Essential thrombocythemia (ET), one of the Ph-negative Chronic Myeloproliferative neoplasms (MPNs), develops as an acquired clonal defect of myeloid precursor cells driving uncontrolled myeloid proliferation [1]. MPNs are characterized by elevated blood cell counts, with every lineage being distinctive to the various entities, albeit with some degree of overlapping. Within MPN, ET is characterized by high platelet counts, a finding which can also be found in polycythemia vera (PV), myelofibrosis (MF) and chronic myeloid leukemia (CML) [2]. Diagnosis of ET as well as of other MPNs has long been addressed by adult hematology and was recently confirmed within the WHO classification of myeloid neoplasm [3,4], gaining from the insight given by the identification of driver mutations and peculiar histological patterns (Table 1).

ET is a rare disease in middle–advanced age and is even rarer in children [5]. Diagnosis and treatment of this clonal condition in pediatrics face both certainties and many dilemmas. First, the definition of thrombocytosis has been the matter of debate in children, because differences in platelets counts are seen in various ages and only a few studies have analyzed the issue. In fact, 30% of neonates and infants show high values, especially in the case of low-weight babies, [6,7]; an upper limit of 600 × 10⁹ is considered normal in these children [8,9]. In older children and adolescents, the upper normal limit (95 percentile) of 450,000 has been identified [10], as suggested by the Italian Association for Pediatric Haematology Oncology (AIEOP) guidelines [11] and by other classifications of thrombocytosis [12]. Nonetheless, transient conditions and secondary reactive thrombocytosis are very common findings in pediatrics and require a thorough approach even when clear causes cannot be identified. The classical partition between primary and secondary/reactive thrombocytosis does not apply straightforwardly to children. Moreover, a third category of hereditary or familial thrombocytosis (HT) is unique to young age and must be ruled out [13]. Only in recent years has interest been focused on pediatric primary thrombocytosis and, in particular, on ET. Some papers [14,15,16,17,18] suggest that ET in children is different than in adults, with lower incidences of thrombotic and hemorrhagic complications and scarce or no evolution into myelofibrosis and acute leukemia. This poses questions regarding the opportunity of adapting the available hematological and management criteria to pediatric patients.

2. Hereditary/Familial Thrombocytosis (HT)

Hereditary and familial thrombocytosis are extremely rare. They share the same clinical aspects of primary thrombocytosis, comprising splenomegaly and the risk of thrombotic complications. Most of them have a Mendelian inheritance, are polyclonal and only affect the platelet lineage [13,19,20]. Affected genes are usually TPO or more frequently, its receptor c-MPL; gain of function mutations in the TPO gene have been described [21] and result in the proliferation of megakaryocytes, the activation of platelets and the significant overexpression of membrane molecules [22]. A founder effect found in families from Central Italy might explain the different percentages of non-clonal cases in Giona’s series [23].

3. Reactive/Secondary Thrombocytosis (ST)

Many children have transitorily increased platelet counts, mostly related to inflammatory conditions (Table 2). Therefore, an isolated finding of thrombocytosis is usually not clinically relevant in children. In contrast, if thrombocytosis is confirmed over at least 3–6 months, it may have a different pathogenesis and clinical impact [12,15].

Table 2. Causes of reactive/secondary thrombocytosis in children (adapted from [18]). The Table reports examples of significant pediatric conditions.

Infections

Inflammations Kawasaki disease Rheumatic diseases Coeliac disease Nephritis, pancreatitis

Surgery, trauma, burns, blood loss

Malignancies

Anemias Iron deficiency Hemolytic anemias

Allergic reactions

Drugs Steroids Vincristine Miconazole Antibiotics (Imipenem, Beta-lactams)

Megakaryopoiesis is controlled by various growth factors and cytokines. By far, the most essential growth factor is thrombopoietin (TPO), which is produced constitutively by the liver [24], but also by marrow stromal cells and by the kidney. TPO intervenes both in stem cell differentiation and in all stages of megakaryocytes maturation [25], through the binding to its receptor c-MPL and the activation of kinases of proliferative pathways (JAK, STAT1, STAT2, PI3K and MAPK). Its production is regulated by the bulk of circulating platelets and of marrow megakaryocytes.

