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.
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.
We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis.
Genotyping for CALR mutations represents a novel useful tool for establishing a clonal myeloproliferative disorder in JAK2 and MPL wt patients with thrombocytosis and may have prognostic and therapeutic relevance.
Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays.
The lack of thrombocytosis suggests that additional events may be required for JAK2V617F to cause ET, but qualitative platelet abnormalities induced by JAK2 V617F may contribute to the hemostatic complications of PV.
K39N represents an identified functional Mpl polymorphism and is associated with altered protein expression of Mpl and a clinical phenotype of thrombocytosis.
The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis.
Affected family members carry a G --> C transversion in the splice donor of intron 3 of THPO that co-segregated with thrombocytosis within the pedigree.
These data also support the hypothesis that level of JAK2(V617F) expression influences the MPN phenotype: higher levels favor erythrocytosis whereas lower levels favor thrombocytosis.
Another patient with stroke and a pulmonary embolism was heterozygous for the p.Pro106Leu variant of the MPL gene, which has been associated with thrombocytosis.
The recently discovered mutations in patients with CMD (V617F and exon 12 of JAK2 gene, MPL gene), and those identified in hereditary erythrocytosis and in hereditary thrombocytosis have improved our ability to discriminate these conditions.
JAK2(V617F) was identified in 9 of 15 cases, including 7 of 9 with thrombocytosis (platelet count, >600 × 10(3)/μL [600 × 10(9)/L]) and 1 with 8% ring sideroblasts.
Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis.