Further investigations for intracoronary thrombus with no underlying atherosclerotic disease revealed positive Janus kinase 2 (JAK2) V617F gene mutation, and this was consistent with a diagnosis of ET with elevated platelet count.
The thrombopoietin receptor (MPL) has been shown to be mutated (MPLW515L) in myelofibrosis and thrombocytosis yet new approaches to treat this disorder are still required.
The identification of somatic calreticulin (CALR) mutations can be used to confirm the diagnosis of a myeloproliferative disorder in Philadelphia chromosome-negative, JAK2 and MPL wild type patients with thrombocytosis.
Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays.
These results demonstrate that TPO gene transcription is not activated in patients with 3q26 chromosomic abnormality, and that abnormal TPO production is not responsible for the observed thrombocytosis.
Recently, germline mutations in Janus kinase 2 (JAK2) and MPL, two genes frequently mutated in sporadic MPD, have been shown to cause inherited thrombocytosis.
In light of the findings from previous reports, screening for the JAK2-V617F mutation should be considered for any Ph(+) CML patients with thrombocytosis, leukocytosis, or erythrocytosis at diagnosis and for patients who subsequently develop thrombocytosis, leukocytosis, or erythrocytosis during follow-up, even for CML patients in complete cytogenetic response and major molecular response.
More studies are needed to prove the role of JAK2 in ineffective erythropoiesis, iron metabolism and thrombocytosis and to determine if using JAK2 inhibitors in thalassemic patients can be a potential therapeutic option.
We conclude, first, that a chronic high level of TPO overexpression stimulates megakaryocytopoiesis and myelopoiesis leading to thrombocytosis and granulocytosis.
A 66-year-old man who presented with progressive and marked thrombocytosis but normal hemoglobin was diagnosed to have essential thrombocythemia upon the demonstration of JAK2V617F mutation.
A decrease in expression of the Mpl protein can cause thrombocytosis even in the absence of mutations in the coding sequence, due to a shift in the balance between stimulation of signaling in megakaryopoiesis and removal of thrombopoietin by receptor mediated internalization in platelets.
A decrease in expression of the Mpl protein can cause thrombocytosis even in the absence of mutations in the coding sequence, due to a shift in the balance between stimulation of signaling in megakaryopoiesis and removal of thrombopoietin by receptor mediated internalization in platelets.
The observed biological difference in circulating granulocyte involvement by the JAK2V617F clone necessitates a sensitive molecular assay for the diagnostic investigation of thrombocytosis.
Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) activity (<i>MPL, JAK2, CALR</i>) and loss-of-function (LOF) activity of negative regulators (<i>CBL, LNK</i>) or the extrinsic MPL signaling by <i>THPO</i> GOF mutations leading to increased TPO synthesis.
These results also suggest that the thrombocytosis in ET may be attributed to an alteration of the normal feedback interaction between TPO and its receptor and not as a result of any defect in the structure of TPO or c-mpl.
This review will focus on the molecular pathogenesis of hereditary thrombocytosis, underlining those clinical pictures that are specifically associated with mutations in the genes of thrombopoietin or in its receptor.
Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2(V617F)-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis.
These observations of our case raise two possibilities: either transient posttreatment thrombocythemia is a feature of AML with JAK2V617F mutation, or this was a case of secondary AML.
By contrast, MPL gene mutations were not associated with erythrocytosis, but segregated primarily with the phenotypes of thrombocytosis, extramedullary disease, myelofibrosis, and osteosclerosis.