Pediatric Thrombocytosis Workup

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

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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.

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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.

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