الفهرس 
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Abstract
Thrombopoietin is the key hormone that regulates the differentiation and proliferation of megakaryocytes, the precursors of platelets, in bone marrow. The cytokines interleukin-6 and interleukin-11 play an accessory role.
Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The threshold for clinically significant thrombocytosis is variable from patient to patient, although a platelet count of ≥450x109/L is a generally accepted value. Thrombocytosis is classified according to its cause into hereditary (inherited) and acquired (primary & secondary).
Hereditary thrombocytosis (HT) is an autosomal dominant disorder that may be due to mutations in the thrombopoietin (TPO)gene or to mutation in TPO receptor (c-MPL): S505N a mutation exchanging a serine in position 505 with an asparagine or lysine to asparagine substitution at amino acid 39 (G1238T) in MPL (Mpl Baltimore). Its prevalence is probably underestimated because it is not often sought.
The primary or clonal thrombocytosis is observed in chronic myeloproliferative neoplasms including essential thrombocythemia (ET), chronic myeloid leukemia (CML), polycythemia vera (PV), and primary myelofibrosis (PMF), and also in some myelodysplasias (5q– syndrome; refractory anemia with ringed sideroblasts and marked thrombocytosis).
The cardinal features of the three main myeloproliferative disorders are a high platelet count in essential thrombocythemia, an increased red-cell mass in polycythemia vera, and bone marrow fibrosis in idiopathic myelofibrosis These disorders share many characteristics, including marrow hypercellularity, a propensity to thrombosis and hemorrhage which are major causes of morbidity and mortality, and a risk of leukemic transformation in the long term.
Once a patient is diagnosed with a clonal form of thrombocythemia, these disorders tend to be indolent, and only a minority of patients, those with potentially fatal thrombotic and bleeding complications, need treatment (alkylating agents, hydroxyurea, anagrelide, interferon, aspirin).
In secondary or reactive thrombocytosis, thrombopoietin is increased because of an underlying condition that either directly produces thrombopoietin or stimulates its production via acute-phase reactants such as interleukin-6. It occurs secondary to bleeding, infections, iron deficiency anemia and others. Even with all the diagnostic tools currently available, the diagnosis ultimately remains a clinical one based on laboratory findings, determination of a likely underlying cause, and when possible, improvement with treatment of the underlying cause. In these situations, the elevated platelet count per se is generally harmless, and does not itself directly pose a risk of thrombosis.
Once the diagnosis of thrombocytosis is confirmed by peripheral blood smear review, the diagnostic evaluation turns to determining whether the process is reactive or clonal in nature. A thorough history and physical examination should allow for the exclusion of multiple of the most common causes of reactive thrombocytosis.
Once a reactive thrombocytosis is excluded and thrombocytosis is persistent, the diagnostic evaluation should turn to distinguishing between hereditary and the various causes of clonal thrombocytosis.
Hereditary thrombocytosis (HT) is diagnosed by detection of mutations in the thrombopoietin (TPO) gene or to mutation in TPO receptor (c-MPL): S505N or G1238T using cytogenetic analysis.
In primary thrombocytosis, the etiologic abnormality and cornerstone for diagnosis of CML is the “Philadelphia chromosome” (t 9; 22) leading to fusion of the BCR and ABL1 genes and BCR-ABL1 fusion protein which is found in most patients with CML, giving evidence of clonality in this disease. It can be detected by cytogenetic analysis as fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR).
In the “Philadelphia chromosome negative” (Ph-) patients, the discovery of JAK2V617F mutation becomes a clonal marker. It is an acquired point mutation in exon 14 of the Janus kinase 2 (JAK2) gene, resulting in a valine to phenylalanine substitution at codon 617. JAK2V617F is present in ≈95% of patients with PV, and ≈40–60% with ET and PMF.
After exclusion of reactive thrombocytosis, detection of gene mutations using different molecular and cytogenetic techniques play a very important role in diagnosis of hereditary and primary thrombocytosis with subsequent prevention and treatment of thrombosis and hemorrhage which are major causes of morbidity and mortality