Abstract

Essential thrombocythemia (ET) is considered a classic” BCR-ABL1-negative chronic myeloproliferative condition (MPD) that’s characterized by thrombocytosis, bleeding, and/or thrombosis. It usually affects the megakaryocytic cell lineage. While the disease is most commonly observed in people between the ages of 50 and 60, ET is an extremely rare myeloproliferative disorder in the pediatric age group. In children under the age of 14, the annual incidence of ET is estimated to be 1 per 10 million, approximately 60 times lower than older ages. Most ET patients, especially children are asymptomatic and discovered incidentally while doing investigations for other reasons. Herein, we introduce a very rare case of essential thrombocythemia in a 5-year-old male patient that was detected incidentally following receiving the influenza vaccine. The patient had a persistent elevated platelet count over 450x109 /L. Bone marrow showed markedly increased megakaryocyte number. Genetic testing and bcr/abl rearrangement were unremarkable. The patient showed no symptoms during the period of follow-up.

1. Introduction

Essential thrombocythemia (ET) is a rare form of myeloproliferative disorder, that mainly targets the megakaryocytes lineage ^{1, 2}. ET was first recognized by Emil Epstein and Alfred Goedel, two Austrian pathologists in 1934 ³. Although the exact mechanism of the disease is still not fully understood, genetic mutations including JAK2 V617F, MPL, and CALR have been detected in a group of patients with ET. This genetic link is observed more in adult patients than in children given that only 25-40% of pediatric cases show one of these mutations. In fact, this may indicate another underlying mechanism for the clonal nature among different patients ^{4, 5, 6}.

The clinical entity of essential thrombocythemia is rare in middle-aged adults, and it's far rarer in pediatrics with an estimated prevalence of 1 in 10 million ¹. The majority of pediatric ET cases are asymptomatic and discovered incidentally, while other patients may experience thrombosis's-related symptoms like headache, paresthesia, and abdominal pain. Furthermore, in cases of extremely high platelets level (up to 4500 × 109/L) patients may unexpectedly suffer from a serious bleeding disorder resulting from acquired von Willebrand syndrome (VW) ^{2, 7}.

Essential thrombocythemia is a diagnosis of exclusion, this emphasizes the great significance of proceeding with extensive workup and clinical investigations to rule out secondary causes such as infections, stress conditions (eg. Surgery), IDA, cancer, and post-splenectomy prior to confirming the diagnosis of ET ⁸.

In 2016, the World Health Organization (WHO) updated the diagnostic criteria for Essential thrombocythemia, which included four major and one minor criterion. The major criteria are as follows: (1) Platelet count ≥450 × 109/L, (2) Bone marrow biopsy showing megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with no significant increase in neutrophil granulopoiesis or erythropoiesis and, rarely, minor reticulin fibers (3) Not meeting WHO criteria for CML, polycythemia vera (PV), primary myelofibrosis, myelodysplastic syndromes, or other myeloid neoplasms. (4) Presence of JAK2, CALR, or MPL mutation. The minor criterion is the presence of a clonal marker or absence of evidence of reactive thrombocytosis (e.g., infection, inflammation, iron deficiency anemia) Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion ⁹. Hereby, we present a rare case of essential thrombocythemia in a 5-year-old male patient that was discovered incidentally following receiving the influenza vaccine.

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2. Case Presentation

J.A., a 5-year- old Palestinian male child with a history of recurrent upper respiratory tract infections requiring hospitalization. The last one was in October 2021 following 10 days of influanza vaccine due to upper respiratory symptoms. At that time, complete blood count test showed an incidentally elevated platelet count approximately 1200 * 10^{^3}/µl. CBC was repeated and revealed the same elevation in platelet count along with iron deficiency anemia measures. The patient was received the appropriate treatment for IDA with normalization of hemoglobin and iron parameters but without correction in the platelet count. On April 20, 2022 the patient was referred to the pediatric hematological department at Al-Istishari Arab Hospital, Ramallah, Palestine, for further evaluation and workup. The patient is a product of normal vaginal delivery of a spontaneous uneventful pregnancy and birth. Immunizations status was up to date and taking no medications. The child’s parents are non-consanguineous and have no hematological issues. Past surgical history is significant for uncomplicated tonsillectomy 2 years ago. Physical assessment of the child was normal except for pallor and dyspnea. There is no visible skin rash, ecchymosis, mucosal bleeding, joint swelling and/or limping. Laboratory evaluation showed extreme thrombocytosis with platelet count of 1978 * 10^{^3}/µl with elevated LDH of 351 u/l while RBCs, WBCs, Hb, ESR and CRP all were within the normal reference values (Table 1). Total body magnetic resonance imaging (MRI) with contrast under general anesthesia showed no significant findings. Bone marrow aspiration and biopsy were performed and disclosed an enlarged clustered megakaryocyte with bone marrow cellularity of 95%, decreased stainable iron, grade I reticulin fibrosis (figure 1). Essential thrombocythemia was suspected. Therefore, genetic analysis was done and myeloid panel was obtained which showed negative JAK-2, MPL and CALR gene mutations. According to the WHO 2016 diagnostic criteria, our patient was diagnosed with Essential thrombocythemia and causes of secondary thrombocytosis were ruled out. Saint Jude children’s Research Hospital-Department of Hematology- was consulted for the management approach of this patient. Given (1) HB level >12 g/dL and normal WBCs (2) No splenomegaly (3) non-contributable family history (4) unlikelihood of myeloproliferative neoplasms at this age (5) the conclusive decision was to observe the patient with no need for medications along with close follow-up plan inflammatory markers (e.g., ESR) monitoring with repetition of genetic studying and bone marrow biopsy if abnormal changes in peripheral blood count seen.

