Standardization of bone marrow features--does it work in hematopathology for histological discrimination of different disease patterns?

Standardized bone marrow (BM) features determined by semiquantitative scoring are valuable tools for the recognition and easily reproducible interpretation of histological patterns in hematopathology. This procedure may help to characterize various disease entities, but especially to differentiate chronic myeloproliferative disorders (MPDs) with increased platelet counts from reactive thrombocytosis (RTh). A clear-cut separation of these conditions continues to present a major problem in hematology. Therefore MPDs are a most suitable model to test the diagnostic relevance of this procedure. By regarding the literature and based on archive material that involved BM biopsies of 319 patients, a semiquantitative grading of histological parameters was performed. Standardized features were applied for a stepwise discriminant analysis to establish different sets of variables exerting a diagnostic impact. A distinction into five histological patterns was achieved that showed a correctly predicted group membership of about 94 %. These were consistent with the clinicopathological diagnosis of polycythemia vera, essential thrombocythemia (ET), prefibrotic or early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally RTh. Variables of discriminating potency according to their ranking included megakaryopoiesis (maturation defects, nuclear lobulation, naked and bulbous nuclei, small and giant size), reticulin fibers, erythro- and granulopoiesis (left shifting and quantity) and cellularity. These findings are in keeping with the assumption that characteristic patterns of BM histopathology can be assigned to different subtypes of MDPs mimicking ET. Discrimination between ET and especially early stage CIMF with thrombocythemia is warranted because of significant implications concerning therapeutic strategies, follow-up examinations and survival. Regarding these results, a schematic procedure is proposed to be used for daily routine diagnosis concerning the discrimination of MPDs.     

Splenomegaly in myelofibrosis-new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

ABSTRACT: Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients' quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60?% of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.     

Therapy-related changes of the bone marrow in chronic idiopathic myelofibrosis

In chronic myeloproliferative disorders (CMPDs) a conflict of opinion exists regarding therapy-induced bone marrow (BM) changes and the evolution of myelofibrosis during the lengthy course of the disease. For a more elaborate study of these features chronic idiopathic myelofibrosis (IMF) seems to be a most suitable condition. Therefore this review is focused on this CMPD and amongst other findings analyzes data from a series of 340 patients with a long follow-up including 893 biopsies (median interval of 32 months). The ensuing results were compared with those communicated in the relevant literature. In addition to a control group of 153 patients with IMF who received only symptomatic treatment, therapy groups included busulfan, hydroxyurea, interferon and various combinations. In all groups hypoplasia of a varying degree was a frequent finding (6%) and often accompanied by a patchy arrangement of hematopoiesis. Most conspicuous was a gelatinous edema showing a tendency to develop a discrete reticulin fibrosis (scleredema). Aplasia developed in 7.7% of patients, usually at terminal stages of the disease independently of treatment. Minimal to moderate maturation defects of hematopoiesis involved especially megakaryocytes and erythroid precursors, but overt myelodysplastic features were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were characterized not only by increasing dysplastic changes, but also by the appearance of blasts including CD34+ cells. Semiquantitative grading of the fiber content revealed that 183 patients (54%) without or with moderate fibrosis at the beginning showed a significant progression and therefore contrasted with the 66 patients with a stable state. Following this calculation no relevant differences in the evolution of myelofibrosis were evident in the various therapy groups especially not following interferon treatment. In a few patients a regression was found which was accompanied by a severe hypoplasia or aplasia compatible with a myelo-ablative effect. In conclusion, peculiar BM changes, in particular conspicuously expressed myelodysplastic features are consistent with therapy-related lesions. Development of myelofibrosis in IMF is obviously due to disease progression unrelated to stage at diagnosis and not significantly influenced by treatment modalities.     

