bl-4162a and Thrombophilia

Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

Topics: Adolescent; Adult; Age of Onset; Algorithms; Anticoagulants; Calreticulin; Child; Disease Management; Female; Germ-Line Mutation; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Male; Myelodysplastic-Myeloproliferative Diseases; Platelet Count; Quinazolines; Receptors, Thrombopoietin; Severity of Illness Index; Thrombocythemia, Essential; Thrombocytosis; Thrombophilia

Essential thrombocythemia is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis, bone marrow megakaryocytic hyperplasia and an increased risk of thrombosis and hemorrhage. The goal of treatment is to prevent the development of vascular complications without increasing the risk of transformation. Patients aged>60 years or a history of thrombosis have a high risk of thrombosis while those with a platelet count>1,500 x 10(9)/l have a higher risk of hemorrhage. Patients with low-risk essential thrombocythemia can be managed appropriately with low-dose of acetylsalicylic acid or even observation only, while patients with a high-risk disease are candidates to receive cytoreductive treatment, hydroxyurea being the first choice therapy. Anagrelide is the most suitable option for patients with resistance or intolerance to hydroxyurea. All patients must be submitted to a rigorous control of cardiovascular risk factors.

Topics: Adult; Age Factors; Aged; Anticoagulants; Aspirin; Cell Transformation, Neoplastic; Disease Progression; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hydroxyurea; Intraoperative Complications; Janus Kinase 2; Leukemia, Myeloid, Acute; Life Expectancy; Male; Middle Aged; Mutation, Missense; Platelet Aggregation Inhibitors; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Primary Myelofibrosis; Quinazolines; Risk Factors; Thrombocythemia, Essential; Thrombophilia

The incidence of essential thrombocythaemia (ET) in children (age ≤18 years) is extremely low. The natural course of the disorder in children has not been clarified. The rarity of patients and the variability of tested parameters make it difficult to draw any definitive conclusion in pathogenesis and diagnosis of paediatric ET. What makes the onset of thrombocytosis earlier in children is still uncertain. A diagnostic algorithm for paediatric ET has not been established, and current risk stratification used to guide therapeutic decisions in adults has not been validated in children. Vascular complications and transformation to myelofibrosis and leukaemia in this special entity have been reported, suggesting that ET in children is not an entirely benign disease. The crucial question is how to identify patients who are at high risk of complications and need treatment. There are insufficient data to recommend a specific agent in children. The purpose of this review is to outline the most recent progress in paediatric ET and to help with understanding the clinical course, molecular features, diagnosis and treatment strategies in this special group.

Topics: Adolescent; Age of Onset; Anticoagulants; Child; Child, Preschool; Clone Cells; Disease Progression; GPI-Linked Proteins; Hemorrhage; Humans; Hydroxyurea; Incidence; Infant; Isoantigens; Janus Kinase 2; Leukemia, Myeloid, Acute; Platelet Aggregation Inhibitors; Point Mutation; Primary Myelofibrosis; Quinazolines; Receptors, Cell Surface; Risk Assessment; Symptom Assessment; Thrombocythemia, Essential; Thrombophilia

Topics: Adult; Aged; Bone Marrow; Cytostatic Agents; Disease Management; Female; Genetic Predisposition to Disease; Hemorrhage; Humans; Interferon-alpha; Janus Kinase 2; Lactation; Male; Middle Aged; Platelet Aggregation Inhibitors; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Quinazolines; Thrombocythemia, Essential; Thrombophilia

The clinical course of the classic myeloproliferative neoplasms (MPNs) is burdened by an increased rate of cardiovascular events, which are the major cause of mortality. Age and history of thrombosis are the criteria used to stratify patients to the most appropriate therapeutic options. However, the mechanisms ultimately responsible for the increased thrombotic tendency have not yet been elucidated; abnormalities of blood cell count, neutrophil and platelet activation, and a state of hypercoagulability can all occur. Recurrent mutations in JAK2 or MPL have been described in MPNs and serve as disease markers. There is also evidence that a JAK2V617F mutant state represents an independent factor associated with thrombosis, and abnormalities of cell function attributable to JAK2V617F have been characterized. It is hoped that elucidation of the role mutant JAK2 plays in MPNs will improve our understanding of the pathophysiology of thrombosis and eventually result in improved patient treatment using molecularly targeted drugs.