Hepatic TPO mRNA expression is increased with inflammation [26]. Moreover, many interleukins (IL) involved in the inflammation processes, mostly IL-6 and IL-11, can stimulate the platelet production in the liver [27,28]. These processes are highly active during childhood: ST is reported in 6–15% of hospitalized children, and up to 1% of children in intensive care units show platelet counts exceeding 1000 × 10⁹/L [5,29,30,31,32,33,34,35].

Infections, both bacterial and viral, are common causes of thrombocytosis in infants (75% of cases [31]), and children (47% [33]), mostly of the respiratory and urinary tracts. All other pediatric inflammatory conditions are associated with ST [34], in particular those seen in young children, such as Kawasaki disease [36], Schoenlein–Henoch syndrome, coeliac disease as well as rheumatic diseases and damages to tissues due to trauma, surgery or burns [8]. Many neoplasms (including acute leukemias) are also described to cause ST as well as chemotherapeutic drugs, steroids or adrenaline. Iron deficiency is a known cause of ST (5–12% [37]), although its precise mechanisms remain to be elucidated. Studies on megakaryocytes demonstrated that iron is essential for their proliferation as for other cells [38], and iron replacement resolves thrombocytosis [39].

The clinical relevance of ST is still debated. Platelet count can be regarded as an “acute phase” reactant [40], and has been shown to correlate with prognosis, mainly the prolongation of hospital staying. Most authors agree that ST is a collateral effect of the underlying disease and does not represent a risk for the patient. In fact, neither thrombotic nor hemorrhagic complications were seen in more than 4000 reported children with ST [32]. In 855 children affected by extreme thrombocytosis, Thom et al. reported 22 thromboses, all related to underlying conditions, and no hemorrhages [33].

Finally, asplenic patients commonly display an increased platelet count. Splenic atrophy or agenesia are extremely rare conditions, while splenectomies are performed in a wide spectrum of hematologic disorders: hereditary and autoimmune hemolytic diseases, thrombocytopenia, myeloproliferative diseases, leukemias and lymphomas [41], and a splenectomy could also be necessary after trauma [42]. Thrombocytosis tends to reduce within 6–12 months after splenectomy, sometimes never resolving. It has been shown that the thrombotic risk is likewise related to the underlying condition; in particular, it is higher in the case of lymphomas and myeloproliferative disorders, as well as in hereditary spherocytosis (HS) [41]. The use of antiaggregant therapy or other prophylactic measures are therefore to be used according to the primitive diagnosis, not only to the platelet count. In conclusion, ST does not usually require treatment, and the platelet count alteration usually normalizes with the resolution of the causal disease. Children with persistent thrombocytosis, but without any recognizable cause, should be investigated for the possible diagnosis of primary clonal or familial condition.

4. Essential Thrombocythemia (ET)

In ET (also commonly assumed as primary thrombocytosis), the increase in platelet count depends on a clonal disease of the bone marrow. These forms were grouped as myeloproliferative diseases and were later considered myeloproliferative neoplasms by the 2016 WHO classification [3,4] and comprise different entities, such as BCR-ABL-positive chronic myeloid leukemia, chronic eosinophilic leukemia, mastocytosis, some myelodysplastic syndromes, and the three entities within BCR-ABL-negative chronic MPN, i.e., ET, PV and MF. Thrombocytosis is the main hematological feature in ET, which, albeit typical of advanced age, is the most common MPN of childhood [5,6,7,8]. ET has an estimated incidence of 1 per 10 million annually [5]. However, ET is now recognized more frequently than in the past and an incidence of 0.6/100,000/year has been reported in children and young people under the age of 20 [43], probably due to the increased number of automated blood counts performed in children [18], and case series, not only case reports, have been published in recent years [8,15,16,17,18,43,44].