Megakaryocytic features useful for the diagnosis of myeloproliferative disorders can be obtained by a novel unsupervised software analysis

An unsupervised method for megakaryocyte detection and analysis is proposed, in order to validate supplementary tools which can be of help in supporting the pathologist in the classification of Philadelphia negative chronic myeloproliferative disorders with thrombocytosis. The experiment was conducted on high power magnification photomicrographs taken from hematoxylin-and-eosin 3 micrometer thick sections of formalin fixed, paraffin embedded bone marrow biopsies from patients with reactive thrombocytosis or chronic myeloproliferative disorders. Each megakaryocyte has been isolated in the photos through an image segmentation process, mainly based on mathematical morphology and wavelet analysis. A set of features (e.g. area, perimeter and fractal dimension of the cell and its nucleus, shape complexity via elliptic Fourier transform, and so on) is used to characterize the disorders and discriminate between essential thrombocythemia and idiopathic myelofibrosis. Features related to the general contour of the cell like cytoplasmic area and perimeter are good markers in distinguishing between normal or reactive and pathologic megakaryocytes while nuclear features and global circularity are helpful in the differential diagnosis between ET and prefibrotic IMF. The method proposed should be considered as a fast preprocessing tool for the diagnostic phase and its use can be extended to solve different object recognition problems.     

Transcriptional Profiling of Whole Blood Identifies a Unique 5-Gene Signature for Myelofibrosis and Imminent Myelofibrosis Transformation

Identifying a distinct gene signature for myelofibrosis may yield novel information of the genes, which are responsible for progression of essential thrombocythemia and polycythemia vera towards myelofibrosis. We aimed at identifying a simple gene signature – composed of a few genes - which were selectively and highly deregulated in myelofibrosis patients. Gene expression microarray studies have been performed on whole blood from 69 patients with myeloproliferative neoplasms. Amongst the top-20 of the most upregulated genes in PMF compared to controls, we identified 5 genes (DEFA4, ELA2, OLFM4, CTSG, and AZU1), which were highly significantly deregulated in PMF only. None of these genes were significantly regulated in ET and PV patients. However, hierarchical cluster analysis showed that these genes were also highly expressed in a subset of patients with ET (n = 1) and PV (n = 4) transforming towards myelofibrosis and/or being featured by an aggressive phenotype. We have identified a simple 5-gene signature, which is uniquely and highly significantly deregulated in patients in transitional stages of ET and PV towards myelofibrosis and in patients with PMF only. Some of these genes are considered to be responsible for the derangement of bone marrow stroma in myelofibrosis. Accordingly, this gene-signature may reflect key processes in the pathogenesis and pathophysiology of myelofibrosis development.     

Bone marrow histopathology in chronic myelogenous leukemia (CML)--evaluation of distinctive features with clinical impact.

Bone marrow features in stable-phase chronic myelogenous leukemia (CML) are characterized by a striking heterogeneity which is determinable by appropriate means including representative pre-treatment trephine biopsies, immunohistochemistry and morphometry. Cell lineages involved to a variable extent consist not only of neutrophil granulopoiesis, but include also megakaryocytes, erythroid precursors, resident macrophages and lymphocytes. Moreover, the stromal compartment, in particular reticulin and collagen fibers, plays a pivotal role in the disease process. Following morphometric analysis significant correlations may be calculated between histological parameters and clinical-laboratory findings. Relevant interactions are detectable between number of megakaryocytes and their precursors with fiber density. This findings is in line with the close functional relationships between megakaryopoiesis and fibroblasts regarding the complex pathomechanisms of myelofibrosis. Moreover, other correlations are observable between reduction of erythropoiesis or increase in fibers with clinical features like anemia, percentages of myelo- and erythroblasts in the peripheral blood, spleen size or LDH level. These variables are in keeping with more advanced stages of CML which indicate a transition to myeloid metaplasia and thus exert a significant impact on survival. Consequently, the different risk profiles of patients are determined by both clinical and morphological parameters of predictive value. Regarding the latter, extent of myelofibrosis, amount of erythroid precursors and numbers of myeloerythroblasts in the peripheral blood are significantly associated with prognosis. For this reason, it should be mandatory to enter morphological criteria into prospective clinical trials on CML, not only for diagnostic purpose, but also for a proper evaluation of different survival patterns.     

