Pediatric Thrombocytosis

The physiologic reference range of platelet counts is 150-400 X 10⁹/L. A platelet count exceeding the upper limit is called thrombocytosis or thrombocythemia. Thrombocytosis is classified as either essential or secondary.

Essential thrombocytosis

ET (also called primary thrombocytosis or primary thrombocythemia) consists of two types. The first is classical ET, which is caused by autonomous production of platelets unregulated by the physiologic feedback mechanism to keep the count within the reference range. It is a subset of MPN, which also includes myelofibrosis with myeloid metaplasia, polycythemia vera (PV), chronic myelocytic leukemia (CML), and acute myelocytic leukemia. ^{[6, 8]}

Hematopoiesis in patients with ET is monoclonal and is caused by Janus kinase 2 gene (JAK2^V617F) mutation, thrombopoietin receptor gene (MPL) mutation, calreticulin gene (CALR) mutation, or other mutations. (In pediatric cases, however, more than half of them have been found to have no obvious driver mutations. ^[5] ) JAK2 mutation and CALR mutation are mutually exclusive, and there is a distinct phenotypic difference between these two. ^{[9, 10, 11]}  There have been other mutations reported, including ASXL1 and MPL^Y252H. ^[6]

The second type of ET is, in most cases, familial and hereditary. It is caused by a mutation of either the thrombopoietin (THPO) gene or MPL. (Details of each gene mutation are described below.) Hematopoiesis in this type of mutation is polyclonal.

Secondary thrombocytosis

In contrast to ET, secondary thrombocytosis is an exaggerated physiologic response to a primary event, such as an infection. In children, the overwhelming majority of thrombocytosis cases are secondary, particularly in infants and very young children.

Secondary thrombocytosis is usually transient and subsides when the primary stimulus ceases. Despite the strikingly high platelet count (on occasions exceeding 1 million/μL), thrombotic and/or hemorrhagic complications are highly exceptional. This is in contrast to the thrombosis and bleeding that are reported complications of ET.

Secondary thrombocytosis

Secondary thrombocytosis is usually mediated by the increased release of numerous cytokines in response to infections, inflammation, vasculitis, tissue trauma, and other factors. Thrombopoietin (THPO), the primary cytokine for platelet production and maturation, and interleukin (IL)-6 levels are usually initially elevated in response to the primary events mentioned earlier; they stimulate platelet production. However, serum or plasma levels of these cytokines do not seem to be correlated with the degree of thrombocytosis.

Other cytokines may participate in the stimulation of platelet production. They include IL-1β, IL-3, IL-11, granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin. These cytokines are directly or indirectly released during the primary events. When the original stimulation stops, the platelet count then returns to the reference range.

In severe infections, such as bacterial meningitis, one of the causes may be a rebound phenomenon after initial thrombocytopenia due to the rapid consumption of platelets. This most commonly occurs in neonates and infants, indicating the labile nature of platelet count control in these subjects. Rebound thrombocytosis is also observed in the recovery phase of chemotherapy-induced thrombocytopenia and during the recovery phase of immune thrombocytopenic purpura (ITP).

The most common infection associated with thrombocytosis is pneumonia. Vlacha and Feketea described 102 children admitted with a diagnosis of lower respiratory tract infection; 49 of these children (median age 31 mo) developed platelet counts of over 500 X 10⁹/L. ^[12]

A retrospective study by Zheng et al found that out of 3156 children with respiratory tract infection, 817 (25.9%) had secondary thrombocytosis (500 X 10⁹ platelets/L or higher). ^[13]

A study from Taiwan on pediatric secondary thrombocytosis (platelet count >500,000/μL) showed a positive correlation between platelet count and WBC count and an inverse relation between platelet count and blood hemoglobin level. The same study reported that thrombocytosis is a significant independent risk factor for the length of hospital stay. A study done on an adult population in Israel showed that thrombocytosis is a risk factor for prolonged hospitalization in adults as well; the mortality rate of patients with thrombocytosis was significantly higher than that of patients without thrombocytosis. ^[14]

In some instances, such as chronic hemolytic anemia, the stimulus (hypoxia) to produce cytokines persists, causing long-term elevation of platelet counts. While thrombocytosis in association with iron-deficiency anemia is well documented, the mechanism remains unclear. Although elevated erythropoietin levels are observed in patients with iron-deficiency anemia and thrombocytosis, one study showed that these elevated levels had no correlation with platelet count or with levels of other cytokines potentially responsible for thrombocytosis, such as IL-6 and THPO. In some cases, an increased number of bone marrow megakaryocytes is observed. ^{[15, 16]}

In this context, a study on patients with chemotherapy-induced anemia shed some light on this subject. Patients randomly received intravenous (IV) iron, oral iron, or no iron, in addition to erythroid-stimulating agents (ESAs). The patients who received IV iron developed the least degree of thrombocytosis, and patients who received no iron developed the greatest degree of thrombocytosis, whereas the patients who received oral iron developed an intermediate degree of thrombocytosis. This observation suggested that although ESAs cause thrombocytosis, iron deficiency itself is an additional factor. ^[17]

A rare disorder of unknown etiology, idiopathic cyclic thrombocytopenia is characterized by female predominance, fluctuation of platelet count with rebound thrombocytosis (with peak >1 million/μL), and a median age of onset of 35 years, although the youngest patient described was aged 1 year. ^[15] If a patient with this diagnosis were to be evaluated during the rebound thrombocytosis, one might erroneously conclude that the patient developed acquired thrombocytosis.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to inhibit megakaryocytopoiesis and platelet function. PACAP deficiency observed in children with congenital nephrotic syndrome causes thrombocytosis in these patients, ^[18] whereas an extra dose of PACAP genes in patients with partial trisomy 18p has been seen to result in prolongation of bleeding time and mild thrombocytopenia. ^[19] .

Asplenia

The spleen is the major organ for the destruction of platelets; therefore, after splenectomy, a sharp rise in the platelet count is routinely observed, although the count subsequently undergoes a slow decrease to the reference range. Similarly, functional asplenia that may occur after splenic artery embolization results in thrombocytosis. Investigators in Israel reported a high frequency of thrombocytosis in asymptomatic hyposplenism or in asplenic children. Assessments of the children for a splenic deficit, using technetium-99m sulfur colloid scintigraphy, were carried out mainly due to the occurrence of severe or recurrent infections and/or thrombocytosis and/or major immunodeficiency syndrome, with 50% of the imaging studies performed mainly because of persistent thrombocytosis. ^[20] Thus, it may be advisable to perform this imaging study in a selected group of patients who exhibit prolonged thrombocytosis without any obvious cause.

Other causes

Additional causes of secondary, noninfectious thrombocytosis reported in the literature are listed below:

• Caffey disease ^[21]

• Granulocyte-colony stimulating factor treatment in neonates ^[22]

• Hepatocellular carcinoma ^[23]

• Low–molecular-weight heparin ^[24]

• Malignant ovarian tumors ^[25]

• Trauma ^[26]

In addition, in a study by Gurria et al, pancreatectomy with islet autotransplantation together with splenectomy resulted in an endogenous rise in THPO, with a maximum median platelet count of 1.4 million/μL in 13 patients. Increased hepatic THPO production caused by inflammation due to islet transplantation in the liver was postulated to be the cause of the THPO increase. Thrombocytosis in these patents was successfully treated with hydroxyurea. ^[27]

In a study by Kagialis-Girard et al, two children who had extreme thrombocytosis along with hypereosinophilia were reported to mimic myeloproliferative disorder, due to toxocariasis. Anthelmintic therapy caused the hematologic abnormalities to subside. ^[28]

In a patient with systemic idiopathic juvenile arthritis (maximum platelet count of 3 million/μL), marked elevation of 1L-1β and a good response to the IL-1β receptor antagonist anakinra were found. This case report indicated 1L-1β to be a common trigger for thrombocytosis associated with systemic inflammatory conditions. ^[29]