5. Managing Thrombocythemia in Children

Therapeutic guidelines for adults with ET are aimed to prevent vascular complications without increasing the risk of transformation [75]. Therefore, disease management is based on the risk stratification for thrombosis that has been internationally validated [60,68]. High risk factors, such as >60 age and a previous thrombotic event, are irrelevant or rare in children [80]. Thus, an identical risk-stratified strategy does not fit completely. To borrow from the experience gained with adults, ET represents a questionable option, also considering the different frequency of driver mutations and the high number of 3NEG, non-clonal cases in children in comparison to adults.

Few studies evaluating the best clinical approach to children with ET exist and, currently, only suggestions or guidelines based on experiences are published [12,18,35,44]. Moreover, any pharmacological treatment should theoretically be administered for a long time, or even for life. Long-term effects on growth, fertility and possible transformation must be weighed against all other options.

In 2015, the Italian Association for Pediatric Haematology Oncology (AIEOP) developed consensus-driven guidelines for diagnosis and treatment, available online [11]. Interestingly, even before the description of CALR mutations, those guidelines and criteria fit the most recent indications of Tefferi and Barbui [55]. The main criterion was to avoid any unnecessary drug administration: the initial aggressive therapeutic approach that was historically seen in many children (47% of Italian patients and most of the cases reported before 2008) has been changed. In asymptomatic children, a wait-and-watch approach is considered the best managing option. This requires careful, strict hematological and clinical observation, and so far (with a follow up of 3 to 30 years), no further complications have been described in our series. On the other hand, any thrombosis is a major event for children: would it be better to avoid any deep thrombosis rather than intervening after its occurrence? Moreover, the ability of anti-aggregation or cytoreduction to prevent major thrombosis in a child is still largely unknown.

Certainly, behavioral, familial or constitutional risk factors such as smoking, obesity, hyperlipemia and diabetes (as well as pregnancy [82]) need to be weighted in the final decision.

5.1. Antiaggregating Agents

Over the years, the efficacy of low-dose Acetylsalicylic acid (ASA) in PV [83] induced a wide use of similar treatments in ET, and low-dose aspirin is commonly used in adults with MPN [84]. However, a recent paper showed that the cardiovascular prophylaxis with 100 mg of aspirin appears inadequate in reducing platelet activation in most ET patients, which questions the classically used dosage [85]. Different schedules (BID/TID) are suggested for resistant symptoms [76].

Microvascular symptoms are common in pediatric ET and can be very disturbing. ASA can be used to control headache or erythromelalgia and doses can be tapered to the minimum according to efficacy. In fact, 1 mg/kg is usually effective for the control of symptoms. Caution is to be used in case of infection by varicella-zoster and influenza virus (for the possibility of hepatotoxicity and Reye syndrome). Moreover, the frequent observation of acquired von Willebrand (VW) disease, especially with extreme platelet counts (>1500 × 10⁹/L), presents hemorrhagic risk. However, it is a common observation in our pediatric series that very high platelet counts are better tolerated by children and adolescents, with a low frequency of even minor hemorrhages.

Antiaggregating agents are suggested for low-risk, JAK2-mutated adult ET. Since, in our experience, JAK2 mutation is also associated with microvascular symptoms and at times major thrombosis, this recommendation can also be used for pediatric ET. It may be helpful to monitor VW ristocetin cofactor activity levels, which should be >20%, and high molecular weight multimers [86].

5.2. Anticoagulants

The use of anticoagulants is suggested in both adults and children with deep vein thrombosis. A recent systematic review of antithrombotic treatments adopted in patients with MPN and a history of VTE showed that direct oral anticoagulants (DOACs) and vitamin K antagonist (VKA) have a comparable, relatively low risk of recurrent thrombosis and bleeding events [87]. In addition, recent guidance suggests the use of DOACs for the treatment of splanchnic thromboses in non-cirrhotic patients in the absence of severe liver dysfunction [88]. Venous thromboembolism (VTE) is, fortunately, extremely rare in children with ET, but some cases of Budd–Chiari syndrome and cerebral sinus thromboses have been reported [77,78]. Approved anticoagulant drugs and management strategies in children with VTE have been reviewed recently [89]. The Einstein-Jr phase 3 study shows that body-weight-adjusted Rivaroxaban provides appropriate treatment for children with VTE [90].

