Pediatric Thrombocytosis 

Updated: Oct 01, 2018
Author: Susumu Inoue, MD; Chief Editor: Hassan M Yaish, MD 

Overview

Practice Essentials

Thrombocytosis, an increased platelet count above the upper limit of normal (ULN) range, is common in infants and children. Unlike in adults, however, the overwhelming majority of pediatric thrombocytosis cases are reactive, ie, secondary and benign.

Common causes of reactive thrombocytosis include the following:

  • Bacterial, viral, or parasitic infections - Particularly common in infants during recovery phase of an infection
  • Inflammation - Eg, rheumatoid arthritis, inflammatory bowel disease, Kawasaki syndrome, vasculitis, collagen vascular disease
  • Postsurgical, trauma, burns
  • Blood loss, hemolytic anemia, iron deficiency anemia
  • Asplenia or hyposplenia
  • Congenital or idiopathic nephrotic syndrome

If reactive thrombocytosis is obvious, no further diagnosis or specific treatment is necessary.

Primary thrombocytosis may be suspected if any or a combination of the following features is present and if no obvious cause of reactive thrombocytosis exists:

  • Enlarged liver and/or spleen
  • History of thrombosis or bleeding
  • Family history of thrombocytosis
  • Persistent (>3 mo) thrombocytosis

In addition, primary thrombocytosis due to myeloproliferative disorder is commonly associated with anemia and leukocytosis. Children suspected of having primary thrombocytosis require a referral to a hematologist to establish diagnosis and for proper management.

Background

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, essential thrombocythemia, or primary thrombocythemia) 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 [ET]), myelofibrosis with myeloid metaplasia, polycythemia vera, chronic myelocytic leukemia (CML) or, in rare cases, acute myelocytic leukemia.[1]

Hematopoiesis in patients with ET is monoclonal and is caused by JAK2V617Fmutation, thrombopoietin receptor gene (MPL) mutation, calreticulin gene (CALR) mutation, or other rare mutations. JAK2 mutation and CALR mutation are mutually exclusive, and there is a distinct phenotypic difference between these two.[2, 3, 4] . There have been other mutations reported, including ASXL1 and MPLY252H.[1] Though CML presenting with extreme thrombocytosis is rare, a boy aged 7 years was reported to have presented with moderate leukocytosis and a platelet count of 2.8 million/μL, with BCR-ABL mutations.[5]

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

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 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. 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.[6]

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).[7]

A study from Taiwan on pediatric reactive 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.[8]

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 TPO. In some cases, an increased number of bone marrow megakaryocytes is observed.[9, 10]

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 (ESA). 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 ESA causes thrombocytosis, iron deficiency itself was an additional factor to contribute to thrombocytosis.[11]

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 median age of onset at age 35 years, although the youngest child described was aged 1 year.[9] 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,[12] whereas an extra dose of PACAP genes in partial trisomy 18p patients has been seen to result in prolongation of bleeding time and mild thrombocytopenia.[13]

Sporadic (nonfamilial) primary thrombocytosis is usually a clonal disorder, although nonclonal essential thrombocythemia has also been well documented. An MPL polymorphism gene, MPLBaltimore, belongs to this polyclonal thrombocytosis (see below). The most common diagnosis in the pediatric age group is chronic myelogenous leukemia (CML). Polycythemia vera and myelofibrosis (MF) with myeloid metaplasia are other, rare diagnoses associated with primary thrombocytosis.

