutations per patient was two (range: 1-6). Within the cohort, 141 patients (53%) harbored MPN driver mutations only, while in 126 (47%) one to 5 additional mutations were found. The most frequent additional mutations were ASXL1 (n=50), TET2 (n=49; thereof 15 biallelic), SRSF2 (n=26), DNMT3A (n=18), U2AF1 (n=11) and TP53 (n=9; thereof 3 biallelic). Regarding PB parameters, high WBC (≥11×10 9/ L) were detected in 127 patients (48%), high PLT (≥450×10 9/ L) in 116 (43%) and anemia (HB <♂12 or ♀11 g/dL) in 50 patients (19%). We then performed Cox regression analyses for overall survival (OS) including only genetic abnormalities and PB values. In univariate analyses, biallelic TET2 inactivation ( TET2bi: hazard ratio/HR: 3.789), RUNX1 (n=4; HR: 13.479), ASXL1 (HR: 1.886), SRSF2 (HR: 3.218) mutations as well as high PLT (HR: 0.440), high WBC (HR: 1.998) and PB blasts >1% (n=57; HR: 1.904) showed significant associations with OS (for all p<0.02), while no effect was observed for MPN driver mutations, DNMT3A and monoallelic TET2 mutations. In addition, anemia showed a trend towards poor prognosis (HR: 1.595; p=0.079). Following this, we determined high and low risk MPN. In the absence of thrombocytosis, high risk MPN was defined if any of the four following risk factors were present: i) mutation in ASXL1 or SRSF2 or RUNX1 or TET2bi, ii) PB blasts >1%, iii) high WBC or iv) anemia. In the presence of thrombocytosis, at least two of these risk factors were required (Figure 1). Survival analysis revealed a significantly worse median OS of high risk (n=137; 51%) compared to low risk MPN (n=130; 49%) (8 years vs. not reached; p<0.001). This proposed novel stratification reflected prognosis better than WHO entities (median OS: MPN-U: 7 years; MF: 8 years; PV/ ET not reached; overall p=0.001) (Figure 1A). All 76 ET cases (100%) and 44/74 PV cases (59%) were classified as low risk MPN, while 63/68 PMF cases (93%) and 44/49 MPN-U cases (90%) were classified as high risk MPN (Figure 1B). Within low risk and high risk MPN, no significant OS differences were observed between the WHO entities ( p=0.114 and p=0.355, respectively). Conclusions: JAK2-pathway mutated Ph - MPN can be categorized into low and high risk MPN based on molecular genetics and PB values only. The presence of these objectively assessable risk factors in a patient with ET or PV warrants for a profound reevaluation of bone marrow histology (eventually by a reference pathologist for MPN) and clinical course before a high risk MPN (including prefibrotic PMF) can be ruled out. Whether the predictive value of low risk MPN based on molecular genetics and PB values only could be sufficient to omit BM biopsy in selected patients, needs to be evaluated in further prospective studies.

Effect of thrombocytosis on cardiovascular risk in rheumatoid arthritis

BACKGROUND: Patients with rheumatoid arthritis have a high level of comorbidity, and their most common and socially significant conditions are cardiovascular diseases, which represent a major cause of mortality. Currently, there are no data on the differences in cardiovascular risk scales in patients with rheumatoid arthritis depending on the presence or absence of thrombocytosis.
 AIM: To assess and compare cardiovascular risk according to conventional scales in patients with thrombocytosis and normal thrombocytes.
 MATERIALS AND METHODS: The study involved 85 patients diagnosed with rheumatoid arthritis: 40 with thrombocytosis [including 25 (62,5%) women] and 45 with normal thrombocytes [including 29 (64,4%) women]. The following scales were used to assess risk of cardiovascular complications: Systematic COronary Risk Evaluation with adjustment factor 1.5 (mSCORE), Reynolds Risk Score (RRS), QRESEARCH Cardiovascular Risk Algorithm (QRISK3), Assessing Cardiovascular Risk to Scottish Intercollegiate Guidelines Network / SIGN to Assign Preventative Treatment (ASSIGN).
 RESULTS: The obtained findings have demontrated that according to the mSCORE and RRS scales the patients of both groups had almost identical parameters; however, according to the ASSIGN and QRISK3 high risk of cardiovascular complications has been detected nearly twice as frequently in the patients with rheumatoid arthritis and thrombocytosis in comparison with those with normal level of thrombocytes. It is also worth noting that more frequent determination of high risk of cardiovascular complications by the QRISK3 was statistically significant.
 CONCLUSIONS: The QRISK3 calculation has shown significantly higher prevalence of high-risk cardiovascular complications among the patients with platelet counts 450 ∙ 109/l compared with those with platelet levels within the reference values. Thus, the QRISK3 scale can be considered as more informative for estimating risk of cardiovascular complications in rheumatoid arthritis.