Familial thrombocytosis

There are two types of familial thrombocytosis. One affects a single cell lineage (platelets), with Mendelian dominant inheritance, high penetrance, and polyclonal hematopoiesis. Some forms are autosomal recessive, and in one family, transmission appeared to be X-linked recessive. ^[30] . The second variety has a high predisposition to true monoclonal MPN, with low penetrance and a somatic mutation ^[31]

At least two classes of molecular mutations leading to familial thrombocytosis are known. One involves mutations of the THPO gene that result in increased THPO production by various mechanisms. The other involves mutations of the c-MPL gene that somehow constitutively maintain activated signal transduction, leading to continuous signaling for megakaryocytic proliferation. In some families, no specific molecular abnormalities have been found. Reported cases in which molecular abnormalities were investigated include those listed below. (Additional new mutations are likely to be reported in the future.)

Familial (hereditary) thrombocytosis (thrombocythemia) reports are as follows:

MPL mutation

A large Arab family with a p.Pro106Leu mutation and no thrombosis was reported by El-Harith et al. ^[17]

Abe et al reported an amino acid substitution of Trp(508) to Ser(508) in the intracellular domain of MPL. ^[32]

Ding et al reported 8 members of a Japanese family with a mutation in the transmembrane domain of MPL. ^[33]

An MPL gene polymorphism, designated as MPO^Baltimore(K39N substitution) causes little-to-moderate thrombocytosis (median of about 400,000) in heterozygous individuals and marked thrombocytosis (800,000-900,000) in homozygous persons. The frequency of MPL^Balitmore was found to be 7% in African American population. ^[34] Thus, some African Americans who were previously diagnosed to have essential thrombocytosis without detectable JAK2 or CALR mutation may have this polymorphism.

Teofili et al reported hereditary thrombocytosis caused by MPL^Ser505Asn, with a high thrombotic risk, splenomegaly, and progression to bone marrow fibrosis. ^[35]

Another study described a heterozygous MPL^R102P mutation in a proband and his daughter. This mutation increases the blood THPO level and is associated with mild thrombocytosis (platelet count around 600,000/μL). ^[36]  Ironically, the homozygous mutation of MPL^R102P was previously reported in an infant with congenital amegakaryocytic thrombocytopenia ^[37]

THPO gene mutation or increased blood THPO level

Fujiwara et al reported on 3 members in a Japanese family with increased serum THPO levels and no mutation found in the THPO or MPL gene. ^[38]

Ghilardi et al and Kikuchi et al reported 4 members in 3 generations in a Japanese family who had a novel point mutation in the THPO gene. ^{[39, 40]}

Graziano et al reported on 3 members in a family who had a THPO mutation (G185T) and associated limb defects. ^[41]

Kondo et al reported on 5 members in 3 generations of a Japanese family who had a base deletion in the THPO gene (5'UTR). ^[34]

Liu et al reported on 11 members in a Polish family with a G→C transversion in the splice donor of intron 3 of the THPO gene. ^[42]

Robins and Niazi reported a mother and child with elevated THPO levels. The mutation was not studied. The child had a limb defect. ^[43]

Wiestner et al and Schlemper et al reported 11 members of a Dutch family with a G→C transversion in the splice donor of intron 3 of the THPO gene. ^{[44, 45]} Thrombosis and hemorrhage were noted.

Stockklausner et al in Germany reported 2 families due to THPO gene c. 13+1 G/C mutation in the splice donor of intron 3. Two members of 1 family had upper limb defects. ^[46] One of the family was previously described by Wiestner et al as above.