In primary thrombocytosis, primary and secondary hypercoagulable states frequently lead to thrombotic episodes and to a hemorrhagic tendency. In about 30% of pediatric cases, JAK2V617Fmutation has been documented. More recently another mutation involving the CALR gene was independently documented by 2 groups of investigators in patients with myeloproliferative disorders. Though JAK2V617mutation has been found in both polycythemia vera and essential thrombocytosis patients, CALR mutation was found only in patients with essential thrombocytosis.[2, 3, 4]

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.[14]

At least two 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 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 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.[11]

    • Abe et al reported an amino acid substitution of Trp(508) to Ser(508) in the intracellular domain of MPL.[15]

    • Ding et al reported 8 members of a Japanese family with a mutation in the transmembrane domain of MPL.[16]

    • An MPL gene polymorphism, designated as MPOBaltimore(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 MPLBalitmore was found to be 7% in African American population.[17] Thus, some African Americans who were previously diagnosed to have essential thrombocytosis without detectable JAK2 or CALR mutation may have this polymorphism.

  • 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.[18]

    • 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.[19, 20]

    • Graziano et al reported on 3 members in a family who had a TPO mutation (G185T) and associated limb defects.[21]

    • 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).[17]

    • 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.[22]

    • Robins and Niazi reported a mother and child with elevated TPO levels. The mutation was not studied. The child had a limb defect.[23]

    • 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.[24, 25] Thrombosis and hemorrhage were noted.

    • Stockklausner et al in Germany reported 2 families due to TPO gene c. 13+1 G/C mutation in the splice donor of intron 3. Two members of 1 family had upper limb defects.[26] One of the family was previously described by Wiestner et al as above.

  • Mutation of other genes

    • Homozygous mutations of interleukin 1 receptor antagonist (IL1RN) reported by Aksentijevich et al[27] and homozygous mutations of interleukin 36 receptor antagonist (IL36RN) reported by Rossi-Semerano L et al[28] caused significant thrombocytosis and leukocytosis in affected individuals. Treatment with anakinra normalized these counts.

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

  • Neither MPL gene nor TPO gene mutation found or studied

    • Stuhrmann et al reported on 4 Arab siblings with familial thrombocytosis.[14]

    • Tecuceanu et al reported on an Israeli-Jewish family with mild thrombocytosis (highest platelet count was 506 X 109/L).[29]

    • 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 loss of function mutation of pericentrin (PCNT) gene.[30]

    • A girl aged 9 years with hypereosinophilic syndrome had, 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.[31]

Causes of secondary noninfectious thrombocytosis reported in the literature are listed below:

  • Caffey disease[32]

  • Granulocyte-colony stimulating factor treatment in neonates[33]

  • Hepatocellular carcinoma[34]

  • Low–molecular-weight heparin[35]

  • Malignant ovarian tumors[36]

  • Trauma[37]

  • Toxocariasis - Two children who had extreme thrombocytosis along with hypereosinophilia were reported to mimic myeloproliferative disorder, due to toxocariasis; antihelmintic therapy caused the hematologic abnormalities to subside[38]

Acquired ET in children is similar to that found in adults, although JAK2V617Fmutation (whose role in myeloproliferation is clear) and PRV-1 RNA positivity are seen less frequently in pediatric patients than in adults. CALR mutation has also been described, but the incidence of this somatic gene mutation in children has not been published. CALR mutation causes features of ET without causing other clinical features characteristic of 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 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 hyposplenic or asplenic children. Assessments of the children for a splenic deficit, using technetium-99m sulphur 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.[39] Thus, it may be advisable to perform this imaging study in a selected group of patients who exhibit prolonged thrombocytosis without any obvious cause.

Epidemiology

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.[40] 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 thrombocytosis, but not the incidence of essential thrombocytosis.[30]

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 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.[32]

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. A Taiwanese study done at a general hospital indicated the incidence of reactive thrombocytosis to be 6.3% of all hospitalized children (birth to age 18 y).[33]

International

See above. The incidence of essential thrombocytosis is estimated to range from 1-4 cases per 10 million people younger than 20 years.[41]

Mortality/Morbidity

A study by Szuber et al of 361 patients aged 40 years or younger with myeloproliferative neoplasms found that those with essential thrombocythemia (ET) had a median survival period of 35 years, compared with 37 years for polycythemia vera and 20 years for primary myelofibrosis.[42]

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, and cardiac complications are the major causes of morbidity and mortality.