Interleukin-6 and thrombopoietin concentrations in dogs with carcinoma with and without thrombocytosis.

BackgroundCarcinoma‐associated thrombocytosis involves tumor production of mediators such as interleukin‐6 (IL‐6) and thrombopoietin (TPO) that increase thrombopoiesis and may play a role in tumor evasion and metastasis. Carcinoma‐associated thrombocytosis is described in people, but has not been described in dogs.Hypothesis/ObjectivesEvaluate the concentrations of IL‐6 and TPO in dogs diagnosed with carcinoma with or without thrombocytosis. We hypothesized that IL‐6 and TPO concentrations would be higher in dogs with carcinoma compared to healthy dogs, and that IL‐6 and TPO concentrations would be higher in dogs with carcinoma and thrombocytosis when compared to dogs with carcinoma and normal platelet counts.AnimalsOne‐hundred sixteen dogs: 63 with carcinoma and 53 healthy control dogs.MethodsComplete blood count was performed in all dogs, and they were stratified for sub‐group analysis based on the presence or absence of thrombocytosis (platelet count > 500 103/µL). Serum TPO and IL‐6 concentrations were measured by ELISA. Results of selected numeric variables were compared using Wilcoxon rank sum tests for pairwise comparisons. A value of P < .05 was considered significant.ResultsTwelve of the dogs with carcinoma (12/63, 19.0%) and none of the healthy control dogs (0%) had thrombocytosis. Thrombopoietin concentrations (median [range]) were significantly higher in dogs with carcinoma when compared to controls (87.42 pg/mL [0 to >600] vs 15.99 pg/mL [0 to >600], P < .001). Interleukin‐6 concentrations (median [range]) were not different between dogs with carcinoma and healthy control dogs (9.70 pg/mL [0‐181.53] vs 3.03 pg/mL [0‐280.77], P = .15). In dogs with carcinoma, the TPO and IL‐6 concentrations were not different between dogs with thrombocytosis and dogs with normal platelet count.Conclusions and Clinical ImportanceThrombopoietin concentrations were significantly higher in dogs with carcinoma, regardless of platelet count. Thrombopoietin is likely to be 1 of multiple factors that can impact platelet number, production, and consumption in dogs with carcinoma.

ERYTHROCYTOSIS POST RENAL TRANSPLANTATION: A SINGLE CENTRE STUDY

Background: Post-transplant erythrocytosis (PTE) is defined as persistently elevated hemoglobin (Hb) and or hematocrit levels that occur following renal transplantation in the absence of thrombocytosis, leukocytosis, or another potential cause of erythrocytosis. PTE occurs in 8 to 15 percent of renal transplant recipients and usually affects patients with well-preserved graft function. Materials and Methods: To evaluate the prevalence and risk factors of PTE, we retrospectively analyzed the records of renal transplant recipients undergoing regular follow-up at our center for at least 6 months. Patients with a history of chronic obstructive pulmonary disease or malignancy were excluded. PTE was defined as Hb >17 g/dl. A total of 215 living-related renal transplant recipients were included. The clinical and laboratory parameters were noted. Results and Discussion: Thirty-eight (17.7%) out of 215 renal transplant recipients developed PTE. The mean age of the PTE group was 38.1± 9.4 years. The median time to onset of PTE was 9.5 (range 4-24) months post-transplant. The mean Hb at the time of diagnosis of PTE was 17.84± 0.54g/dl. There was a significant correlation of PTE with male sex, history of smoking before transplantation, history of ≥1 episode of acute rejection and cyclosporine (versus tacrolimus) containing triple-drug immunosuppression (p<0.05). There was not any significant correlation of PTE with age, blood pressure, renal function, HLA matching, induction immunosuppression regime, transplant renal artery stenosis or new-onset diabetes after transplantation (NODAT). Other pre-transplant factors including history of hypertension, diabetes mellitus, underlying renal disease, hemoglobin levels, blood transfusions, erythropoietin dose and duration of dialysis were not significantly correlated to PTE. Conclusion: PTE was observed in 17.7% of renal transplant recipients. PTE developed more frequently within the first year of transplantation. In addition to male sex and history of smoking, episodes of acute rejection and cyclosporine containing immunosuppression were associated with PTE.

