Pediatric Thrombocytopenia 

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 primary or secondary.

Primary thrombocytosis

Primary thrombocytosis (also called essential thrombocytosis) consists of 2 types. The first is classical primary thrombocytosis and 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 myeloproliferative disorder (eg, essential thrombocythemia, myelofibrosis with myeloid metaplasia, polycythemia vera, chronic myelocytic leukemia [rare]) or, in rare cases, of acute myelocytic leukemia. Hematopoiesis in these patients is monoclonal, is characterized by endogenous erythroid colony growth, shows overexpression of granulocyte polycythemia rubra vera-1 (PRV-1) RNA, and is accompanied by JAK2^V617Fmutation in about 30% of pediatric cases.^[1]

The second type of primary thrombocytosis is, in most cases, familial and is caused by a mutation of either thrombopoietin (TPO) gene or thrombopoietin receptor gene (mpl). Hematopoiesis in the latter is polyclonal.

Secondary thrombocytosis

In contrast to primary thrombocytosis, secondary thrombocytosis is an exaggerated physiologic response to a primary event, such as an infection. In pediatrics, primary thrombocytosis is exceedingly rare, whereas secondary, or reactive, thrombocytosis is exceedingly common, particularly in infants.

Secondary thrombocytosis (the term reactive thrombocytosis is used in all subsequent discussions) is usually transient and subsides when the primary stimulus ceases. Despite the strikingly high platelet count (on occasions exceeding 1000 X 10⁹/L, or 1 million/mcL), thrombotic and/or hemorrhagic complications are highly exceptional. This is in contrast to thrombosis and bleeding that are more common complications of primary thrombocythemia.

Reactive thrombocytosis is usually mediated by increased release of numerous cytokines in response to infections, inflammation, vasculitis, tissue trauma, and other factors. Thrombopoietin (TPO), 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 an increase in platelet production. However, serum or plasma levels of these cytokines do not seem to be correlated with degree of thrombocytosis.

Other cytokines may participate in the stimulation of platelet production. They include 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 rapid consumption of platelets. This most commonly occurs in neonates and infants, indicating the labile nature of platelet count control in these subjects.

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 over 500,000.^[2] Rebound thrombocytosis is also observed in the recovery phase of chemotherapy-induced thrombocytopenia and during the recovery phase of immune thrombocytopenic purpura (ITP). None of the patients developed thrombotic episodes.

In some instances, such as chronic hemolytic anemia, the stimulus (hypoxia) to produce cytokines persists, causing long-term elevation of platelet counts. Although thrombocytosis in association with iron-deficiency anemia is well documented, the mechanism remains unclear. Although elevated erythropoietin levels are observed in patients with thrombocytosis who have iron-deficiency anemia, one study showed that these elevated levels had no correlation with platelet count. levels of other cytokines potentially responsible for thrombocytosis, such as IL-6 and TPO, were not elevated. In some cases, an increased number of bone marrow megakaryocytes is observed.^{[3, 4]}

In contrast, sporadic (nonfamilial) primary thrombocytosis is usually a clonal disorder, although nonclonal essential thrombocythemia has also been well documented. The most common diagnosis in the pediatric age group is chronic myelogenous leukemia (CML). Polycythemia vera, essential thrombocytosis (ET), and myelofibrosis (MF) with myeloid metaplasia are other diagnoses that are associated with primary thrombocytosis; however, these are rare in children. In primary thrombocytosis, primary and secondary hypercoagulable states frequently lead to thrombotic episodes and to a hemorrhagic tendency. In about 30% of pediatric cases, JAK2^V617Fmutation has been documented.

Familial or hereditary primary ET in children are heterogeneous disorders of different molecular abnormalities. Inheritance patterns vary; most familial thrombocythemia cases due to TPO gene mutations are transmitted in autosomal dominant manner. However, some are autosomal recessive. In one family, transmission appears to be X-linked recessive.