Topics: Amino Acid Substitution; Aspirin; Cardiovascular Diseases; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Incidence; Interferon-alpha; Janus Kinase 2; Multicenter Studies as Topic; Mutation, Missense; Myeloproliferative Disorders; Phenotype; Point Mutation; Quinazolines; Thrombophilia; Thrombosis

The last four years have seen an explosion in our understanding of the myeloproliferative neoplasms. Important and often unexpected insights into the molecular mechanisms responsible for these disorders have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between the different disease entities. This review will focus on recent developments in the pathogenesis and management of essential thrombocythemia with a particular emphasis on its phenotypic overlap with polycythemia vera and primary myelofibrosis.

Topics: Acute Disease; Aged; Aspirin; Clone Cells; Disease Management; Disease Progression; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Leukemia, Myeloid; Middle Aged; Models, Biological; Mutation, Missense; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Protein Kinase Inhibitors; Quinazolines; Thrombocythemia, Essential; Thrombophilia

Topics: Abnormalities, Drug-Induced; Adult; Aged; Anticoagulants; Contraindications; Female; Humans; Hydroxyurea; Interferon-alpha; Male; Middle Aged; Myeloproliferative Disorders; Phlebotomy; Polycythemia Vera; Pregnancy; Pregnancy Complications, Hematologic; Prognosis; Quinazolines; Randomized Controlled Trials as Topic; Thrombocythemia, Essential; Thrombophilia

Essential thrombocythemia must now be regarded as a heterogeneous disease. Recent availability of clonality studies have repeatedly shown that a significant number of female patients diagnosed as E.T. according the most stringent criteria had a definitely polyclonal myelopoiesis. Although the incidence of patients newly diagnosed every year is low, there is in fact a conspicuous population of E.T., followed as outpatients in every department of hematology or internal medicine, including a large number of young females. These eventualities should be integrated in further discussions of the benefit/risk ratio of cytoreduction with the presently available drugs. The combination of several evidence-based data is the basis of a widely accepted stratification of high-risk patients defined by any of the following features. Age > 60 to 65. History of thrombosis or embolic or major ischemic events. Platelet counts in excess of 1000 or 1500 x 10(9)/L. In the question of chemotherapy in E.T., growing concern comes from the potential leukemogenic risk associated with the presently available drugs and extends beyond Melphalan, Busulfan and other alkylating agents and includes non-alkylating agents like Hydroxyurea. At the same time, much attention has been paid to the introduction of very precise initial diagnostic criteria directed to elimination of other myeloproliferative or myelodysplastic disorders with an increased risk of transformation. Present treatment of E.T. is a compromise between prevention of E.T. related thrombotic and bleeding complications on one hand and long term side effects and toxicity of the presently available drugs on the other hand. The recent availability of non mutagenic drugs like Interferon and most of all Anagrelide; the recognition of the role of antiaggregating agents in the treatment of platelet related microvascular ischemic events gives the opportunity for further comparative prospective trials. The use of aspirin in the management of pregnant E.T. patients is now widely accepted but there is still controversies concerning the use of Interferon in this situation.

Topics: Adult; Aged; Aspirin; Case Management; Clinical Trials as Topic; Diagnosis, Differential; Disease Progression; Female; Hemorrhagic Disorders; Humans; Hydroxyurea; Interferons; Leukemia; Male; Middle Aged; Pipobroman; Platelet Aggregation Inhibitors; Platelet Count; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Quinazolines; Risk; Safety; Thrombocythemia, Essential; Thrombophilia

Topics: Acute Disease; Alkylating Agents; Aspirin; Cardiovascular Diseases; Clone Cells; Gene Expression; Hemorrhage; Humans; Hydroxyurea; Leukemia, Myeloid; Megakaryocytes; Platelet Aggregation Inhibitors; Quinazolines; Risk; Thrombocythemia, Essential; Thrombophilia

The current consensus on the diagnosis, prognosis, and treatment of essential thrombocythemia (ET) is based on experts' recommendations. However, several aspects of the diagnosis of, prognosis of, and therapy for ET are still controversial. The Delphi method was employed with an expert panel of members of the Spanish Group of Ph-negative Myeloproliferative Neoplasms in order to identify the degree of agreement on the diagnosis, prognosis, and treatment of ET. Nine leading experts selected a total of 41 clinical hematologists with well-known expertise in ET. An electronic questionnaire was used to collect the questions rated in a four-step scale. The questions were grouped into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. After the first round consisting of 80 questions, a second round including 14 additional questions focused on the recommendations advocated by experts of the European LeukemiaNet in 2011 was analyzed. The median and mean values for the first and second rounds were calculated. A summary of the conclusions considered as the most representative of each block of questions is presented. The Delphi method is a powerful instrument to address the current approaches and controversies surrounding ET.