Prouzet-Mauleon et al reported a novel THPO mutation, NM_001290003:c.433G>A, hg38:Chr3:184,376,247C>T, in a White family. ^[47]

JAK2 germline mutation

While a somatic JAK2^V617F mutation results in MPN, germline mutations at various loci can result in single-lineage familial thrombocytoses. Six different mutations in five kindreds were summarized in an article by Langabeer. ^[48]  One needs to be aware, however, as patients age, they may develop monoclonal MPN, an example being a patient described with an R876Q mutation in the kinase domain of the JAK2 gene. This individual initially had thrombocytosis only, but as he became older, the platelet count decreased, while his hemoglobin increased to 18.2 g/dL. ^[49]

Mutation of other genes

Homozygous mutations of interleukin-1 receptor antagonist (IL1RN), reported by Aksentijevich et al, ^[50] and homozygous mutations of interleukin-36 receptor antagonist (IL36RN), reported by Rossi-Semerano L et al, ^[51]  have caused significant thrombocytosis and leukocytosis in affected individuals.

In addition to blood count abnormalities, patients with IL1RN mutation showed skin pustulosis, skeletal abnormalities, hepatosplenomegaly, and pulmonary disease, whereas patients with IL36RN mutation showed only dermatologic manifestations (ie, systemic pustular psoriasis).

Neither MPL gene nor THPO gene mutation found or studied

Stuhrmann et al reported on four Arab siblings with familial thrombocytosis. ^[30]

Tecuceanu et al reported on an Israeli-Jewish family with mild thrombocytosis (highest platelet count was 506 X 10⁹/L). ^[52]

Patients with microcephalic osteodystrophic primordial dwarfism (MOPD) type II have been described to have a moderate degree of thrombocytosis and leukocytosis. MOPD type 2 is caused by a loss of function mutation of the pericentrin (PCNT) gene. ^[53]

A girl aged 9 years with hypereosinophilic syndrome demonstrated, along with thrombocytosis and eosinophilia, dermatologic, neurologic, cardiac, pulmonary, and intestinal abnormalities. The patient, who had a FIP1L1-PDGFRA fusion gene, displayed a good response to imatinib therapy. ^[54]

Sporadic essential thrombocytosis secondary to somatic mutation

Sporadic (nonfamilial) ET is usually a clonal disorder (although nonclonal ET has also been well documented). An MPL polymorphism gene, MPL^Baltimore, belongs to this polyclonal thrombocytosis.

Frequency

United States

Dame and Sutor stated that the annual incidence of newly diagnosed ET in childhood is 1 case per 10 million population. ^[55] According to these authors, about 75 children with ET were reported from 1966-2000.

Dror et al published the results of an analysis of 36 children with ET, but not the incidence of ET. ^[53]

The frequency of secondary thrombocytosis is far more common than essential thrombocytosis and depends on age. Rates are highest during the first 3 months of life. Preterm infants have higher frequencies than those of term infants. According to Sutor's summary of several studies, 3-13% of hospitalized pediatric patients had a thrombocyte count of more than 500 X 10⁹/L. In one study, 0.5% of hospitalized children had a platelet count more than 800 X 10⁹/L. ^[21]

No evidence suggests that the incidences of either essential or secondary thrombocytosis vary significantly from one country to another or from one ethnic group to another. A Taiwanese study done at a general hospital indicated the incidence of secondary thrombocytosis to be 6.3% of all hospitalized children (birth to age 18 y). ^[22]

International

See above. The incidence of essential thrombocytosis is estimated to range from 1-4 cases per 10 million people younger than 20 years. ^[56]

Mortality/Morbidity

A study by Szuber et al of 361 patients aged 40 years or younger with myeloproliferative neoplasms found that those with ET had a median survival period of 35 years, compared with 37 years for PV and 20 years for primary myelofibrosis. ^{[57, 58]}

Thrombotic or hemorrhagic complications caused by secondary thrombocytosis are described only anecdotally and must be regarded as extremely rare. However, in children with autoimmune disease or vasculitis, such as Kawasaki syndrome, thromboses do develop. In Kawasaki syndrome, this occurs particularly in the coronary arteries, and cardiac complications are the major causes of morbidity and mortality.

In patients with essential nonfamilial thrombocytosis, which is a myeloproliferative disorder, the frequency of thrombosis and/or hemorrhage widely varies among various reports in adults (20-84% for thrombotic complications and 4-41% for bleeding complications).