Hepatoblastoma-An Unusual Presentation: A Case Report

Hepatoblastoma (HB) is the most common primary hepatic malignancy in children and accounts for 43% of the pediatric liver tumors. The usual presentation is the presence of an abdominal mass, vomiting, elevated αfetoprotein levels and thrombocytosis and it occurs in infants and children under 3 years of age. A 6-year-old male child presented to the outpatient department with complaints of mild to moderate grade fever, vomiting and loose stools for 3 days. The child was otherwise active and there was no palpable abdominal mass. USG abdomen and CT scan revealed the presence of an encapsulated solid hepatic tumor suggestive of HB. Complete blood count showed an elevated WBC count, high ESR and high α-fetoprotein levels (958 ng/ml) but no thrombocytosis. A nonanatomical excisional biopsy of the tumor confirmed it to be hepatoblastoma. The unusual features noticed in this case was presentation at a slightly later age (6 years), absence of abdominal mass and absence of thrombocytosis.

A Case Report on Post-Transplant Erythrocytosis

Post-transplant erythrocytosis is defined as persistently elevated haemoglobin and haematocrit levels that occur following renal transplantation and persist for more than six months in the absence of thrombocytosis, leukocytosis or other potential causes of erythrocytosis. Here, we report the case history of a 35-year-old male, who underwent live related kidney transplantation ten months ago, presented with high haemoglobin level and high haematocrit. It is an uncommon complication of kidney transplant recipient,whichprompted us to report the case&#x0D; Birdem Med J 2019; 9(2): 170-173

Fever of unknown origin (FUO): de Quervain's subacute thyroiditis with highly elevated ferritin levels mimicking temporal arteritis (TA)

Fever of unknown origin (FUO) refers to prolonged fevers of ≥101°F and that persists for >3 weeks that remain undiagnosed after an intensive in-hospital/outpatient workup. The most common FUO categories of are infectious, neoplastic, rheumatic/inflammatory, and miscellaneous causes. Malignancies have supplanted infectious diseases as the most common cause of FUOs in the adult population. Rheumatic/inflammatory causes of FUO are relatively less common than previously because of the introduction over the years of sophisticated diagnostic tests for most rheumatic diseases. The rheumatic/inflammatory disorders that remain important causes of FUO today are those that cannot be readily diagnosed by readily available/noninvasive tests, for example, adult Still's disease and temporal arteritis (TA). In older patients with FUO, TA can be a difficult diagnosis when the characteristic findings (ie, scalp tenderness, jaw claudication) are not present. Patients with TA presenting as FUO often have only headaches that may be accompanied by bilateral jaw discomfort. Endocrine causes of FUOs are rare. The most common endocrine disorder rarely presenting as an FUO is de Quervain's subacute thyroiditis. As in TA, subacute thyroiditis may present with headache and pain at the angle of the jaw. Both TA and subacute thyroiditis may be accompanied by fatigue, weight loss, and night sweats. We present a case of 55-year-old woman who presented with an FUO with clinical and laboratory findings suggesting TA. However, the absence of thrombocytosis and a normal alkaline phosphatase argued against the diagnosis of TA. Also against the diagnosis of TA was weight loss without loss of appetite and a slightly increased pulse. After nonspecific laboratory test results suggested that TA was not the cause of her FUO, additional tests were ordered. Thyroid function test results suggested the possibility of de Quervain's subacute thyroiditis as the cause of her FUO. To the best of our knowledge, this is the first case of de Quervain's subacute thyroiditis presenting as an FUO with elevated ferritin levels.

Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF‐E2

Summary The molecular aetiology of polycythaemia vera (PV) remains unknown and the differential diagnosis between PV and secondary erythrocytosis (SE) can be challenging. Gene expression profiling can identify candidates involved in the pathophysiology of PV and generate a molecular signature to aid in diagnosis. We thus performed cDNA microarray analysis on 40 PV and 12 SE patients. Two independent data sets were obtained: using a two-step training/validation design, a set of 64 genes (class predictors) was determined, which correctly discriminated PV from SE patients. Separately 253 genes were identified to be upregulated and 391 downregulated more than 1.5-fold in PV compared with healthy controls (P < 0.01). Of the genes overexpressed in PV, 27 contained Sp1 sites: we therefore propose that altered activity of Sp1-like transcription factors may contribute to the molecular aetiology of PV. One Sp1 target, the transcription factor NF-E2 [nuclear factor (erythroid-derived 2)], is overexpressed 2- to 40-fold in PV patients. In PV bone marrow, NF-E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF-E2 leads to the development of erythropoietin-independent erythroid colonies and that ectopic NF-E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. Transcription factor concentration may thus control lineage commitment. We therefore propose that elevated concentrations of NF-E2 in PV patients lead to an overproduction of erythroid and, in some patients, megakaryocytic cells/platelets. In this model, the level of NF-E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.

