AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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 is caused by autonomous production of platelets unregulated by the physiologic feedback mechanism to keep the count within the reference range. Primary thrombocytosis is a component of a myeloproliferative disorder (eg, essential thrombocythemia, myelofibrosis with myeloid metaplasia, polycythemia vera, chronic myelocytic leukemia [rare]) or, in rare cases, of acute myelocytic leukemia.

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 common, particularly in infants.

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

Pathophysiology

Reactive thrombocytosis is usually mediated by increased release of a number of 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, are usually initially elevated in response to the primary events mentioned earlier, and 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 released directly or indirectly 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. In a recent article, 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 500,000.¹ 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, 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 (PV), essential thrombocythemia (ET), and myelofibrosis (MF) with myeloid metaplasia are other diagnoses that are associated with primary thrombocytosis; however, these are rare in children than CML. In primary thrombocytosis, primary and secondary hypercoagulable states frequently lead to thrombotic episodes and to a hemorrhagic tendency.

ET in children is either familial (hereditary) or acquired. Familial thrombocytosis consists of 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 different 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. Janus kinase 2 mutation (V617F) and polycythemia rubra vera (PRV)-1 RNA positivity may be lower than in adults, but frequency of JAK2 mutation increases with age. Although the role of JAK2 mutation in myeloproliferation is clear, many 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.

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.² 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.³ 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.⁴

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.

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 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.⁵ These authors reported 0% rate of thrombosis in children with essential thrombocytosis, as opposed to 10 of 32 patients in a study of adults. On the contrary, 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.² These figures are similar to those of adults. The exception may be complication rates of familial thrombocythemia, which are lower.^{3, 6} Bleeding mainly involves the mucous membranes and skin (eg, GI hemorrhage, hemoptysis, postsurgical bleeding, bruises, epistaxis). Thrombosis involves the veins and arteries.

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.⁷

Matsubara et al reported an age-related shift in mean platelet counts.⁸ 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

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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.⁴ 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 may be a common feature in the history.
  • 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.
  • 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, though the frequencies are unknown.³

Physical

• Reactive thrombocytosis: No specific physical findings are related to the increased platelet count.
• 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 ITP
  • Postsplenectomy - ITP, splenectomy for hereditary spherocytosis, other conditions
  • 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
  • Chronic myelocytic leukemia
  • Familial ET