In patients with primary 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 primary thrombocytosis of children are not known.

On the basis of experiences in young adults with primary thrombocytosis, these complications seem to occur less often in children than in adults.[43] 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.[34] 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.[40] These figures are similar to those of adults. Bleeding mainly involves the mucous membranes and skin (eg, 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.[44, 43]

Race

Essential thrombocytosis has no reported racial predisposition.

Sex

Although previously, no sex difference was reported in the frequency of essential or reactive thrombocytosis, the aforementioned study by Szuber et al found a female preponderance in ET in patients aged 40 years or younger.[42]

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.[36]

Matsubara et al reported an age-related shift in mean platelet counts.[37] 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.[45] According to this article, the 95th percentile line exceeds 700,000 at 35-49 postnatal days in this cohort of patients.

 

Presentation

History

The history of patients with thrombocytosis may include the following:

  • Reactive thrombocytosis

    • The history is that of a preceding illness (eg, pneumonia, upper respiratory tract infection, urinary tract infection, iron-deficiency anemia, surgery, hemorrhage, burn, and many others) that triggers thrombocytosis. In some instances, no clear etiology is found; in these cases, investigative efforts may be necessary to exclude asymptomatic asplenia/hyposplenia, primary thrombocytosis, and hereditary thrombocytosis.

    • In general, symptoms (thrombotic or hemorrhagic) caused by a high platelet count are absent in virtually all cases of reactive thrombocytosis. However, there are exceptions as described below.

    • In a review article, Sutor reported two children with severe iron-deficiency anemia and platelet counts of more than 1 million/μL who had cerebral infarction.[32] Other comorbid factors, such as vasculitis or hereditary thrombophilia, could not be excluded. An additional four cases of stroke were reported with iron-deficiency anemia, but only one of the four had thrombocytosis.[46] Thus, it is unclear to what degree thrombocytosis contributes to these rare vascular events.

    • Though extremely rare, children with congenital nephrotic syndrome have a high frequency of thrombosis due to persistent thrombocytosis, activated states of platelets, elevated level of coagulation factors such as von Willebrand factor and factors V and VIII, and a  reduced level of antithrombotic factors such as antithrombin, protein C, and protein S.[12]

  • Essential (primary) thrombocytosis (ET)

    • The history is that of mucocutaneous bleeding, such as GI, epistaxis, or postsurgical bleeding, and excessive bruising. Though rare, children also develop hemorrhagic and/or thrombotic complications, although the frequencies are unknown. Ten of 36 children that were reviewed by Dror et al had bleeding or thrombotic episodes before the diagnosis was established.[30]

    • Headache is the most 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. High levels of TPO assay in multiple family members indicate TPO mutation.

Physical

Physical findings may include the following:

  • 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. A thrombotic event may be the presenting symptom of ET.

    • Classic erythromelalgia (throbbing, aching burning of palms and soles) associated with ET and polycythemia rubra vera has not been described in children.

Causes

Causes are as follows:

  • Reactive (secondary) thrombocytosis

    • Infection - Meningitis, upper and lower respiratory tract infections, septic arthritis, osteomyelitis, urinary tract infection, gastroenteritis, sepsis, severe dermatitis, toxocariasis, HIV infection

    • Chronic inflammations and vasculitis - Rheumatoid arthritis, Kawasaki syndrome, Henoch-Schönlein purpura, Caffey disease, TNF (tumor necrosis factor) receptor–associated periodic (TRAP) syndrome, inflammatory bowel disease, autoimmune disease, collagen vascular disease

    • Hemorrhage, iron-deficiency anemia

    • Tissue damage - Postsurgical, burns, trauma, fracture[47]

    • Rebound thrombocytosis - cancer chemotherapy, recovery phase of immune thrombocytopenic purpura (ITP)

    • Postsplenectomy - ITP, splenectomy for hereditary spherocytosis, traumatic asplenia, post splenic artery embolization, autosplenectomy in sickle cell disease