5.3. Cytoreductive Drugs

The recommendations from the European Leukemia Net (ELN) reserve cytoreductive drugs for intermediate/high-risk patients with ET [75]. Hydroxyurea (HU) and interferon-alpha (IFN-a) or pegylated IFN alpha (Peg-IFNa) are considered first-line therapies for ET at any age. Initially, cytoreductive drugs such as HU, anagrelide and IFN-a were quite commonly used in thrombocythemic children even in the absence of high-risk factors. Careful analysis of the literature and of the national experiences led to a more careful, risk-adapted therapy. Therefore, high-risk children who have already experienced a thrombotic event (usually the first event leading to diagnosis) need cytoreduction, together with the addition of antithrombotic drugs [89]. Cytoreduction can be also considered in the case of low-risk ET children with resistant vascular symptoms and/or bleeding tendencies under ASA therapy [11,44,63,80]. In these cases, the reduced number of platelets to be obtained is still unknown.

Because the necessary duration of cytoreduction is unknown—yet probably very long—the histological modification of bone marrow and cytogenetical analysis should be monitored periodically in young patients undergoing cytoreduction.

There exists insufficient clinical data to recommend a specific agent in children. Moreover, no clear preference emerges among the available drugs. In the cases that need it, individually tailored treatment must be adopted. The child and the parents must be informed about the risk/benefit ratio of each choice, both interventional and observational, with a clear and thorough discussion regarding the possible long-lasting adverse effect of drugs adopted for therapy. Therefore, efforts should be made to summon prospective collaborative studies to evaluate types of drugs, duration and endpoints of treatment for ET in children.

5.3.1. Hydroxyurea (HU)

HU is usually considered the first-line treatment for any MPN and is usually the benchmark to confront any other available drug [91]. HU requires chronic oral administration and is generally well-tolerated. Its major concern is the possible risk of inducing transformation into acute leukemia [92]. This, however, has not definitively been ascertained. Experience suggests that HU is efficient and safe in young adults with ET [93] and that it does not induce adverse effects on growth and fertility when used in children with sickle-cell anemia [94]. However, HU might have different (and detrimental) effects in lifelong treatment for patients with a clonal diseases such as ET.

5.3.2. Interferon-Alpha (IFN-a)

IFN-a has been used since many years, but only with the introduction of its pegylated form has its side effects become more acceptable. IFN-a is capable of reducing platelet count; it is not leukemogenic nor teratogenic. PEG-IFN-a has been shown to be effective in PV resistant to HU [95,96], but results regarding ET are still controversial [97]. The possible ability of IFN-a to induce molecular and histological remission has encouraged its use [98,99].

Recently, a series of 13 children and young adults, six ET and seven PV, has been reported, where Peg-IFN-a has obtained acceptable results, with eight patients still on treatment. However, three complications were observed, and five patients discontinued treatment. Some collateral effects persist, including intolerance but also lack of complete response, and in three cases major complications were the reasons for discontinuation. Three cases showed a reduction in JAK2V617F allele burden [44].

5.3.3. Anagrelide

Anagrelide, a nonchemotherapeutic cytoreductive drug, is an alternative to HU. It is tolerable in the long-term, but anemia occurs in about 25% of patients, and it has been suggested that it could decrease the myelofibrosis-free survival [91,100]. However, Anagrelide in adult patients with ET has been considered useful and suitable for the prevention of thrombotic complications [101]. Therefore, it has also recently been widely used in younger patients [102] and was successful mainly in children poorly compliant to HU or IFN-a.

5.4. JAK2-Inhibitors

Ruxolitinib is the first developed JAK2 inhibitor, mainly used for MF and recently approved for HU-resistant PV [97,103]. In children, there exist some experiences in different conditions such as post-transplant graft versus host disease [104], and dose-finding studies have been carried out in pediatric neoplasms [105]. One infant with JAK2-positive polycythemia and Budd–Chiari syndrome was treated with success [106].