DIFFERENTIALS

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WORKUP

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Lab Studies

• Laboratory studies to identify whether the thrombocytosis is primary or reactive. When a reactive thrombocytosis is strongly suspected, no additional laboratory studies are indicated. For the differentiation of secondary from primary thrombocytosis, Messinezy et al found determination of acute-phase reactants (eg, erythrocyte sedimentation rate [ESR]) is most useful.⁹ Blood ESR, C-reactive protein (CRP) level, fibrinogen level, factor VIII procoagulant activities, and von Willebrand antigen values are significantly elevated in patients with secondary thrombocytosis, whereas they were normal in patients with primary thrombocythemia.
• See Myeloproliferative Disease for recommended laboratory studies when primary thrombocytosis is suspected.
• The Polycythemia Vera Study Group established the following criteria to diagnose ET:
• • Platelet count of more than 600 X 10⁹/L
  • Hemoglobin of 13 g/dL or less or normal RBC mass (adult men, <36 mL/kg; adult women, <32 mL/kg)
  • Stainable iron in marrow or failure of therapeutic iron trial after 1 month
  • No Philadelphia chromosome
  • Either absent fibrosis of marrow or fibrosis seen in less than one third of the biopsy area without splenomegaly or leukoerythroblastosis picture
  • No known cause of reactive thrombocytosis
• Serious consideration of this diagnosis requires that results of all laboratory investigations fulfill the criteria above.
• • The problem is that, in children, physiologic hemoglobin levels are less than 13 g/dL, and no age-related normal RBC masses have been established. Furthermore, in young children, stainable iron in the bone marrow is physiologically absent. Therefore, criteria for adults are not applicable to children. However, examination of bone-marrow morphology and bone-marrow cytogenetic study are highly recommended to exclude myelofibrosis and rule out chronic myelocytic leukemia CML. In the chronic phase of CML, leukocyte alkaline phosphatase (LAP) is extremely low, and the serum vitamin B-12 level is abnormally high; therefore, these tests may be helpful in suggesting primary thrombocytosis.
  • For adults and some children with ET, various qualitative platelet abnormalities have been found. Giant, bizarre-shaped platelets are seen on light microscopy. Platelets lack granules or are hypogranular. Often, megakaryocytic fragments are found in the blood smear. The bleeding time is usually normal. Platelet-function study shows loss of primary- and secondary-wave aggregation with epinephrine due to loss of membrane alpha-adrenergic receptors. (This finding is the most helpful in differentiating primary from secondary thrombocytosis.) Many other platelet function abnormalities are described; however, no correlations with laboratory results and clinical risk of bleeding or thrombosis have been reported.
  • In patients with primary thrombocythemia, plasma TPO level was reported to be in the reference range or mildly elevated, whereas most patients with reactive thrombocytosis had an elevated level of TPO and IL-6 at least at the onset of the thrombocytosis-triggering event. In 1 study, platelet membrane expression of the c-mpl receptor in patients with primary thrombocythemia was markedly reduced compared with platelets from control subjects.
  • Other laboratory tests that may be useful in determining nature of thrombocytosis (cause and mechanisms of thrombocytosis, functional evaluation of platelets and/or megakaryocytes) include tests of the following:
  • • Serum TPO level: This is usually elevated in reactive thrombocytosis but only in the beginning of the event that triggered thrombocytosis. The TPO level may have declined to a normal level when it is measured at the time of peak elevation of platelet count. Results of a TPO assay are normal or elevated in primary thrombocytosis. In a familial thrombocytosis syndrome, TPO values may be elevated because of a mutation in the 5' untranslated region (UTR), which inhibits TPO mRNA repression, resulting in excessive TPO production and thus thrombocytosis. However, in other families, TPO levels were normal.
    • Platelet aggregation: Variable results have been reported in patients with primary thrombocytosis, ranging from totally normal aggregation to abnormal.
    • Platelets and bone marrow megakaryocytes: Electromicroscopy may be useful for further determining the nature of thrombocytosis (structural evaluation). Abnormality of granules, tubular systems, or open canalicular system has been reported in some but not all patients with primary thrombocytosis.
    • Factor VIIIC, von Willebrand factor (vWF), vWF multimers: Quantitative abnormalities have been reported in some patients with primary thrombocytosis.
    • Some molecular abnormalities recently described specifically in association with myeloproliferative disorder may be helpful in estabilshing a diagnosis of primary thrombocytosis: JAK2 mutation V617F (in a study by Teofili et al, 7 of 18 patients had this mutation) and PRV1 (polycythemia rubra vera-1) RNA expression.⁵ None of 11 patients with familial essential thrombocytosis had these abnormalities. 
• Although the laboratory tests discussed above may be useful in select patients, they should not be performed routinely in pediatric patients with thrombocytosis.

Imaging Studies

• Doppler study of suspected blood vessels for thrombosis and ultrasonography of vessels may show evidence of thrombosis as a complication of thrombocytosis. These imaging studies should be used as clinically indicated.
• For persistent thrombocytosis of undetermined cause, chest radiography and ultrasonography of the abdomen may be helpful to uncover undetected sources of infection/inflammation or malignancy.

Histologic Findings

Bone marrow in reactive thrombocytosis show increased number of normal-appearing megakaryocytes. No other abnormalities are present. In primary thrombocytosis, bone marrow is usually hypercellular, with a markedly increased number of megakaryocytes. The megakaryocytes may appear in clusters. In some patients, bone marrow is described as normal.

In patients in transition to agnogenic myeloid metaplasia (AMM), bone marrow aspiration may be unsuccessful because of increased fibrosis. In these patients, bone-marrow biopsy would show increased marrow reticulin with reticulin staining. In AMM, a variety of morphologic abnormalities is found in the bone marrow, including hypolobulation and hyperlobulation of megakaryocytes. In children, primary thrombocytosis alone is extremely rare, and thrombocytosis as an initial abnormality of AMM is even rarer.