Incidences of hemorrhagic and thrombotic complications in pediatric ET have not been well ascertained but are very rare. ^[59] Teofili et al reported a 0% rate of thrombosis in children with ET, as opposed to 10 of 32 patients in a study of adults. ^[23] On the other hand, Dame and Sutor reported that about 30% of children with ET had thromboembolic or hemorrhagic complications at the time of diagnosis or later. ^[55] These figures are similar to those of adults. Another study, by Dror et al, found that of 36 children with ET, nine had severe hemorrhagic phenomena. ^[53]  However, one has to be aware of a high probability of sampling bias in these greater complication rates.

The previously discussed article by Ianotto et al demonstrated much smaller rates of thrombosis and hemorrhage. The investigators documented that splenomegaly was found in 54.7% and thrombosis (mostly venous thrombosis) in 3.8% of patients with ET younger than age 20 years, though the follow-up length varied. Moreover, prior to and after diagnosis, hemorrhage occurred in 1% and 4.8% of the study's patients with ET, respectively. Thromboses were most frequently in the splanchnic territories, with Budd-Chiari syndrome being predominant. The same article stated that antithrombotic therapy did not increase the bleeding complication. ^[5]

Bleeding mainly involves the mucous membranes and skin (eg, gastrointestinal [GI] hemorrhage, hemoptysis, postsurgical bleeding, bruises, epistaxis). Thrombosis involves the veins and arteries. The complication rates in familial thrombocythemia are not well described due to its rarity, but both thrombosis and hemorrhage occur. ^{[59, 60]}

Chatterjee and Yadav reported on a girl who was diagnosed with ET at age 6 years and developed massive splenomegaly and portal vein thrombosis at age 13 years, though the platelet count was normal at that time. ^[61]

Complications associated with secondary thrombocytosis are extremely rare, examples being ischemic stroke and/or thrombosis associated with iron deficiency anemia or nephrotic syndrome. ^{[18, 21, 62]}

An excessively high platelet count combined with other risk factors (eg, vasculitis) or a separate thrombophilic factor (eg, heterozygous protein C deficiency) may increase the risk of thrombosis and/or hemorrhage in secondary thrombosis. Again, however, the risk of these types of complications can be regarded as being extremely small.

In a case report by Akins et al, a woman aged 20 years with secondary thrombocytosis developed right carotid artery thrombosis and was found to have a hemoglobin level of 6.3 g/dL due to severe iron deficiency. Her platelet count was 544,000/μL. The authors speculated that abnormal platelet activation and function together with vascular endothelial alteration were more important than the platelet count itself in triggering such thrombotic events. ^[63]

The evolution of ET to frank acute myeloblastic leukemia (AML), myelofibrosis/agnogenic myeloid metaplasia (AMM), or myelodysplastic syndrome (MDS) has been documented in adults but is exceedingly rare in children.

Race

Essential thrombocytosis has no reported racial predisposition.

Sex

Although previously, no sex difference was reported in the frequency of essential or secondary thrombocytosis, the aforementioned study by Szuber et al found a female preponderance in ET in patients aged 40 years or younger. ^[57]

Age

Preterm infants and young infants do not maintain a platelet count in a range that is defined as normal for adults.

The frequency of secondary thrombocytosis is higher in infants and young children (see Frequency) than in older children. Preterm healthy infants have platelet counts higher than those of nonpreterm children. Lundstrom reported that the 95% limit for platelet counts in infants with a birth weight of less than 2000 g was 160-675 X 10⁹/L, with a median value of 375 X 10⁹/L. ^[25]

Matsubara et al reported an age-related shift in mean platelet counts. ^[26] According to the authors, 12.5% of infants younger than 1 month, 35.9% of infants aged 1 month, and 29.2% of those aged 2 months had platelet counts of 500 X 10⁹/L or more, whereas only 0.6% of children aged 11-15 years had such counts.

An age-related reference range of platelet counts in preterm infants (22-42 weeks' gestation) is available. ^[64] According to this article, the 95th percentile line exceeds 700,000 at 35-49 postnatal days in this cohort of patients.