Iron stores in essential thrombocythaemia. A study of 26 patients

The iron status of 26 patients with essential thrombocythaemia (ET) was evaluated at diagnosis by means of bone marrow iron and blood studies, including serum ferritin determination. Nine patients were males, 17 females, and the mean age was 53 years (range 7-81). A decreased or absent iron level by semiquantitative estimation on bone marrow smears was observed in 77% of patients, and 81% had a low sideroblast score. Such a marrow pattern of iron depletion was equally distributed between both sexes. Contrasting with this, normal Hb, MCV, serum iron and serum ferritin were registered in the majority of cases. According to these results, absent or decreased marrow iron would be a common feature in ET, generally not reflecting true iron deficiency, as it occurs in the remaining chronic myeloproliferative disorders. Thus, in patients in whom ET is suspected, the diagnostic criterion of ruling out iron deficiency would be better served by serum ferritin measurement than by bone marrow iron estimation.     

Essential thrombocythaemia as cause of myocardial infarction

Abnormalities in the number and function of platelets may contribute to thromboembolic complications in patients with essential thrombocythaemia (ET). Rarely this can lead to an acute myocardial ischaemic syndrome. We describe a young patient with a myocardial infarction, in whom ET was found as the probable cause. We discuss the clinical presentation of ET and the therapeutic possibilities.     

Stem cell defects in Philadelphia chromosome negative chronic myeloproliferative disorders: a phenotypic and molecular puzzle?

Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD) comprise a group of heterogenous haematological stem cell disorders. These diseases harbour a pathological bone marrow stem cell which overwhelms normal stem cells due to sustained and uncontrolled proliferation. By clonal evolution, acute leukaemia or bone marrow fibrosis evolve in a proportion of cases with as yet unknown underlying mechanisms. Previously, groundbreaking investigations in Ph(-) CMPD detected an acquired mutation in the Janus kinase 2 (JAK2) in the majority of patients with polycythaemia vera (PV) and in up to 50% of patients with essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (CIMF). Unlike the stem cell defect in Philadelphia chromosome-positive chronic myeloid leukaemia only a subfraction of clonally proliferating haematopoiesis may be affected by the JAK2 mutation. More recently, another mutation in the juxtamembrane domain of the thrombopoietin receptor Mpl was discovered in about 5% of patients with CIMF and ET. In accordance with the uncontrolled Abl kinase activity in Ph(+) chronic myloid leukaemia these mutations in Ph(-) CMPD apparently represent a key to unlock some of the as yet unknown basic molecular defects and this raises hope for an upcoming efficient targeted therapy. However, neither the JAK2(V617F) nor the Mpl(W515L/K) provide the initiating molecular events. Moreover, apart from distinction between reactive and neoplastic lesions, detection of these mutations does not allow a clear-cut discrimination between the particular subtypes. This review will focus on previous and recent findings in the field of molecular defects in Ph(-) CMPD.     

Myelofibrosis in chronic myeloproliferative disorders--dynamics and clinical impact

In chronic myeloproliferative disorders, presenting or evolving myelofibrosis (MF) is associated with significant morbidity and mortality. A systematically conducted evaluation of previous studies and data from our own material reveals a strikingly expressed heterogeneity of findings. Assessment of MF should be performed by a recently established semiquantitative scoring system regarding quantity and quality (reticulin versus collagen). It is important to differentiate between a fiber increase in bone marrow specimens and the clinical diagnosis that is explicitly based on extramedullary hematopoiesis (myeloid metaplasia). For this reason, prodromal stages of (reticulin) fibrosis are overlooked by the clinicians. Up to 30% of patients with chronic myelogenous leukemia show a minimal to advanced MF that is significantly associated not only with corresponding clinical parameters but more importantly with prognosis. In polycythemia vera about 20% of patients may display some degree of reticulin fibrosis at diagnosis, depending on stage of the disease. Transformation into (collagen) MF after more than 10 years is accompanied by clinical signs of myeloid metaplasia (spent phase). Essential thrombocythemia (ET) is characterised by the absence of increased reticulin at onset and an insignificant progression into MF, provided diagnosis is performed by the WHO criteria. Discrimination of prefibrotic and early stages of chronic idiopathic myelofibrosis (CIMF) from ET is relevant, especially concerning the rate and time usually required for the development of MF with myeloid metaplasia (full-blown CIMF). In conclusion, more elaborate evaluations including standardized grading of MF is warranted by regarding bone marrow biopsy specimens in association with clinical parameters including follow-up examinations.     

