eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thrombocytosis

Author: Susumu Inoue, MD, Professor of Pediatrics and Human Development, Michigan State University College of Human Medicine; Clinical Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Hematology/Oncology, Associate Director of Pediatric Education, Department of Pediatrics, Hurley Medical Center
Contributor Information and Disclosures

Updated: Jul 28, 2009

Introduction

Background

The physiologic reference range of platelet counts is 150-400 X 10⁹/L. A platelet count exceeding the upper limit is called thrombocytosis.

Thrombocytosis is classified as either primary or secondary. Primary 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^V617F mutation 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 gene or thrombopoietin receptor gene (mpl). Hematopoiesis in the latter is polychronal.

In contrast to primary thrombocytosis, secondary thrombocytosis is an exaggerated physiologic response to a primary problem, 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.

Pathophysiology

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, a recent 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 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^V617F mutation has been documented.

Familial or hereditary primary ET in children are heterogeneous disorders of different molecular abnormalities. Inheritance patterns vary; some are autosomal dominant, some are autosomal recessive, and some are likely 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.

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.³ 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.⁴ 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.⁵

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.⁶ The authors 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.³ 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.^4,7

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.⁸

Matsubara et al reported an age-related shift in mean platelet counts.⁹ 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.

Clinical

History

• Reactive thrombocytosis
  • The history is that of a preceding illness (eg, pneumonia, upper respiratory tract infection, iron-deficiency anemia, surgery, hemorrhage, and many others) that triggers thrombocytosis. However, one is often unable to find a definitive identifiable cause in the history.
  • In general, symptoms caused by a high platelet count are absent in virtually all cases of reactive thrombocytosis.
  • In a review article, Sutor reported 2 children with severe iron-deficiency anemia and platelet counts of more than 1000 X 10⁹/L who had cerebral infarction.⁵ Other comorbid factors, such as vasculitis, could not be excluded in these cases.
• Essential (primary) thrombocytosis
  • The history is that of mucocutaneous bleeding, such as GI or postsurgical bleeding, and excessive bruising is common.
  • Headache is the most common feature in the history.^10,11
  • The patient's family members may have the same disorder. To establish familial thrombocythemia, a careful family history and platelet counts should be obtained from the suspected family members when indicated. High levels of TPO assay in multiple family members indicate TPO mutation.
  • According to Dror et al, 10 of 36 children that were reviewed had bleeding or thrombotic episodes before the diagnosis was established; therefore, children may develop hemorrhagic and/or thrombotic complications, although the frequencies are unknown.⁴

Physical

• Reactive thrombocytosis: No specific physical findings are related to the increased platelet count.
• Essential thrombocytosis (ET)
  • Splenomegaly is common but not always present; less commonly, hepatomegaly may be present. Splenomegaly is also common in familial thrombocythemia.
  • Other physical findings may be found, depending on the hemorrhagic (typically mucous membrane bleeding) or thrombotic complications.
  • Thrombosis may affect the cerebral, coronary, and/or mesenteric arteries; the portal vein; and/or the inferior vena cava.
  • Classic erythromelalgia (throbbing, aching burning of palms and soles) associated with ET and polycythemia rubra vera has not been described in children.

Causes

• Reactive (secondary) thrombocytosis
  • Infection - Meningitis, upper and lower respiratory tract infections, septic arthritis, osteomyelitis, urinary tract infection, gastroenteritis, sepsis, severe dermatitis
  • Chronic inflammations and vasculitis -Rheumatoid arthritis, Kawasaki syndrome, Henoch-Schönlein purpura, inflammatory bowel disease (Thrombocytosis is common in patients with inflammatory bowel disease; the increase in the platelet count is a reactive phenomenon to the inflammatory process.)
  • Tissue damage - Postsurgical, burns, trauma, fracture
  • Rebound thrombocytosis - Iron-deficiency anemia, bleeding, cancer chemotherapy, recovery phase of immune thrombocytopenic purpura (ITP)
  • Postsplenectomy - ITP, splenectomy for hereditary spherocytosis, other conditions, traumatic asplenia, post splenic artery embolization
  • Hemolytic anemia -Sickle cell disease, thalassemia, and other hemolytic anemia
  • Renal disorders -Nephrotic syndrome, nephritis
  • Malignancy - Soft tissue sarcoma, osteosarcoma
  • Low birth weight/ preterm infants
  • Multiple causes
• Primary or essential thrombocytosis
  • Myelofibrosis with myeloid metaplasia
  • Polycythemia vera: PRV-1 overexpression may be present.
  • Chronic myelocytic leukemia: bcr-abl fusion gene is present.
  • Familial ET: MPL or TPO gene mutation may be present.
  • ET: JAK2^V617F mutation may be present; the frequency is lower in children (11-50%) than in adults (>50%).

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