Secondary Thrombocytosis 

Updated: Dec 01, 2020
Author: Devapiran Jaishankar, MBBS; Chief Editor: Srikanth Nagalla, MD, MS, FACP 

Overview

Practice Essentials

Platelets are acute-phase reactants; therefore, platelet counts increase in response to various stimuli, including systemic infections, inflammatory conditions, bleeding, and tumors.[1, 2, 3] This phenomenon 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]  

Secondary thrombocytosis is usually identified on routine laboratory evaluation, as most patients are asymptomatic, However, patients may have symptoms related to the primary condition that may have precipitated the thrombocytosis (see Presentation). 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 (see Workup).

The primary treatment of secondary thrombocytosis should address the underlying cause of the thrombocytosis. 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 (see Treatment).

Pathophysiology

The pathophysiology of secondary thrombocytosis may vary, depending on the cause of thrombocytosis. Elevated platelet counts can be due to megakaryocyte proliferation; decreased platelet sequestration; or increased cytokine production, which stimulates platelet production.

Megakaryocyte proliferation can be seen with iron deficiency or blood loss. Decreased platelet sequestration occurs in conditions such as asplenia. Overproduction of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-11, occurs in chronic inflammatory, infective, and malignant states.[6, 7, 8, 9]  Elevated levels of IL-1, IL-6, C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) lead to megakaryocyte growth and increased production of platelets​ as part of secondary thrombocytosis.

Etiology

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

  • Infection and Inflammatory disorders
  • Postsplenectomy or hyposplenism
  • Malignancy
  • Trauma
  • Chronic inflammatory conditions [10]
  • Hemorrhage, blood loss, or both
  • Iron-deficiency anemia
  • Rebound thrombocytosis
  • Asplenia (anatomic or functional) [11]
  • Electric shock [12]
  • Idiopathic

A retrospective chart review of 305 patients with extreme thrombocytosis (platelet count of 1,000 × 109/L or greater) found that in appromixmately 80% of cases, the cause was multifactorial.  Secondary thrombocytosis due to surgical complications accounted for 54.1% of cases.  Among those cases, splenectomy (50.5%) and infections (44.9%) were the most common causes.[13]   

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%.[14]  In a retrospective review of patients with iron deficiency anemia, the prevalence of reactive thrombocytosis was found to be 31%.[15]

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,[16] 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 × 109/L or greater), 82% had secondary thrombocytosis.[17]

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.[16, 18]

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],[19]  ovarian cancer,[20]  esophageal cancer,[21]  colorectal cancer[22] ), the presence of thrombocytosis indicates a worse prognosis than for patients 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. Antiplatelet therapy was associated with significantly lower 1-year mortality in patients with secondary thrombocytosis and may have a protective role in acute exacerbations of COPD.[19]  

Similarly, in both early-stage and recurrent ovarian cancer, thrombocytosis is a poor prognostic sign. In recurrent ovarian cancer, an elevated platelet count at the time of secondary cytoreductive surgery was associated with suboptimal resection and poor overall survival, and thrombocytosis prior to chemotherapy was associated with lower response to chemotherapy and shorter survival.[20, 23]

 

Presentation

History

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

Thrombotic, vascular, and bleeding complications are rare in secondary thrombocytosis; they are more suggestive of a clonal thrombocytosis.[10]

Physical Examination

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination. Physical examination findings reflect the underlying condition. In patients who have postsplenectomy thrombocytosis, evidence of a previous splenectomy should be apparent on physical examination.[14]

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

Differential Diagnoses

 

Workup

Approach Considerations

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

  • Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
  • Cytogenetic analysis
  • Leukocyte alkaline phosphatase
  • Vitamin B12
  • Antinuclear antibody (ANA), rheumatoid factor (RF)
  • Iron studies (serum iron, total iron-binding capacity [TIBC], serum ferritin)
  • Peripheral blood smear review

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:

  • Bone marrow aspiration and biopsy

  • Cytogenetic studies: The presence of the Philadelphia chromosome (Ph) found in chronic myelogenous leukemia (CML) may also be identified using reverse transcriptase polymerase chain reaction (RT-PCR) to identify the bcr-abl fusion transcript or by using Southern blot analysis for identification of bcr-abl genomic rearrangements.

Essential thrombocythemia is a diagnosis of exclusion. The 2017 World Health Organization (WHO) diagnostic criteria for essential thrombocythemia include 4 major and 1 minor criteria.[4]  Diagnosis requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion. The major criteria are as follows::

  1. Platelet count ≥450 × 109/L
  2. Bone marrow biopsy showing megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with no significant increase in neutrophil granulopoiesis or erythropoiesis and, rarely, minor reticulin fibers.
  3. Not meeting WHO criteria for CML, polycythemia vera (PV), primary myelofibrosis, myelodysplastic syndromes, or other myeloid neoplasms.
  4. Presence of JAK2CALR or MPL mutation

The minor criterion is the presence of a clonal marker or absence of evidence of reactive thrombocytosis (eg, infection, inflammation, iron deficiency anemia).

 

 

 

 

Treatment

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.[24]

In general, no treatment is indicated to directly reduce the platelet count.[25]  However, 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.[26]  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.[27]

Long-Term Monitoring

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).

 

Medication

Medication Summary

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

Antiplatelet Agents

Class Summary

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

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

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.

 

Questions & Answers