3. Discussion

Essential thrombocythemia (ET), formerly known as hemorrhagic thrombocythemia, is one of the chronic myeloproliferative disorders characterized by persistent proliferation of megakaryocytes and a subsequent increase in circulating platelet count ^{10, 11}. The myeloproliferative neoplasms (MPNs) are a family of chronic hematologic malignancies that share the same features on a molecular and clinical basis. They include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) ^{12, 13}. All of these disorders share a common driving mutation and overlapping clinical features ¹⁴.

ET is the most common form of MPN ¹⁵. MPN in general and ET in particular is an adult disease that is extremely rare in the pediatric age group. Limited data is available on incidence of ET in children, ET is estimated to be diagnosed in 1/1,000,000 children ¹⁶. thus, we are reporting one of the very rare hematological diseases in pediatrics. Only 20% of cases are detected in patients younger than 40 years of age ¹⁷. ET is 60 times more common in adults than in pediatric patients ¹⁸. The incidence of ET is 1-2.5 cases per 100,000 per year. The incidence increases with age, and the average age at diagnosis is 60 years. In young adults, the disease is more common in women ¹⁹. while in older adults, the incidence is the same in both sexes ¹⁰. Although thrombocytosis is generally a common finding in pediatrics, the primary (even essential) cause is extremely rare ¹⁶. The main problem in ET is the increased production of platelets by megakaryocytes in the bone marrow (thrombopoiesis). Current theories agree that thrombopoietin (TPO) plays an important role in the pathogenesis of ET. Thrombopoietin is a glycoprotein hormone produced by the liver and kidney and is an essential factor in stem cell differentiation and further maturation of megakaryocytes and platelet production ^{20, 21, 22, 23}.

The 3 most common mutations, also known as "driver" mutations, found in ET are: JAK 2 (Janus kinase 2), which is found in 50-60% of adults and in less than 30% of children ^{24, 25}. This mutation is a gain of function that results in permanent activation of the TPO receptor and continuous signal transduction, resulting in platelet overproduction ^{26, 27}. MPL (myeloproliferative leukemia virus oncogene), This mutation is found in only 3-5% of children. The MPL gene encodes the TPO receptor protein, and the mutation results in receptor activation, leading to increased platelet proliferation and production ²⁴. CALR (endoplasmic reticulum-associated chaperone calreticulin) mutation found in 25% of adults. The mechanism by which this mutation leads to thrombocytosis is not fully understood ²⁷. Only 10-20% are triple negative (driver mutation negative) ²⁴. The proposed theories of molecular pathogenesis are relatively well understood and aligned in adults compared with children, who generally do not have any of the aforementioned mutations ²⁵.

Since the incidence in children is very rare, there are no clear data yet on the clinical presentation in children. Our patient is considered to have an incidental diagnosis. In the comparison group (adults), only 25-30% of patients are asymptomatic and most of them have non-specific symptoms. The most common symptoms are headache, migraine, and dizziness ²⁸. Our patient was incidentally diagnosed after doing CBC test for another purpose.

Symptoms can generally be classified according to their mechanism: A microvascular occlusion occurring in the microcirculation of the toes, causing pain with a sensation of heat, known as erythromelalgia, and sometimes even affecting blood flow to the limbs, leading to gangrene.Thrombotic complications, which occur in 10-20% of affected patients ²⁸. Affecting small or large, arterial or venous vessels ¹⁴. Bleeding complications that occur mainly in patients with extremely high platelet counts (> 1 million). The possible mechanism of this paradoxical complication is acquired von Willebrand disease ²⁹. The most common site for bleeding is the gastrointestinal tract ¹⁰. 20-30% of the affected population present with constitutional symptoms.

