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1308 Part X: Malignant Myeloid Diseases Chapter 85: Essential Thrombocythemia 1309

JAK2
CALR

MPL

SH2B3
Unknown

100%
Proportion of mutated cases 50%
75%

25%

0%
JAK2 CALR MPL SH2B3 TET2 ASXL1 EZH2 IDH1/2 DNMT3A RNA
splicing
Gene harboring mutations
Essential thrombocythemia Polycythemia vera Primary myelofibrosis
Acute myeloid leukemia Myelodysplasia
Figure 85–1. The spectrum and frequency of somatic mutations in myeloid neoplasms. A. Frequency of mutations in essential thrombocythemia
associated with activated cytokine signaling pathways. B. Comparison of mutation frequencies in ET, related myeloproliferative neoplasms and other
myeloid malignancies.

JAK2 harboring a V617F substitution shows nuclear localization in the Erythromelalgia, a distinct clinicopathologic syndrome caused by
absence of cytokine stimulation. 28,29 occlusion of small blood vessels, is manifest by discomfort and burning
sensations in the fingers or toes, sometimes accompanied by mottling
32
CLINICAL FEATURES or discoloration of the skin. Venous events mainly comprise deep vein
thrombosis and pulmonary embolism. Involvement of unusual sites
SYMPTOMS AND SIGNS such as hepatic, portal or mesenteric veins also occurs and may precede
the onset of clinically overt ET (Fig. 85–2A). In one series, half of all
ET is often diagnosed following the incidental finding of a high plate- patients presenting with hepatic vein thrombosis and a normal blood
let count, although a proportion of patients present with thrombotic count tested positive for the JAK2 V617F mutation, and a quarter of these
or hemorrhage complications. A detailed clinical history and physical subsequently developed a clinically overt MPN, most commonly ET. 33
examination are necessary to exclude causes for a reactive thrombo- The strongest predictive factors for thrombotic complications are
cytosis. Approximately 10 percent of ET patients have a mild degree older than 60 years of age or a history of previous thrombosis. The
34
of palpable splenomegaly at diagnosis, although significant splenic platelet count and leucocyte count at diagnosis are poor predictors of
30
enlargement should raise the possibility of another MPN such as PMF thrombotic risk. Meta-analysis confirmed detection of a JAK2 V617F
35
or chronic myeloid leukemia (CML). mutation as a risk factor for both arterial and venous thrombosis. 36,37
Other reported risk factors include predisposition to cardiovascular dis-
THROMBOSIS ease or increased marrow fibrosis at diagnosis. 38
Thrombotic complications are the major source of morbidity and mor-
tality in ET, with a prospective study indicating a cumulative incidence HEMORRHAGE
of 24 percent over 27 months for untreated high-risk patients. Arte- Serious bleeding is less common than thrombosis and mainly affects the
31
rial thrombosis predominates, affecting the central nervous system nasal and buccal mucosa and the gastrointestinal tract, although central
(stroke, transient ischemic attack) and cardiovascular system (myo- nervous system hemorrhage may occur. 30,31 ET patients often demon-
cardial infarction, unstable angina, peripheral arterial occlusion). 30,31 strate prolongation of the bleeding time and various abnormalities of

Kaushansky_chapter 85_p1307-1318.indd 1308 9/21/15 11:08 AM