Topics: Bone Marrow Examination; Delphi Technique; Diagnosis, Differential; Disease Management; DNA Mutational Analysis; Humans; Hydroxyurea; Janus Kinase 2; Mutation, Missense; Platelet Count; Polycythemia Vera; Prognosis; Quinazolines; Receptors, Thrombopoietin; Risk Assessment; Surveys and Questionnaires; Thrombocythemia, Essential; Thrombophilia

We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis. The clinical course of our patient was complicated by symptomatic thrombophilia and chemoresistance. In addition, our case exhibited FLT3 (Fms-related tyrosine kinase 3) internal tandem duplication. Although anagrelide was successful in controlling elevated platelet counts, allogeneic stem cell transplantation failed to overcome chemoresistance due to simultaneous graft-versus-host-disease and relapse of acute myeloid leukemia. Given the dismal outcome of our case and previously reported cases, we propagate the implementation of targeted therapies to newly diagnosed patients with acute myeloid leukemia t(2;3). Preclinical models indicate drugs that plausibly target the EVI1-related molecular vulnerability as candidates for basket trials. Anagrelide exhibited a hopeful signal of activity in 3q26-related thrombocytosis and should be evaluated for implementation as supportive care.

Topics: Blood Platelets; DNA-Binding Proteins; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; MDS1 and EVI1 Complex Locus Protein; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Proto-Oncogenes; Quinazolines; Stem Cell Transplantation; Thrombophilia; Transcription Factors; Translocation, Genetic

Evidences suggest an association between leukocytosis and thrombotic or hemorrhagic complication in polycythemia vera (PV) and essential thrombocythemia (ET), but clinical implication is not well known.. To evaluate whether leukocyte burden during follow-up is related to thrombotic or hemorrhagic events in PV and ET.. We retrospectively analyzed patients with PV or ET treated at Seoul National University Bundang Hospital, Korea. Time-weighted averages of leukocytes during the follow-up period were defined as leukocyte burden and were calculated for each patient and compared between patient subgroups. In each patient with events, leukocyte burden for the 3-month period before the event was compared with that for the entire follow-up period.. In 102 patients with PV or ET, 35 events (16 thrombotic, 19 hemorrhagic) occurred in 29 patients (median follow-up, 54months). Leukocyte burden were significantly higher in patients with events than in event-free patients (12,015×10(3) /μL vs. 9,567×10(3)/μL, P=0.003). The difference was more prominent in ET patients than in PV patients, and in patients with hemorrhagic events than in those with thrombotic events. In patients with events, the leukocyte burden in the pre-event period was higher than in the entire follow-up period (16,767×10(3)/μL vs. 12,015×10(3)/μL, P=0.002). In all patients, leukocyte burden during entire follow-up period of 11,000×10(3)/μL or higher was an independent risk factor for vascular events.. In PV or ET patients, leukocyte burden during disease course is related to increased incidence of thrombotic or hemorrhagic events.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Blood Cell Count; Comorbidity; Databases, Factual; Female; Follow-Up Studies; Hemorrhage; Hemorrhagic Disorders; Humans; Hydroxyurea; Leukocyte Count; Male; Middle Aged; Phlebotomy; Platelet Aggregation Inhibitors; Polycythemia Vera; Prognosis; Quinazolines; Retrospective Studies; Risk Factors; Thrombocythemia, Essential; Thrombophilia; Thrombosis; Young Adult

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients.

Topics: Anticoagulants; Disease Susceptibility; Drug Interactions; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hydroxyurea; Incidence; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Male; Myeloproliferative Disorders; Phlebotomy; Platelet Aggregation Inhibitors; Postoperative Complications; Pregnancy; Pregnancy Complications, Hematologic; Preoperative Care; Protein Kinase Inhibitors; Quinazolines; Secondary Prevention; Thrombophilia; Venous Thromboembolism; von Willebrand Diseases

Topics: Adolescent; Adult; Anemia; Cohort Studies; Follow-Up Studies; Hemorrhage; Humans; Hydroxyurea; Incidence; Middle Aged; Quinazolines; Risk; Thrombocythemia, Essential; Thrombophilia; Thrombosis

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Antithrombin III; Child; Female; Humans; Hydroxyurea; Male; Middle Aged; Platelet Aggregation Inhibitors; Protein C; Prothrombin; Quinazolines; Reference Values; Thrombocythemia, Essential; Thrombophilia