Polycythemia Vera and Essential Thrombocythemia

Diagnostic Criteria

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].

Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].