TREATMENT

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Medical Care

No treatment is necessary for reactive thrombocytosis. Rarely, in patients who have reactive thrombocytosis and a known risk factor for thrombosis, such as factor V Leiden mutation, the thrombotic risk may be increased. However, no information is currently available regarding the magnitude of the risk. Therefore, one should consider each case individually for prophylaxis of thrombosis. In vasculitis syndrome with thrombocytosis (in particular, in Kawasaki syndrome), treatment with aspirin is recommended (see Kawasaki Disease). In primary thrombocytosis, prophylactic use of antithrombotic agents has not been well delineated. In general, platelet-lowering agents have been recommended for high-risk patients (all adults) with an increased cardiovascular risk, have a previous history of thrombosis, or who are older than 60 years (see Medication).

In patients in whom primary thrombocytosis is strongly suspected, laboratory studies mentioned in the previous section and evaluation of family members may be needed to confirm the diagnosis. Morphologic and cytogenetic examination of bone-marrow cells and marrow reticulin stains should be repeated in patients with a changing hematologic picture (refer patients to a hematologist). Evolution of primary thrombocytosis to frank acute myeloblastic leukemia (AML), myelofibrosis/AMM, or myelodysplastic syndrome (MDS) has been documented in adults and represents a progression of disease. The prognosis after this progression is poor. However, successful allogeneic bone-marrow or stem-cell transplantation has been reported in patients who developed AML/MDS and/or myelofibrosis. Therefore, keep this modality in mind when treating primary thrombocytosis.

Consultations

A persistent increase in neutrophil counts with immature forms (eg, metamyelocytes, myelocytes), as persistent increase in basophils and eosinophils, and splenomegaly suggest a CML. Kastan et al described 2 children whose clinical findings and blood counts best fit ET but whose bone-marrow cytogenetic analyses showed the presence of the Philadelphia (Ph1) chromosome.¹⁰ Both of these patients presented with platelet counts in excess of 2000 X 10⁹/L.

A persistent increase in the hematocrit (with or without a change in the WBC count) with thrombocytosis suggests polycythemia vera. Image 1 shows suggested workup algorithm for thrombocytosis.

One should consult a hematologist if a workup for ET is needed. Older children with thrombocytosis with thrombosis (suspected or demonstrated) or a history of thrombosis, increased bleeding tendency despite thrombocytosis, or splenomegaly must promptly be referred to a hematologist.

Activity

No medical reason exists to limit or encourage the activity of a child with thrombocytosis. A child with a substantially enlarged spleen (usually caused by essential or familial thrombocythemia) requires necessary precautions regarding their activity to prevent splenic rupture.

MEDICATION

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In a child with reactive thrombocytosis, drug therapy is not required. Thrombohemorrhagic complications are exceedingly rare. To date, no studies have demonstrated a benefit of prophylactic use of antithrombotic or antiplatelet agents. In general, use of these drugs is not warranted. One exception in which antithrombotic or antiplatelet drugs should be used is for Kawasaki syndrome. A clear guideline for aspirin use with this syndrome has been established (see Kawasaki Disease).

Symptomatic patients with ET should receive treatment to lower their platelet count. For pediatric use, anagrelide or hydroxyurea is recommended. In a study by Harrison et al, adult patients (median age, about 60 y) were randomly assigned to receive low-dose aspirin plus hydroxyurea or anagrelide.¹¹ Significantly more patients in the anagrelide arm than in the hydroxyurea arm reached the study endpoint; this result indicated that the patients did not die or develop thrombotic or hemorrhagic complications. The authors concluded that hydroxyurea plus aspirin was more effective than anagrelide plus aspirin in preventing complications in adults with ET.

Radioactive phosphorus should not be used for young patients because of its carcinogenic potential.

Use of pharmacologic agents to prevent thrombotic complications in primary or ET is controversial, even in the internal medicine literature, because no laboratory studies offer predictive value in terms of the risk of thrombosis or hemorrhage. Tefferi et al recommend their use in only patients older than 60 years, individuals with a history of thrombosis, or persons with cardiovascular risk factors, virtually eliminating pediatric patients.¹²

Patients who do develop a thrombosis should be treated appropriately (see Thromboembolism).