Bone marrow engraftment: histopathology of hematopoietic reconstitution following allogeneic transplantation in CML patients

Following myelo-ablative treatment and allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) histopathological features assumed to exert a significant impact on engraftment have been rarely investigated systematically. This review is focused on immunohistochemical and morphometric techniques involving nucleated erythroid precursors, resident macrophages and their various subsets, megakaryocytes and finally argyrophilic (reticulin-collagen) fibers. Regarding standardized intervals of examination in the postgraft sequential trephine biopsies a pronounced reduction in cellularity was obvious and accompanied by a decrease in the quantity of erythro- and megakaryopoiesis. A significant correlation between the number of erythroid precursors and CD68+-macrophages could be determined in the areas of regenerating hematopoiesis. This finding is in keeping with the important functional role of the centrally localized mature macrophages during erythropoiesis. A relevant pretransplant reduction of the red cell lineage and an early to advanced reticulin fibrosis were correlated with a low hemoglobin level (anemia) and splenomegaly and furthermore associated with a significant delay to reach transfusion independence. This result was supported by corresponding findings in biopsy specimens performed shortly after day 30 following BMT (standard interval for assessment of engraftment). Samples revealed an enhancement of fiber density and a conspicuous decrease in the amount of erythropoiesis in the small fraction of patients who did not conform with the usually accepted criteria for successful hematopoietic reconstitution. Considering the compartment of histiocytic reticular cells the recurrence of Pseudo-Gaucher cells (PCGs) in the engrafted donor marrow was remarkable and most prominently expressed in the first two months following BMT. This feature was presumed to be functionally linked with a pronounced degradation of cell debris in the sequel of myelo-ablative therapy (scavenger macrophages). According to planimetric measurements in the postgraft bone marrow the atypical dwarf-like CD61+-megakaryocytes characteristic for CML disappeared. On the other hand, normalization of megakaryocyte size and nuclear lobulation were absent in sequential examination of the few patients developing a leukemic relapse. In a number of patients with manifest myelofibrosis at onset, an initial regression after BMT was followed by an insidiously occurring retrieval which was concentrated on the areas of reconstituting hematopoiesis. Similar to its relevant pretransplant association the postgraft reappearance of myelofibrosis was significantly correlated with the quantity of CD61+-megakaryocytes. Altogether a number of histological features in the pre-and postgraft bone marrow exhibited significant correlations with each other and thus indicated functional relationships. Moreover, quantity of erythropoiesis and amount of reticulin fibers (myelofibrosis) exerted a significant impact on engraftment status.     

CD34+ stem cells in chronic myeloproliferative disorders

Contrasting the wealth of information that is available about various biological and therapeutic aspects of human CD34+ stem cells, little data exist concerning their quantity and dynamics as well as their mutual relationships with other hematopoietic constituents in the bone marrow of patients with chronic myeloproliferative disorders. In comparison with a control group frequency of progenitors is significantly increased in chronic myeloid leukemia (CML). Following different therapeutic modalities their quantity reflects therapeutic efficacy (responder and non-responder patients) and therefore exerts a predictive value regarding acceleration and blastic crisis. The significant correlations between fiber content and number of these precursors elucidates the complex interactions between stroma and progenitor cell differentiation and maturation. Following allogeneic bone marrow transplantation there is a rapid recovery of the CD34+ stem cell population in the first month. A higher number of these cells is related with graft size, an earlier independence for platelet transfusion and a more extended regeneration of erythro- and megakaryopoiesis. The slight increase in reticulin fibers in these patients may be associated with the complex and so far ill-defined pathomechanism of homing (adherence to the fibrous matrix). In idiopathic myelofibrosis (IMF) an increased number of CD34+ stem cells is found predominantly in the early (prefibrotic or mild fibrotic) hypercellular stages and probably indicates a higher proliferative activity of the precursor cell pool. According to sequential biopsies most patients with early IMF that later evolved into an overt fibrosclerotic stage usually display a reduction of progenitor cells during the development of myelofibrosis. The unequal distribution of CD34+ stem cells in the bone marrow versus spleen in IMF (advanced fibrosclerotic stage) is in support of the currently discussed hypothesis of splenic filtration and concentration of precursor cells as an essential feature of myeloid metaplasia. Regarding prognosis in CML a higher amount of CD34+ stem cells is significantly associated with an unfavorable survival and thus confirms the assumed implication of an accelerated phase of disease at onset. On the other hand, in polycythemia vera (PV) and IMF a low number of progenitors is probably due to a decreased proliferation rate (reduced hematopoietic turnover index) and therefore reflects a reduction in the regenerative capacity of hematopoiesis. For this reason, a presumptive defect in the recovery of normal and clonally transformed stem cells is speculated to add to the worsening of prognosis by causing the well-known bone marrow insufficiency in terminal stage PV and IMF.     

