Secondary Thrombocytosis

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Background

Platelets are acute-phase reactants; therefore, they increase in response to various stimuli, including systemic infections, inflammatory conditions, bleeding, and tumors.[1, 2, 3] This is called reactive or secondary thrombocytosis, which is a benign form of thrombocytosis. In contrast, clonal thrombocytosis (primary or essential thrombocytosis) is an unregulated abnormality of platelet production due to a clonal expansion of bone marrow progenitor cells.[4, 5]

Pathophysiology

Secondary thrombocytosis (reactive thrombocytosis) may be due to the overproduction of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-11, that occurs in chronic inflammatory, infective, and malignant states.[6, 7, 8, 9] The presence of elevated IL-1, IL-6, C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in individuals with these conditions suggests that these cytokines may be involved in secondary thrombocytosis.

Epidemiology

Secondary thrombocytosis (reactive thrombocytosis) is a relatively common condition. The incidence varies with the underlying condition. The incidence of postsplenectomy secondary thrombocytosis is approximately 75-82%.[10]

Overall, secondary thrombocytosis occurs in 3-13% of hospitalized children. However, in a Greek study of children 10 days to 8 years old who were hospitalized with viral pneumonia,[9] and an Italian study of children 1 to 24 months old who were hospitalized for community-acquired infections,[11] approximately half had thrombocytosis.

Secondary thrombocytosis is more common than primary thrombocytosis. In a series from a large US university hospital that included 280 patients with extreme thrombocytosis (platelet count of 1,000 x 109/L or greater), 82% had secondary thrombocytosis.[12]

Race-, Sex-, and Age-related Demographics

No race predilection exists for secondary thrombocytosis (reactive thrombocytosis). No sex predilection exists for secondary thrombocytosis, except that iron deficiency is more prevalent in females during childbearing years. No age predilection exists for secondary thrombocytosis.[11, 13]

History

No unique symptoms are suggestive of secondary thrombocytosis (reactive thrombocytosis). Most patients are asymptomatic and are identified on routine blood counts. Patients may have symptoms that are referable to the primary condition that may have precipitated the thrombocytosis.

Physical

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination. Physical findings reflect the underlying condition. In patients who have postsplenectomy thrombocytosis, evidence of a previous splenectomy should be eapparent on physical examination.[10]

Causes

Etiologic conditions associated with secondary thrombocytosis (reactive thrombocytosis) include the following:

Laboratory Studies

The laboratory workup in cases of secondary thrombocytosis (reactive thrombocytosis) includes the following:

If the clinical presentation does not clearly differentiate between primary (clonal) and secondary thrombocytosis, further tests may be indicated to exclude or confirm a diagnosis of disorders that cause clonal thrombocytosis, as follows:

Essential thrombocythemia is a diagnosis of exclusion that is based on the following numeric criteria (adapted from Hoffman R. Primary thrombocythemia. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. Philadelphia, Pa: Churchill Livingstone; 2000:1188-204).[4] Patients who meet criteria 1-5 and more than three of criteria 6-11 are considered to have essential thrombocytosis.

  1. Platelet count greater than 600,000/mm3 on two occasions, separated by a 1-month interval
  2. Absence of an identifiable cause of secondary thrombocytosis
  3. Normal red blood cell mass
  4. Absence of significant bone marrow fibrosis (ie, less than one third of the bone marrow)
  5. Absence of the Philadelphia chromosome (Ph) by karyotyping or absence of the bcr-abl fusion product
  6. Splenomegaly by physical examination or ultrasonography
  7. Bone marrow hypercellularity with megakaryocyte hyperplasia
  8. Presence of abnormal bone marrow hematopoietic progenitor cells as determined by the growth of endogenous erythroid cells and/or megakaryocyte colonies with increased sensitivity to interleukin-3 (IL-3)
  9. Normal levels of CRP and IL-6
  10. Absence of iron deficiency anemia, as documented by either a normal bone marrow–stainable iron or normal serum ferritin level
  11. In females, demonstration of clonal hematopoiesis by restriction fragment length polymorphism (RFLP) analysis of genes present on the X chromosome

Imaging Studies

Perform an ultrasound of the abdomen if the presence of splenomegaly is uncertain.