Drug Category: Agents to reduce platelet count and reduce platelet function

These agents are used to treat thrombotic complications and to prevent thrombosis (in some cases) in patients with an established diagnosis of ET.

Drug Category: Cytoreductive agents

These agents should be used only in patients with thrombotic complications (or in some in need of prevention of thrombosis) with an established diagnosis of primary thrombocythemia.

FOLLOW-UP

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Complications

• In primary thrombocytosis, thrombosis and/or hemorrhage may occur.
• In reactive thrombocytosis, an excessively high platelet count combined with other risk factor (eg, vasculitis) or a separate thrombophilic factor (eg, heterozygous protein C deficiency) may increase the risk of thrombosis and/or hemorrhage. However, the risk of this type of complications can be regarded as being extremely small.

Prognosis

• Reactive or secondary thrombocytosis is self-limited and transient. However, in certain situations, it may persist. These situations include postsplenectomy thrombocytosis, thrombocytosis associated with chronic hemolytic disease, and thrombocytosis associated with vasculitis and/or connective tissue disorder and/or chronic inflammation.
• The prognosis of children with ET appears no different from that of adults. Adult patients have near-normal life expectancy because of the low rate of leukemic conversion. However, no child has been monitored long enough for that statement to be applicable to children. The major morbidity factor is the increased risk of thrombohemorrhagic complications.

Patient Education

• For reactive thrombocytosis, assuring the patient that the disease is self-limited and harmless is the only patient education required.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Bruises.

MISCELLANEOUS

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Medical/Legal Pitfalls

• No data demonstrate the benefit of antithrombotic prophylaxis in reactive thrombocytosis.
• • Sutor's 1995 literature review included only 2 pediatric patients with thrombotic complications (cerebral infarctions).⁴ Both patients' conditions were associated with iron-deficiency anemia; however, in these cases, no studies have been performed to exclude the possibility of other thrombophilic conditions.
  • A rare thrombotic or hemorrhagic complication resulting from thrombocytosis could be a medicolegal problem.
  • Because of the absence of studies documenting any benefit of prophylactic treatment and because of the extreme rarity of complications, it is preferable and logical not to treat the patient with clearly recognizable reactive thrombocytosis.


• If no etiologies are found for thrombocytosis, if the patient is beyond the age group for common reactive thrombocytosis (ie, >10 y), and if platelet count persists over 1 million/µL (particularly in the presence of enlarged spleen), referral to a hematologist is highly advisable. These patients are likely to have primary thrombocytosis, and prophylactic hydroxyurea or anagrelide is justified.

MULTIMEDIA

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Media file 1:  Algorithm for thrombocytosis workup and potential need for medication
	View Full Size Image
Media type:  Image