野生大熊猫与放牧家畜的活动格局比较

活动格局是动物内在机制和环境作用所表现出来的昼夜活动节律及其活动水平的行为生态特征,影响着动物的能量代谢能力、觅食行为策略和进化适应。通过内置活动传感器的GPS颈圈,于2010—2012年在四川卧龙国家级自然保护区的"核桃坪"及其毗邻区域,采集了野生大熊猫和放牧家畜的大量活动数据。分别选择3只成年大熊猫和3个马群的代表性个体作为样本,引入活动强度、活动时间百分率、活动时间片段率和活动片段时长等指标进行了两者之间的比较,以揭示大熊猫和放牧家畜在时间利用方面的内在特征。结果表明:野生大熊猫和放牧家畜在活动强度、活动时间百分率和活动时间片段率等方面都具有极显著性差异(P0.0001),仅两者之间的活动片段时长无明显的统计学意义(P=0.4107)。野生大熊猫表现为活动水平低、活动时间少、活动片段率高和活动片段时长短等特征的活动格局,且不同月份(季度)之间变化较大(P0.0001);放牧家畜则呈现出相异的时间利用规律,即活动水平高、活动时间多、活动时间片段率稍低和活动片段时长略长等特性。不同的时间利用规律和不同的空间利用模式,造成动物之间对栖息地、食物资源和伴生动物的利用方式、影响强度和空间分布的截然不同。因而,合理规划和管控放牧家畜的散养区域与数量,是自然保护管理与社区经济发展相协调的有效途径之一。     

Morphometric analysis of myelofibrosis in agnogenic myeloid metaplasia and chronic myelogenous leukemia.

A morphometric analysis of bone marrow biopsy specimens from patients with myelofibrosis was made to determine the amount of lattice fiber and the number of megakaryocytes, to compare the degree of myelofibrosis in primary and secondary myelofibrosis, and to assess the relationship between the morphometric findings and other parameters. Eight patients with agnogenic myeloid metaplasia (AMM) and six with chronic myelogenous leukemia associated with frank myelofibrosis (CML-MF) were studied. When the main clinical, hematological, and laboratory features of both groups of patients were compared, the only significant difference was in the neutrophil alkaline phosphatase score. Morphometric study showed that the amount of lattice fiber and the number of megakaryocytes in AMM were not statistically different from those in CML-MF, and that neither the number of megakaryocytes nor the platelet count correlated with the amount of lattice fiber.     

In vitro megakaryocyte differentiation and proplatelet formation in Ph-negative classical myeloproliferative neoplasms: distinct patterns in the different clinical phenotypes

Background

Ph-negative myeloproliferative neoplasms (MPNs) are clonal disorders that include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Although the pathogenesis of MPNs is still incompletely understood, an involvement of the megakaryocyte lineage is a distinctive feature.