The Transcription Factor Nf-E2 Is Overexpressed in Patients with Polycythemia Vera.

Despite recent advances in characterizing molecular markers for the diagnosis of polcycythemia vera (PV), the aberrations leading to disease development remain unknown. We therefore used expression profiling to identify candidate genes involved in the pathophysiology of PV. RNA from purified granulocytes of 40 PV patients was analyzed by hybridizing individual samples to a pool of 50 healthy controls. Of the 7,496 genes represented in the cDNA array, 253 were upregulated more than 1.5 fold in PV compared to healthy controls (p< 0.01, FDR corrected). Promoters for 26 of the 253 genes overexpressed in PV are regulated by members of the Sp1 family of transcription factors. We have therefore hypothesized that altered activity of one or several Sp1-like transcription factors may contribute to the molecular etiology of PV. Here we report that one of the Sp1 target genes identified, the transcription factor NF-E2, is overexpressed in 37 of the 40 PV patients (92.5%) assayed by microarray. NF-E2 overexpression was confirmed by Northern Blot and quantitative RT-PCR analysis. Transcription factor overexpression varies from 2.3 to 40 fold, with a median increase of 7 fold in PV patients compared to healthy controls. The NF-E2 protein is readily detected in PV granulocytes by Western Blot whereas it is undetectable in healthy control cells. Immunohistochemistry revealed that in PV bone marrow, NF-E2 is overexpressed in megakaryocytes as well as erythroid and granulocytic precursors. Several published observations suggest that NF-E2 is an exceptionally promising candidate in the molecular etiology of PV. Firstly, the transcription factor is expressed in hematopoietic precursors as well as in erythroid, megakaryocytic and granulocytic cells, those lineages affected in PV. Secondly, Sayer et al. have shown that overexpression of NF-E2 in fetal liver cells leads to the development of Epo-independent erythroid colonies, analogous to the endogenous erythroid colonies (EECs) observed in PV patients. Furthermore, ectopic expression of NF-E2 results in the spontaneous emergence of morphologically mature erythroid cells in the absence of Epo and can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. These data support the hypothesis that the concentration of an individual transcription factor can control lineage commitment. We thus propose that in PV patients elevated concentrations of NF-E2 alter the physiological transcription factor balance leading to an overproduction of erythroid and, in select patients, megakaryocytic cells/platelets. In this model the level of NF-E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.

The Significance of Thrombocytosis in Patients with Locally Advanced Cervical Carcinoma: A Gynecologic Oncology Group Study

Objective. The aim of this study was to determine the incidence of thrombocytosis and its possible impact on survival probability among women with locally advanced cervical carcinoma.Methods. The database of 294 patients with Stages IIB–IVA cervical carcinoma without periaortic node metastasis who were treated with standardized radiation therapy and concurrent hydroxyurea or misonidazole was analyzed. Pretreatment platelet counts were available for 291 patients who are the subject of this study.Results. Thrombocytosis (platelet count >400 × 109/liter) was present in 86 (29.6%) of the 291 patients. A multivariate Cox proportional hazards model showed that patients without extrapelvic disease and with thrombocytosis had a 55% greater chance of dying than those without thrombocytosis (relative risk = 1.55, 95% confidence interval 1.08–2.21). Patients with thrombocytosis had larger tumors and more frequently had bilateral parametrial involvement, tumor fixation to the sidewall, and positive pelvic lymph nodes than patients without thrombocytosis. Thrombocytosis was not found to be a prognostic factor in patients with positive pelvic nodes. However, in patients with negative pelvic nodes, the presence or absence of thrombocytosis was related to survival.Conclusion. Thrombocytosis is a frequent finding among patients with advanced cervical carcinoma and seems to be related to tumor burden. Among patients with locally advanced cervical carcinoma who had negative pelvic nodes, those with thrombocytosis had a poorer survival.