REFERENCES

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1. Vlacha V, Feketea G. Thrombocytosis in pediatric patients is associated with severe lower respiratory tract inflammation. Arch Med Res. Aug 2006;37(6):755-9. [Medline].
2. Dame C, Sutor AH. Primary and secondary thrombocytosis in childhood. Br J Haematol. Apr 2005;129(2):165-77. [Medline].
3. Dror Y, Zipursky A, Blanchette VS. Essential thrombocythemia in children. J Pediatr Hematol Oncol. Sep-Oct 1999;21(5):356-63. [Medline].
4. Sutor AH. Thrombocytosis in childhood. Semin Thromb Hemost. 1995;21(3):330-9. [Medline].
5. Teofili L, Giona F, Martini M, et al. Markers of myeloproliferative diseases in childhood polycythemia vera and essential thrombocythemia. J Clin Oncol. Mar 20 2007;25(9):1048-53. [Medline].
6. Eyster ME, Saletan SL, Rabellino EM, et al. Familial essential thrombocythemia. Am J Med. Mar 1986;80(3):497-502. [Medline].
7. Lundstrom U. Thrombocytosis in low birthweight infants: a physiological phenomenon in infancy. Arch Dis Child. Sep 1979;54(9):715-7. [Medline].
8. Matsubara K, Fukaya T, Nigami H, et al. Age-dependent changes in the incidence and etiology of childhood thrombocytosis. Acta Haematol. 2004;111(3):132-7. [Medline].
9. Messinezy M, Westwood N, Sawyer B, et al. Primary thrombocythaemia: a composite approach to diagnosis. Clin Lab Haematol. Jun 1994;16(2):139-48. [Medline].
10. Kastan MB, Zehnbauer BA, Leventhal BG, Corden BJ, Dover GJ. Philadelphia-chromosome positive essential thrombocythemia. Two cases in children. Am J Pediatr Hematol Oncol. 1989;11(4):433-6. [Medline].
11. Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood. Jan 15 1999;93(2):417-24. [Medline].
12. Tefferi A, Silverstein MN, Hoagland HC. Primary thrombocythemia. Semin Oncol. Aug 1995;22(4):334-40. [Medline].
13. Akan H, Guven N, Aydogdu I, Arat M, Beksac M, Dalva K. Thrombopoietic cytokines in patients with iron deficiency anemia with or without thrombocytosis. Acta Haematol. 2000;103(3):152-6. [Medline].
14. Buss DH, Cashell AW, O'Connor ML, Richards F 2nd, Case LD. Occurrence, etiology, and clinical significance of extreme thrombocytosis: a study of 280 cases. Am J Med. Mar 1994;96(3):247-53. [Medline].
15. Cazzola M, Skoda RC. Translational pathophysiology: a novel molecular mechanism of human disease. Blood. Jun 1 2000;95(11):3280-8. [Medline].
16. Ding J, Komatsu H, Wakita A, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood. Jun 1 2004;103(11):4198-200. [Medline].
17. Fernandez-Robles E, Vermylen C, Martiat P, Ninane J, Cornu G. Familial essential thrombocythemia. Pediatr Hematol Oncol. 1990;7(4):373-6. [Medline].
18. Fujiwara T, Harigae H, Kameoka J, et al. A case of familial thrombocytosis: possible role of altered thrombopoietin production. Am J Hematol. Aug 2004;76(4):395-7. [Medline].
19. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. Jan 15 1999;353(1):33-45. [Medline].
20. Hollen CW, Henthorn J, Koziol JA, Burstein SA. Elevated serum interleukin-6 levels in patients with reactive thrombocytosis. Br J Haematol. Oct 1991;79(2):286-90. [Medline].
21. Horikawa Y, Matsumura I, Hashimoto K, et al. Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood. Nov 15 1997;90(10):4031-8. [Medline].
22. Jurado M, Deeg H, Gooley T, et al. Haemopoietic stem cell transplantation for advanced polycythaemia vera or essential thrombocythaemia. Br J Haematol. Feb 2001;112(2):392-6. [Medline].
23. Kilpi T, Anttila M, Kallio MJ, Peltola H. Thrombocytosis and thrombocytopenia in childhood bacterial meningitis. Pediatr Infect Dis J. Jun 1992;11(6):456-60. [Medline].
24. Mitus AJ, Schafer AI. Thrombocytosis and thrombocythemia. Hematol Oncol Clin North Am. Feb 1990;4(1):157-78. [Medline].
25. Randi ML, Putti MC, Scapin M, et al. Pediatric patients with essential thrombocythemia are mostly polyclonal and V617FJAK2 negative. Blood. Nov 15 2006;108(10):3600-2. [Medline].
26. Uppenkamp M, Makarova E, Petrasch S, Brittinger G. Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis. Ann Hematol. Nov 1998;77(5):217-23. [Medline].
27. Vora AJ, Lilleyman JS. Secondary thrombocytosis. Arch Dis Child. Jan 1993;68(1):88-90. [Medline].
28. Yohannan MD, Higgy KE, al-Mashhadani SA, Santhosh-Kumar CR. Thrombocytosis. Etiologic analysis of 663 patients. Clin Pediatr (Phila). Jun 1994;33(6):340-3. [Medline].

Article Last Updated: Jun 29, 2007