At least 2 classes of molecular mutations that lead to familial thrombocytosis are known. One involves mutations of the TPO gene that result in increased TPO production by various mechanisms. The other involves mutations of the C-MPL (TPO) receptor gene that somehow constitutively maintains 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 the following:

• Familial thrombocytosis 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.^[5]
    • Abe et al reported an amino acid substitution of Trp(508) to Ser(508) in the intracellular domain of MPL.^[6]
    • Ding et al reported 8 members of a Japanese family with a mutation in the transmembrane domain of MPL.^[7]
  • TPO gene mutation or increased blood TPO level
    • Fujiwara et al reported on 3 members in a Japanese family with increased serum TPO levels and no mutation found in the TPO or MPL gene.^[8]
    • 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 TPO gene.^{[9, 10]}
    • Graziano et al reported on 3 members in a family who had a TPO mutation (G185T) and associated limb defects.^[11]
    • Kondo et al reported on 5 members in 3 generations of a Japanese family who had a base deletion in the TPO gene (5'UTR).^[12]
    • 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 TPO gene.^[13]
    • Robins et al reported a mother and child with elevated TPO levels. The mutation was not studied. The child had a limb defect.^[14]
    • 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 TPO gene.^{[15, 16]} Thrombosis and hemorrhage were noted.
  • Neither MPL gene nor TPO gene mutation found or studied
    • Stuhrmann et al reported on 4 Arab siblings with familial thrombocytosis.^[17]
    • Tecuceanu et al reported on an Israeli-Jewish family with mild thrombocytosis (highest platelet count was 506 X 10⁹/L).^[18]
• Secondary thrombocytosis causes have been reported and studied as follows:

  • Caffey disease^[19]
  • Granulocyte-colony stimulating factor treatment in neonates^[20]
  • Hepatocellular carcinoma^[21]
  • HIV infection^[22]
  • Low molecular–weight heparain^[23]
  • Malignant ovarian tumors^[24]
  • Toxocariasis^[25]
  • Trauma^[26]

Acquired ET in children is similar to that found in adults. JAK2^V617F mutation and PRV-1 RNA positivity are less frequent than in adults, but frequency of JAK2 mutation increases with age. Although the role of JAK2 mutation in myeloproliferation is clear, many pediatric patients do not exhibit this mutation; therefore, it is only one of the multiple genetic mutations that result in myeloproliferative disorder.

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 slowly decreases to the reference range. Similarly, functional asplenia that may occur after splenic artery embolization results in thrombocytosis.

Frequency

United States

Dame and Sutor stated that the annual incidence of newly diagnosed primary thrombocytosis in childhood is 1 case per 10 million population.^[27] According to these authors, about 75 children with primary thrombocytosis were reported from 1966-2000.

Dror et al published the results of an analysis of 36 children with essential thromboctyosis.^[28] The frequency of reactive 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 summarization of the findings from 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.^[29]

No evidence suggests that the incidences of either primary or reactive thrombocytosis vary significantly from one country to another or from one ethnic group to another.

International

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

Mortality/Morbidity

Thrombotic or hemorrhagic complications caused by reactive or 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.

In patients with primary nonfamilial thrombocytosis, which is a myeloproliferative disorder, the frequency of thrombosis and/or hemorrhage widely varies among various reports (20-84% for thrombotic complications and 4-41% for bleeding complications). However, these statistics are for adult patients, and incidences of hemorrhagic and thrombotic complications in primary thrombocytosis of children are not known.

On the basis of experiences in young adults with primary thrombocytosis, these complications may occur less often in children than in adults.^[30] Teofili et al reported a 0% rate of thrombosis in children with essential thrombocytosis, as opposed to 10 of 32 patients in a study of adults. On the other hand, Dame and Sutor reported that about 30% of children with essential thrombocytosis had thromboembolic or hemorrhagic complications at the time of diagnosis or later, and that about 20% of initially asymptomatic children had these complications later.^[27] These figures are similar to those of adults. Bleeding mainly involves the mucous membranes and skin (eg, GI hemorrhage, hemoptysis, post surgical 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.^{[28, 31]}

Race

Essential thrombocytosis has no reported racial predisposition.

Sex

No sex difference is reported in the frequency of essential or reactive thrombocytosis.

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 reactive 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.^[32]

Matsubara et al reported an age-related shift in mean platelet counts.^[33] 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.

More recently, an age-related reference range of platelet counts in preterm infants (22-42 weeks' gestation) was published.^[34] According to this study, the 95th percentile line exceeds 700,000 at 35-49 postnatal days in this cohort of patients.