    • Congenital asplenia, or hyposplenia associated with immunodeficiency syndrome

    • Hemolytic anemia -Sickle cell disease, thalassemia, and other hemolytic anemia

    • Renal disorders -Nephrotic syndrome, nephritis

    • Malignancy - Soft tissue sarcoma, osteosarcoma, hepatoblastoma, hepatocellular carcinoma, malignant ovarian tumor[48]

    • Low birth weight/preterm infants

    • Miscellaneous causes - Use of low molecular–weight heparin, granulocyte-colony stimulating factor treatment in neonates, familial urticaria pigmentosa

    • PACAP deficiency

  • 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 essential thrombocytosis - MPL or TPO gene mutation may be present; blood TPO assay may be helpful (high); this includes K39N substitution of MPL gene, MPLBaltimore (polymorphism is limited to African American population)

    • Essential thrombocytosis - JAK2V617Fmutation or CALR gene mutation may be present; the frequency of JAK2V617F is lower in children (11-50%) than in adults (>50%); frequency of CALR mutation in children is not known; JAK2V617I mutation somatic cells described in one family; MPL gene mutations

 

DDx

Diagnostic Considerations

In pediatric patients with suspected secondary thrombocytosis (eg, iron deficiency anemia), if the patient has a thrombotic episode, other etiologies for thrombosis need to be considered (eg, hereditary thrombophilic disorder, antiphospholipid syndrome, nephrotic syndrome) because thrombosis as a complication of reactive thrombocytosis is extremely rare in children.

Reactive thrombocytosis is always temporary. If thrombocytosis persists long after the primary cause subsides or if it persists longer than 3 months, consider primary thrombocytosis, such as myeloproliferative disorder, asymptomatic hyposplenia or asplenia, or TPO or MPL mutation or polymorphism.

Differential Diagnoses

 

Workup

Approach Considerations

No extensive diagnostic workup is needed if the primary causes of reactive thrombocytosis are apparent. Serial blood counts often reveal the temporary and secondary nature of thrombocytosis. Indeed, reactive thrombocytosis is so common in children that the platelet count should be serially followed for at least 6 weeks to confirm the persistence of thrombocytosis before primary thrombocytosis is suspected, unless hemorrhagic or thrombotic complication is present or the history or family history is positive for thrombocytosis.

If primary thrombocytosis is suspected because of the presence of previously described features, the diagnostic algorithm below may be followed according to the recommendations published in a review article[1] :

  • If a platelet count >450,000/μL persists longer than 6 weeks, then obtain (1) a detailed family history and blood counts on each family member; (2) genetic testing for BCR-ABL, JAK2V617F, CALR, and MPLW515L; and (3) a bone marrow biopsy
  • If the bone marrow shows hyperproliferation of megakaryocytes and any of the above genetic testing is positive, the patient most likely has myeloproliferative disorder, including ET
  • If the above genetic testing is negative but the bone marrow shows megakaryocyte hyperproliferation or the family history is positive, do additional genetic testing for an alternate TPO or MPL mutation

Laboratory Studies

Laboratory studies are used to identify whether the thrombocytosis is primary or reactive. An algorithm for thrombocytosis workup and the potential need for medication is shown in the image below.

Algorithm for thrombocytosis workup and potential Algorithm for thrombocytosis workup and potential need for medication.

See the list below:

  • 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. 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.

  • Reactive thrombocytosis is a temporary condition, although it may last for several months. Thus, sequential platelet counts are important. If thrombocytosis does not subside, and if no primary cause is obvious, then work-up for essential thrombocytosis is in order. Obtaining platelet counts in all family members is important.

  • See Myeloproliferative Disease for recommended laboratory studies when primary thrombocytosis is suspected.

  • The Polycythemia Vera Study Group established the following criteria to diagnose essential thrombocytosis (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 or absence of bcr-abl rearrangement

    • 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

    • 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). If CML is a consideration, fluorescent in situ hybridization (FISH) analysis of bone marrow cells for bcr-abl is indicated.

