eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thrombocytosis: Differential Diagnoses & Workup

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

Differential Diagnoses

Asplenia
Kawasaki Disease

Workup

Laboratory 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.12 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
    • 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, the leukocyte alkaline phosphatase (LAP) level is extremely low, and the serum vitamin B-12 level is abnormally high. If CML is a consideration, fluorescent in situ hybridization (FISH) analysis of bone marrow cells for bcr-abl 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.
    • 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 establishing 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.6 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 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, 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, 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.

More on Thrombocytosis

Overview: Thrombocytosis
Differential Diagnoses & Workup: Thrombocytosis
Treatment & Medication: Thrombocytosis
Follow-up: Thrombocytosis
Multimedia: Thrombocytosis
References
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References

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  2. 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].

  3. Dame C, Sutor AH. Primary and secondary thrombocytosis in childhood. Br J Haematol. Apr 2005;129(2):165-77. [Medline].

  4. Dror Y, Zipursky A, Blanchette VS. Essential thrombocythemia in children. J Pediatr Hematol Oncol. Sep-Oct 1999;21(5):356-63. [Medline].

  5. Sutor AH. Thrombocytosis in childhood. Semin Thromb Hemost. 1995;21(3):330-9. [Medline].

  6. 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].

  7. Eyster ME, Saletan SL, Rabellino EM, et al. Familial essential thrombocythemia. Am J Med. Mar 1986;80(3):497-502. [Medline].

  8. Lundstrom U. Thrombocytosis in low birthweight infants: a physiological phenomenon in infancy. Arch Dis Child. Sep 1979;54(9):715-7. [Medline].

  9. 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].

  10. El-Moneim AA, Kratz CP, Boll S, Rister M, Pahl HL, Niemeyer CM. Essential versus reactive thrombocythemia in children: retrospective analyses of 12 cases. Pediatr Blood Cancer. Jul 2007;49(1):52-5. [Medline].

  11. Nakatani T, Imamura T, Ishida H, Wakaizumi K, Yamamoto T, Otabe O. Frequency and clinical features of the JAK2 V617F mutation in pediatric patients with sporadic essential thrombocythemia. Pediatr Blood Cancer. Dec 2008;51(6):802-5. [Medline].

  12. 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].

  13. [Guideline] Matthews JH, Smith CA, Herst J, et al. The management of malignant thrombocytosis in Philadelphia chromosome-negative myeloproliferative disease: guideline recommendations. Evidence-based series; no. 6-9. Jan 15 2008;Cancer Care Ontario (CCO):[Full Text].

  14. 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].

  15. 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].

  16. Tefferi A, Silverstein MN, Hoagland HC. Primary thrombocythemia. Semin Oncol. Aug 1995;22(4):334-40. [Medline].

  17. 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].

  18. 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].

  19. Cazzola M, Skoda RC. Translational pathophysiology: a novel molecular mechanism of human disease. Blood. Jun 1 2000;95(11):3280-8. [Medline].

  20. 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].

  21. Fernandez-Robles E, Vermylen C, Martiat P, Ninane J, Cornu G. Familial essential thrombocythemia. Pediatr Hematol Oncol. 1990;7(4):373-6. [Medline].

  22. 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].

  23. [Best Evidence] 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].

  24. 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].

  25. 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].

  26. 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].

  27. 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].

  28. Mitus AJ, Schafer AI. Thrombocytosis and thrombocythemia. Hematol Oncol Clin North Am. Feb 1990;4(1):157-78. [Medline].

  29. 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].

  30. 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].

  31. Vora AJ, Lilleyman JS. Secondary thrombocytosis. Arch Dis Child. Jan 1993;68(1):88-90. [Medline].

  32. 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].

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Further Reading

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Keywords

thrombocytosis, essential thrombocythemia, primary thrombocythemia, idiopathic thrombocythemia, primary thrombocytosis, secondary thrombocytosis, reactive thrombocytosis, myeloproliferative disorder, myelofibrosis with myeloid metaplasia, polycythemia vera, chronic myelocytic leukemia, acute myelocytic leukemia, platelet count, thrombopoietin, TPO, interleukin 6, IL-6, treatment, diagnosis, bacterial meningitis, pneumonia, hemolytic anemia, iron-deficiency anemia, chronic myelogenous leukemia, upper respiratory tract infections, lower respiratory tract infections, septic arthritis, osteomyelitis, urinary tract infection, gastroenteritis, sepsis, severe dermatitis, rheumatoid arthritis, Kawasaki disease, inflammatory bowel disease, sickle cell disease, thalassemia, nephrotic syndrome, nephritis, soft tissue sarcoma, osteosarcoma, treatment, diagnosis

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Contributor Information and Disclosures

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
Susumu Inoue, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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