Medical Care

The primary treatment of secondary thrombocytosis (reactive thrombocytosis) should address the underlying cause of the thrombocytosis. For example, iron supplementation may normalize platelet counts in patients with thrombocytosis secondary to inflammatory bowel disease.[16] In general, no treatment is indicated to directly reduce the platelet count.[17]

For patients with platelet counts in excess of 1,000,000/μL, aspirin 65 mg daily may be considered to minimize the rare development of stroke or thrombosis.[18]  A case report describes effective use of plateletpheresis for treatment of an internal carotid artery thrombus resulting in a right middle cerebral artery stroke, in a patient with previously undiagnosed reactive thrombocytosis (platelet count of 1,014,000/μL) secondary to iron deficiency anemia.[19]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications in cases of secondary thrombocytosis (reactive thrombocytosis).

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Clinical Context:  Irreversibly acetylates (and inactivates) platelet and endothelial cell cyclooxygenase. A lower dose (65 mg) preferentially inhibits the platelet cyclooxygenase system (responsible for thromboxane A2 production) while preserving the beneficial effects of endothelial cell prostacyclin production due to difference in sensitivity to the inhibition by aspirin of cyclooxygenases at different sites and due to turnover of the endothelial cell cyclooxygenases.

Class Summary

Antiplatelet agents inhibit platelet function by inhibition of the platelet cyclooxygenase system.

Further Outpatient Care

In patients with secondary thrombocytosis (reactive thrombocytosis) for whom the causal comorbid condition has not been identified, maintain complete careful outpatient monitoring with physical examination and routine laboratory tests to exclude the development of an occult disorder (eg, malignancy).

Prognosis

In general, secondary thrombocytosis (reactive thrombocytosis) is a temporary laboratory anomaly that resolves when the primary causative condition is addressed.

The overall prognosis in patients with secondary thrombocytosis reflects that of the underlying associated condition. With certain disorders, however (eg, chronic obstructive pulmonary disease [COPD],[20] ovarian cancer[21] ), the presence of thrombocytosis indicates a worse prognosis than for patients with the disorder who do not have thrombocytosis. For example, Harrison et al reported that thrombocytosis was an independent risk factor for increased 1-year mortality after COPD exacerbations; however, patients with thrombocytosis who received antiplatelet therapy had significantly lower 1-year mortality.[20]

What is secondary thrombocytosis?What is the pathophysiology of secondary thrombocytosis?What is the prevalence of secondary thrombocytosis?What are the demographic predilections in the prevalence of secondary thrombocytosis?What are the signs and symptoms of secondary thrombocytosis?Which physical findings are characteristic of secondary thrombocytosis?What causes secondary thrombocytosis?Which conditions should be included in the differential diagnoses of secondary thrombocytosis?What are the differential diagnoses for Secondary Thrombocytosis?Which lab studies are performed in the workup of secondary thrombocytosis?Which lab studies are performed to differentiate between primary (clonal) and secondary thrombocytosis?What are the diagnostic criteria for essential thrombocytosis?What is the role of imaging studies in the workup of secondary thrombocytosis?What is focus of treatment for secondary thrombocytosis?What are the goals of drug treatment for secondary thrombocytosis?Which medications in the drug class Antiplatelet Agents are used in the treatment of Secondary Thrombocytosis?What is included in long-term monitoring of patients with secondary thrombocytosis?What is the prognosis of secondary thrombocytosis?

Author

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

Coauthor(s)

Devapiran Jaishankar, MBBS, Associate Professor, Division of Oncology, East Tennessee State University, James H Quillen College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP, Associate Professor of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam.

Acknowledgements

Wadie F Bahou, MD Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

References

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