Physical findings are generally unremarkable, with the exception of an enlarged spleen in 40-50% of patients and hepatomegaly in 20% ^{28, 30}. To make the diagnosis ET, other causes of secondary (also known as reactive) thrombocytosis must be excluded ³¹. In children, the two most common causes of increased platelet count are infections and iron deficiency anemia (IDA) ^{32, 33}. Platelets are among the acute phase reactions. In the presence of infection or inflammatory state, IL-6 increases TPO mRNA expression and TPO levels, and this upregulation consequently leads to increased platelet production ³⁴. Recently, TPO levels were found to correlate with the well-known and commonly used C-reactive protein ³⁵.

In iron deficiency anemia, increased EPO levels bind to TPO receptors (known as MPL) and result in a TPO-like effect leading to thrombopoiesis and platelet formation ^{36, 37, 38}. Other causes of secondary thrombocytosis that must be excluded are: inflammation ³³, collagen disease ¹⁰, other causes of anemia (hemorrhage, hemolytic anemia) ^{31, 33}, Asplenia or decreased splenic function leading to platelet accumulation in the peripheral circulation, nephrotic syndrome ¹⁰.

Other less common causes include: Familial thrombocytosis, in which an enhancement infusion mutation leads to excessive production of TPO ^{39, 40}.This mutation can be inherited either autosomal dominant, recessive, or x-linked ¹⁰. Other MPN, Considering the overlapping clinical presentations of myeloproliferative disorders, all CML, MDS, PV, primary myelofibrosis are important differential diagnoses ^{28, 33}.

Our patient was initially diagnosed and iron deficiency anemia, although it is uncommon for platelet counts to reach such high counts in IDA. After correcting the anemia, the platelet counts were still high, thus raising the suspicion of another differential diagnosis. Workup was done to rule out secondary causes, including CBC of both parents, excluding familial thrombocytosis, and eventually as ET diagnostic criteria were met, the diagnosis was confirmed.

Investigations should be performed to confirm the diagnosis and exclude secondary causes.

A CBC is mandatory, with a platelet count greater than 450. Other common findings include leukocytosis, erythrocytosis, and mild anemia ¹⁵. Peripheral blood smear shows immature progenitor cells, platelets (large platelets), mild basophilia or eosinophilia ¹⁰. Bone marrow biopsy showing in case of ET an increased cellularity in 90% of patients, especially increased proliferation of megakaryocytes ¹⁰. Hyperplasia of granulocytes or reticulocyte precursor cells is a common finding. However, dysplasia in any of the progenitor cells is not a common finding, nor is bone marrow fibrosis ¹⁰. Genetic testing for driver mutations. Other tests to rule out secondary causes include Acute phase reactants, iron and coagulation studies, platelet aggregation tests, in addition to U/S or Ct scan for organomegaly ⁴¹. The Diagnosis of ET is made using the 2016 WHO criteria ⁹.

Unfortunately, there is no cure for ET, and the main purpose of treatment is to prevent vascular complications, namely thrombosis and bleeding ^{14, 15, 42}. These complications are the main causes of mortality and morbidity in ET patients ⁴³. There are no current guidelines for the treatment of children ⁴². The proposed treatment approach in adults is based on risk stratification, in which patients are classified into different risk groups based on two main factors: Age and history of thrombotic events. The low-risk group is defined as individuals younger than 60 years with no history of thrombotic events. These patients receive a low dose of aspirin unless there is a contraindication ⁴¹. In the pediatric age group, low-risk children are considered asymptomatic; these patients should be monitored and their blood count and platelet counts checked every 3-6 months. In adults, the high-risk group is considered to be those older than 60 years or with a history of thrombosis ¹⁴. Recent studies consider mutation status as an independent risk factor for thrombotic events, namely the JAK -2 mutation. In high-risk patients, cytoreductive therapy aimed at lowering platelet counts should be initiated ^{30, 44}. The first line of treatment is hydroxyurea, which reduces both platelet and white blood cell counts ¹². Other drug options include anagrelide which is considered the second line of treatment acting by inhibiting megakaryocyte and platelet differentiation ^{21, 45}, IFN-alpha ⁴⁶, Busulfan ³⁷, and Targeted therapy with ruxolitinib (JAK 1/ 2-inhibitor), which is FDA approved for MPD ⁴⁷.

In children, the high-risk population is divided into the following groups: Intermediate-risk children who are asymptomatic but at additional risk of thrombophilia (e.g., HSM, headache, erythromelalgia, CVS RF, thrombophilia, or bleeding). These children are treated with low-dose aspirin, although this is not recommended in children younger than 12 years ^{12, 48}, High-risk children are those in whom low- or intermediate-risk treatment has failed or who have developed a thrombosis or bleeding complication. These children must be treated with cytoreductive therapy ¹⁷. There is no evidence of the effects of therapy on long-term complications such as leukemic transformation, the incidence of which over 15 years ranges from 2.1 to 5.3% of patients from ET ⁴⁹, And fibrotic transformation of the bone marrow, which occurs in up to 11% of patients ^{46, 49, 50}.

Acknowledgements

None.

References