Methodology/Principal Findings

We analyzed the in vitro megakaryocyte differentiation and proplatelet formation in 30 PMF, 8 ET, 8 PV patients, and 17 healthy controls (CTRL). Megakaryocytes were differentiated from peripheral blood CD34⁺ or CD45⁺ cells in the presence of thrombopoietin. Megakaryocyte output was higher in MPN patients than in CTRL with no correlation with the JAK2 V617F mutation. PMF-derived megakaryocytes displayed nuclei with a bulbous appearance, were smaller than ET- or PV-derived megakaryocytes and formed proplatelets that presented several structural alterations. In contrast, ET- and PV-derived megakaryocytes produced more proplatelets with a striking increase in bifurcations and tips compared to both control and PMF. Proplatelets formation was correlated with platelet counts in patient peripheral blood. Patients with pre-fibrotic PMF had a pattern of megakaryocyte proliferation and proplatelet formation that was similar to that of fibrotic PMF and different from that of ET.

Conclusions/Significance

In conclusion, MPNs are associated with high megakaryocyte proliferative potential. Profound differences in megakaryocyte morphology and proplatelet formation distinguish PMF, both fibrotic and prefibrotic, from ET and PV.     

High Resolution Melting Analysis: A Rapid and Accurate Method to Detect CALR Mutations

Background

The recent discovery of CALR mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients without JAK2/MPL mutations has emerged as a relevant finding for the molecular diagnosis of these myeloproliferative neoplasms (MPN). We tested the feasibility of high-resolution melting (HRM) as a screening method for rapid detection of CALR mutations.

Methods

CALR was studied in wild-type JAK2/MPL patients including 34 ET, 21 persistent thrombocytosis suggestive of MPN and 98 suspected secondary thrombocytosis. CALR mutation analysis was performed through HRM and Sanger sequencing. We compared clinical features of CALR-mutated versus 45 JAK2/MPL-mutated subjects in ET.

Results

Nineteen samples showed distinct HRM patterns from wild-type. Of them, 18 were mutations and one a polymorphism as confirmed by direct sequencing. CALR mutations were present in 44% of ET (15/34), 14% of persistent thrombocytosis suggestive of MPN (3/21) and none of the secondary thrombocytosis (0/98). Of the 18 mutants, 9 were 52 bp deletions, 8 were 5 bp insertions and other was a complex mutation with insertion/deletion. No mutations were found after sequencing analysis of 45 samples displaying wild-type HRM curves. HRM technique was reproducible, no false positive or negative were detected and the limit of detection was of 3%.

Conclusions

This study establishes a sensitive, reliable and rapid HRM method to screen for the presence of CALR mutations.     

Essential thrombocythemia

Essential thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) characterized by a sustained elevation of platelet number with a tendency for thrombosis and hemorrhage. The prevalence in the general population is approximately 30/100,000. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age. The female to male ratio is about 2:1. The clinical picture is dominated by a predisposition to vascular occlusive events (involving the cerebrovascular, coronary and peripheral circulation) and hemorrhages. Some patients with ET are asymptomatic, others may experience vasomotor (headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia), thrombotic, or hemorrhagic disturbances. Arterial and venous thromboses, as well as platelet-mediated transient occlusions of the microcirculation and bleeding, represent the main risks for ET patients. Thromboses of large arteries represent a major cause of mortality associated with ET or can induce severe neurological, cardiac or peripheral artery manifestations. Acute leukemia or myelodysplasia represent only rare and frequently later-onset events. The molecular pathogenesis of ET, which leads to the overproduction of mature blood cells, is similar to that found in other clonal MPDs such as chronic myeloid leukemia, polycythemia vera and myelofibrosis with myeloid metaplasia of the spleen. Polycythemia vera, myelofibrosis with myeloid metaplasia of the spleen and ET are generally associated under the common denomination of Philadelphia (Ph)-negative MPDs. Despite the recent identification of the JAK2 V617F mutation in a subset of patients with Ph-negative MPDs, the detailed pathogenetic mechanism is still a matter of discussion. Therapeutic interventions in ET are limited to decisions concerning the introduction of anti-aggregation therapy and/or starting platelet cytoreduction. The therapeutic value of hydroxycarbamide and aspirin in high risk patients has been supported by controlled studies. Avoiding thromboreduction or opting for anagrelide to postpone the long-term side effects of hydrocarbamide in young or low risk patients represent alternative options. Life expectancy is almost normal and similar to that of a healthy population matched by age and sex.