Drug-induced agranulocytosis: Case series

Introduction: Agranulocytosis is a life-threatening disorder characterized by disappearance of granulocytes from peripheral blood or decrease of peripheral neutrophil count below 0.5x109 /l. It frequently occurs as idiosyncratic adverse drug reaction. It occurs especially in association with the use of antithyroid drugs, metamizole, aminopyrine and clozapine. The patients usually present with severe acute infections and sepsis. With modern management of broad-spectrum antibiotics and hematopoietic growth factors (G-CSF) the prognosis has been significantly improved. Methods and results: We present 15 patients with drug-induced agranulocytosis, discuss the criteria for diagnosis, management and prognosis. Median patients age was 36 years (ranging from 25 to 61 years). The male/female ratio was 2/13. Underlying diseases were found in 10/15 (66.6%) patients, consisting of hyperthyreosis in 7 (46.6%) patients, mental disorders in 2 patients (13.3%) and in 1 (6.6%) patient suffering from perianalfistula. Nadir median neutrophil count was 0.3x109 /l, range 0-0.5x109 /l, hemoglobin was between 104 and 128 g/L, anaemia was present in 6 (54.5%) patients, platelet count was between 170 and 230x109 /l. The treatment consisted of broad spectrum antibiotics, hematopoietic growth factor in 10, and antimycotic fluconazole in 3 patients. The outcome was favorable in 14 (93.3%) patients and 1 patient who had thyreotoxic crisis and agranulocytosis died. After 4 months, 1 (6.6%) patient, who had a complete recovery from agranulocytosis, developed an acute myeloid leukemia and died. Conclusions: Drug-induced agranulocytosis is a rare haematological complication, with stable incidence and mortality rate of 5% to 10%. The responsible drug for agranulocytosis must be identified, discontinued and permanently contraindicated

Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments

The emergence of non-secretory multiple myeloma during the non-cytotoxic treatment of essential thrombocythemia: A case report

Introduction. The emergence of multiple myeloma as a second malignancy in patients with essential thrombocythemia is extremely rare. Several cases have been published so far, pointing out the impact of a cytotoxic effect during treatment of essential thrombocythemia on the development of multiple myeloma. Case presentation. We report the case of a 52-year-old Caucasian man who presented to our hospital because of leukocytosis, a slightly decreased hemoglobin level and thrombocytosis. After a complete hematological work-up, essential thrombocythemia was diagnosed. The patient was included in a multicenter clinical study, treated with anagrelide and his platelet counts were maintained in the normal range for more than 3 years. A sudden drop in his hemoglobin level with normal leukocyte and platelet count occurred at the same time as a back pain. Magnetic resonance imaging of his spine revealed the existence of a pathological fracture of Th4, the collapse of the upper edge of Th7 and osteolytic lesions of multiple thoracic vertebrae. Repeated hematological examinations, including bone biopsy with immunohistochemistry, disclosed diagnosis of multiple myeloma of the non-secretory type. Conclusions: To the best of our knowledge this is the first published case in which multiple myeloma developed during the treatment of essential thrombocythemia with the non-cytotoxic drug anagrelide. Our attempts to find a common origin for the coexistence of multiple myeloma and essential thrombocythemia have not confirmed the genetic basis of their appearance. Further studies are needed to determine the biological impact of this coexistence

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs

Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway

The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34(+) cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34(+) cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34(+) cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34(+) cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34(+) cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34(+) cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling

Treatment by bloodletting in the past and present

Introduction. Therapeutic bloodletting has been practiced at least 3000 years as one of the most frequent methods of treatment in general, whose value was not questioned until the 19th century, when it was gradually abandoned in Western medicine, while it is still practiced in Arabic and traditional Chinese medicine. Content. In modern medicine bloodletting is practiced for very few indications. Its concept was modeled on the process of menstrual bleeding, for which it was believed to “purge women of bad humours.” Thus, bloodletting was based more on the belief that it helps in the reestablishment of proper balance of body “humours” than on the opinion that it serves to remove excessive amount of blood as well as to remove toxic “pneumas” that accumulate in human body. It was indicated for almost all known diseases, even in the presence of severe anemia. Bloodletting was carried out by scarification with cupping, by phlebotomies (venesections), rarely by arteriotomies, using specific instruments called lancets, as well as leeches. In different periods of history bloodletting was practiced by priests, doctors, barbers, and even by amateurs. In most cases, between one half of liter and two liters of blood used to be removed. Bloodletting was harmful to vast majority of patients and in some of them it is believed that it was either fatal or that it strongly contributed to such outcome. In the 20th century in the “Western” medicine bloodletting was still practiced in the treatment of hypertension and in severe cardiac insufficiency and pulmonary edema, but these indications were later abandoned. Conclusion. Bloodletting is still indicated for a few indications such as polycythemia, haemochromatosis, and porphyria cutanea tarda, while leeches are still used in plastic surgery, replantation and other reconstructive surgery, and very rarely for other specific indications

Can we always take analysis of complete blood count by automated blood cell analyzer as absolutely correct?

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Eosinophilia as a first sign of Hodgkin´s lymphoma: A case report

Introduction. It is well known that eosinophilia appears in a malignant disease. Frequency of all Hodgkin`s lymphoma patients is estimated to about 15%. Prognostic importance of this phenomenon is not completely investigated. Therefore we decided to present a female patient with eosinophilia, six months before lymphoma appearance. Case report. We presented a 51- years old female, from Serbia, who had eosinophilia (1,530–2,040 eosinophils per μL of blood), six months before Hodgkin's lymphoma appearance. Eosinophilic granuloma was confirmed by tumor’s biopsy and histopathologic examination, from the right femoral region. As eosinophilia was increasing, lymph nodes became enlarged (120 × 65 mm diameter), in the right parailiac region. All infectious and allergic examinations did not reveal eosinophilia's cause. Histopathologic revision was made with added immunohistochemical stains 17 months after tumor's biopsy. The diagnosis was changed from eosinophilic granuloma to mixed cellularity Hodgkin's lymphoma. After conducted Ann Arbor staging classification, II B clinical stage was established. The treatment was done by chemotherapy according to adriamycin, bleomycin, vinblastine, dacarbarine (ABVD) protocol, with 6 courses. Complete remission of the disease was achieved after 4 courses. Eosinophils number dropped to 640 per μl blood. Conclusion. Eosinophilia without revealed cause can precede Hodgkin's lymphoma. We suggest careful search for enlarged lymph nodes, anywhere in the patients’ body who suffer from eosinophilia. Timely and accurate histopathologic diagnostic is a right way to resolve such conditions

Vojislav Arnovljević described "Sézary syndrome" ten years before Sézary and Bouvrain

In 1938 Sezary and Bouvrain reported on a patient with a set of symptoms which later began to carry an eponymous designation “Sezary syndrome.” Ten years previously, Vojislav Arnovljević had described a patient with exactly the same set of symptoms, as well as physical, laboratory, autopsy, and histopathology findings. Unfortunately, his contribution remained unnoticed, not only by the international but Serbian audience as well. In 1928, in the Serbian Archives of Medicine, in Serbian, Vojislav Arnovljević published an article titled “The chronic lymphoid leukaemia with skin lymphomatosis,” in which he described a 43-year-old man with a two-year history of progressive development of a diffuse erythroderma with itching and hair loss over the entire torso, leukemia of 240,000/mm3, 91% of which lymphocytes and 5% eosinophils, who soon after admission developed a bronchopulmonary infection and died. The autopsy showed a pronounced lymphadenopathy in axillae, chest, and abdomen, enlarged liver and spleen with multiple infiltrates and thick skin. The histology confirmed a profound lymphocyte infiltration of axillar, mediastinal and abdominal lymph nodes, as well as liver, spleen and skin, while “the reaction of the other parts of the lymph and blood systems was relatively weak.” There is more than enough clinical, laboratory, autopsy and histological evidence to support that the patient Arnovljević described in 1928 had a syndrome that ten years later was described by Sezary and Bouvrain, which now bears the eponymous designation of Sezary syndrome