    • JAK2, or CALR mutation is present in a majority of adult patients with essential thrombocytosis, but not in patients with reactive thrombocytosis. Therefore, this test should be done if essential thrombocytosis is a likely diagnosis. If the patient is an African American with thrombocytosis without any other features, then a genetic test for MPLBaltimore is indicated.

    • 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-wave 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 non-familial 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 interleukin (IL)-6 at least at the onset of the thrombocytosis-triggering event. In the familial form of ET, extremely elevated TPO indicates TPO mutation. In one study, platelet membrane expression of the c-mpl receptor in patients with primary thrombocythemia was markedly reduced compared with platelets from control subjects (see Pathophysiology).

    • 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.

  • Although the laboratory tests discussed above may be useful in select patients, they should not be routinely performed 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, technetium-99m sulphur colloid scintigraphy may be useful for detecting asymptomatic hyposplenia. In this instance, it is important to obtain the ratio of the splenic isotope uptake relative to the liver uptake.[39] An ultrasonography of the abdomen may be helpful to uncover undetected sources of infection/inflammation, malignancy, or absence of spleen.

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, various 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

Medical Care

Normally, 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 adult patients, ie, those with an increased cardiovascular risk or a previous history of thrombosis or who are older than 60 years (see Medication). Indications for thrombosis prophylaxis are not firmly established for children; the use of antithrombotics and anticoagulants should be individualized, weighing the risks and benefits.

In adult patients with posttrauma thrombocytosis (platelet count >1 million), treatment with aspirin showed no effect in the rate of mortality, complications, and length of ICU stay. However, these results are from a retrospective, nonrandomized study; thus, they do not answer whether aspirin is useful in this group of patients. Anticoagulation to prevent thrombosis with heparin or low–molecular-weight heparin is the standard of care for these adult patients, unless there are bleeding problems.

In patients in whom primary thrombocytosis is strongly suspected, laboratory studies mentioned in the previous section and evaluation of family members are 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/agnogenic myeloid metaplasia (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. More detailed discussion of pediatric primary thrombocytosis is found in an article by Kucine et al.[1]

Consultations

A persistent increase in neutrophil counts with immature forms (eg, metamyelocytes, myelocytes), persistent increase in basophils and eosinophils, and splenomegaly suggest a chronic myelocytic leukemia (CML). Kastan et al described two children whose clinical findings and blood counts best fit essential thrombocytosis (ET) but whose bone-marrow cytogenetic analyses showed the presence of the Philadelphia (Ph1) chromosome. Both of these patients presented with platelet counts in excess of 2 million/μL.[49] Another child with CML presented with the initial platelet count of 2.8 million/μL.[5]

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

Algorithm for thrombocytosis workup and potential Algorithm for thrombocytosis workup and potential need for medication.

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. Also, a family history of thrombocytosis requires consultation with a hematologist and geneticist because a genetic work-up is necessary.

Activity

No medical reason warrants the limitation or encouragement of activity in 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

Medication Summary

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 essential thrombocytosis (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.[50] Significantly more patients in the anagrelide arm than in the hydroxyurea arm reached the study endpoint. 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.[46]

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

Agents to reduce platelet count and reduce platelet function

Class Summary

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

Anagrelide (Agrylin)

Specifically lowers platelet count, presumably by reducing megakaryocyte size and ploidy. Not FDA approved for use in patients < 16 y, but a small number of pediatric patients have been treated without significant adverse effects. Long-term adverse effects totally unknown; therefore, clearly positive benefit-risk ratio must be shown before administering drug to any child.

Cytoreductive agents

Class Summary

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.

Hydroxyurea (Hydrea)

Inhibits DNA synthesis (RNA reductase inhibitor), reducing all 3 blood cell counts.

 

Follow-up

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 essential thrombocytosis (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 eMedicineHealth's Skin Conditions and Beauty Center. Also, see eMedicineHealth's patient education article Bruises.