Platelets are acute-phase reactants; therefore, platelet counts increase in response to various stimuli, including systemic infections, inflammatory conditions, bleeding, and tumors.[1, 2] This phenomenon is called reactive or secondary thrombocytosis, and it 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.[3, 4]
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 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. Once the causal agent is managed, platelets counts typically normalize. An exception to this is patients postsplenectomy. For these patients, daily low dose aspirin may be considered to minimize the rare development of stroke or thrombosis, however studies to support this practice are still lacking [5] (see Treatment).
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.
Etiologic conditions associated with secondary thrombocytosis (reactive thrombocytosis) include the following:
Although COVID-19 most often causes thrombocytopenia, rare cases of thrombocytosis have been reported.[14, 15]
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.[16]
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%.[17] In a retrospective review of patients with iron deficiency anemia, the prevalence of reactive thrombocytosis was found to be 31%.[18]
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,[19] 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 1,000 × 109/L or greater), 82% had secondary thrombocytosis.[20]
No race predilection exists for secondary 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.[19, 21]
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],[22] ovarian cancer,[23] esophageal cancer,[24] colorectal cancer[25] ), 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.[22]
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.[23, 26]
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 precipitated the thrombocytosis.
Thrombotic, vascular, and bleeding complications are rare in secondary thrombocytosis; they are more suggestive of a clonal thrombocytosis.[10]
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.[17]
The laboratory workup in suspected 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:
Molecular testing is increasingly part of the initial workup for thrombocytosis, as it has relatively high specificity and sensitivity for diagnosis of myeloproliferative neoplasms. However, Almanaseer and colleagues point out that this testing is expensive, and may be postponed in many patients with clear secondary causes. These authors provide an algorithm for differentiating patients with probable secondary thrombocytosis, who could be observed for resolution of thrombocytosis once the likely cause is addressed, and patients who should undergo a full workup that includes molecular diagnostics.[27]
Essential thrombocythemia (primary thrombocytosis) is a diagnosis of exclusion. The World Health Organization (WHO) diagnostic criteria for essential thrombocythemia include 4 major and 1 minor criteria.[4, 28] Diagnosis requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion. The major criteria are as follows:
The minor criterion is the presence of a clonal marker or absence of evidence of reactive thrombocytosis (eg, infection, inflammation, iron deficiency anemia).
In contrast, British Society of Haematology (BSH) diagnostic criteria for essential thrombocythemia include bone marrow biopsy results as a minor criterion, and thus not essential for diagnosis. In patients with a platelet count ≥ 450 × 109/L, the BSH considers the presence of an acquired pathogenic mutation (JAK2, CALR, MPL) and the absence of any alternative myeloid malignancy as sufficient for diagnosis.[29]
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.[30]
In general, no treatment is indicated to directly reduce the platelet count.[31] However, for patients with platelet counts in excess of 1,000,000/μL, daily low-dose aspirin may be considered to minimize the rare development of stroke or thrombosis.[32] 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.[33]
In patients with secondary thrombocytosis (reactive thrombocytosis) for whom the causal condition has not been identified, maintain careful outpatient monitoring with physical examination and routine laboratory tests to exclude the development of an occult disorder (eg, malignancy).