A secondary increase in platelet count, initiated by cytokines such as interleukin-6 and directly driven by the induction of hepatic thrombopoietin production is associated with a number of infectious, inflammatory and malignant disorders (see Table 85–2; Chap. 119). In reports of unselected patients attending various hospital departments, an increased platelet count was attributable to reactive causes in more than 80 percent of cases; the degree of thrombocytosis did not permit distinction between a clonal versus a reactive pathogenesis.52,53
Familial thrombocytosis is a rare disorder caused by mutations in the thrombopoietin gene, MPL, or other unknown genes. Changes in the 5´-untranslated region or splice donor/acceptor sites of the thrombopoietin gene are associated with increased translation of thrombopoietin and consequent thrombocytosis.54 These alleles are dominantly inherited and have not been seen in clonal MPNs.55 A dominantly inherited, activating MPL allele (MPLS505N) has been reported in Japanese and Italian kindreds.54 Of interest, this allele has also been reported as a somatic mutation in patients with a clonal MPN.17 Several different inherited JAK2 alleles have been reported in families with autosomal dominant thrombocytosis (including JAK2R564Q, JAK2V617I, JAK2R867Q, and JAK2S755R/R938Q).56,57 Although complicated by occasional thrombotic or bleeding episodes, the clinical phenotype of familial thrombocytosis is relatively mild, although exceptions occur.54 The genetic cause underlying a subset of familial cases remains to be elucidated.
PV (Chap. 84) is often associated with thrombocytosis, and may present with a normal hemoglobin level in the presence of iron depletion, mimicking ET, although in such cases the mean corpuscular volume is usually decreased. In addition, ET and PV form a phenotypic spectrum, resulting in diagnostic difficulties in a subset of patients. There are inherent limitations to the utility of continuous variables, such as hematocrit, to make this distinction, as the group of patients with intermediate values will inevitably include both disorders (Fig. 85–4). Controversy persists over how to best distinguish these two conditions.58
Distribution of diagnostic hematocrit levels in a cohort of 243 patients with JAK2V617F-positive disease (essential thrombocythemia or polycythemia vera).
PMF may present with an isolated thrombocytosis, but palpable splenomegaly, circulating teardrop red cells and progenitor cells, and marrow fibrosis are usually present (Chap. 86). An area of ongoing controversy relates to the 15 to 20 percent of ET patients who harbor distinct marrow morphology, coined prefibrotic PMF, at diagnosis in the absence of other features to indicate PMF. Although such patients have higher rates of myelofibrotic transformation, thrombosis, and hemorrhage, their overall survival is not different from other patients with ET.59 A second area of controversy relates to the suggestion that marrow trephine appearances can distinguish ET and prefibrotic PMF from the early stages of PMF60; however, the reproducibility and clinical utility of this distinction is unclear.41,58
Occasional patients with CML present with an isolated thrombocytosis. Such cases are predominantly female with absent or minimal splenomegaly and a normal or marginally elevated white cell count, often without basophilia or circulating myeloid progenitors.61 Marrow studies, however, are usually informative, showing small hypolobulated megakaryocytes typical of CML, and not the large hyperlobulated forms observed in ET. Given the significant impact of tyrosine kinase inhibitors on the prognosis of CML, it is important that this unusual presentation is not overlooked. It is therefore recommended that suspected cases of ET that are negative for a relevant somatic mutation undergo molecular analysis of blood for the BCR-ABL1 fusion gene. Marrow aspiration, biopsy and G-banding cytogenetic analysis, may be useful in a specific case.
Thrombocytosis, usually in association with anemia, may be seen in the myelodysplastic disorder associated with an isolated deletion of chromosome 5q (“5q-minus syndrome”). Although often increased in number, the megakaryocytes are generally small and hypolobulated,60 in contrast to the large hyperlobulated forms typical of ET. A raised platelet count is also a feature of refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and may be associated with thrombotic complications. Approximately half of patients with RARS-T harbor a JAK2V617F mutation or, rarely, a mutation in MPL.
PATHOGENETIC RELATIONSHIP OF ESSENTIAL THROMBOCYTHEMIA TO OTHER MYELOPROLIFERATIVE NEOPLASMS
The same JAK2V617F mutation is present in the vast majority of patients with PV (Chap. 84) and in approximately half of those with ET, raising questions as to how a single mutation is commonly associated with apparently distinct clinical phenotypes. Clones that are homozygous for the JAK2V617F mutation (arising by a mitotic recombination event termed uniparental disomy; Fig. 85–5) are larger and more frequent in patients with PV compared with ET,62,63 suggesting a role for increased JAK2-STAT5 signaling in driving erythrocytosis. In support of this hypothesis, in both mouse and human model systems strong JAK2-STAT5 activation drives erythropoiesis whereas weaker activation favors a megakaryopoiesis.16,64,65 Other contributing factors include the effects of patient gender63 and modulation of STAT1 signaling.66
Mitotic recombination leads to duplication of the JAK2V617F mutation, resulting in a V617F-homozygous subclone.
Myelofibrosis and Accelerated Phase Disease
A proportion of patients diagnosed with ET experience progression to an accelerated phase characterized by increasingly disordered hematopoiesis. The phenotypic manifestations are variable and include hyperproliferation, myelodysplasia, or, most commonly, myelofibrosis. Myelofibrotic transformation of ET, characterized by marrow fibrosis, extramedullary hematopoiesis and marrow failure, is clinically indistinguishable from PMF (Chap. 86), suggesting PMF may represent presentation with accelerated phase disease. Consistent with this, patients with PMF may have thrombocytosis for many years prior to diagnosis, suggestive of undiagnosed ET.58
The prevalence of mutations in JAK2, CALR, or MPL is similar in ET compared to myelofibrosis; however, karyotypic abnormalities are present in up to 50 percent of myelofibrosis patients (Chap. 86) compared to only approximately 5 percent of patients in ET, indicating a greater degree of genetic instability. In addition, mutations in genes implicated in transcriptional regulation (including ASXL1, IDH1/2, and EZH2) appear more common in patients with PMF compared with ET. Together, these findings suggest that progression to advanced phase disease arises through a process of clonal evolution driven by the acquisition of additional genetic events or epigenetic alterations; to date, however, no combination of genetic events has been shown to reliably distinguish ET from PMF. Constitutive activation of JAK2 has been implicated as a driver of clonal progression, as expression of mutant JAK2 leads to the accumulation of reactive oxygen species, increased DNA damage, and aberrant DNA repair.67,68,69,70
For a minority of patients with ET, their disease terminates in AML, also referred to as blastic phase. In some patients, the disease phenotype shows a stepwise transition from ET to PMF to AML, thus mimicking the triphasic disease pattern of CML observed in the preimatinib era (Chap. 89). In other cases, AML arises directly following ET.71
The mutational profile of blastic phase disease shares some similarities with de novo AML. Mutations in transcriptional control pathways (including TET2, ASXL1, EZH2, and IDH1) are more common in blastic phase than in the early disease phases. In addition, mutations are seen in DNA repair and cellular differentiation pathways (including TP53, RUNX1, and IKZF1) which are rarely mutated in early stage MPNs. In contrast to de novo AML, balanced chromosomal translocations are rare in post-MPN AML.72,73,74 Of note, patients with JAK2V617F-positive ET may develop AML that is negative for the JAK2 mutation.49,71