Primary thrombocytosis in children

Abstract

Myeloproliferative neoplasms are uncommon disorders in children, for which we have limited understanding of the pathogenesis and optimal management. JAK2 and MPL mutations, while common drivers of myeloproliferative neoplasms in adult patients, are not clearly linked to pediatric disease. Management and clinical outcomes in adults have been well delineated with defined recommendations for risk stratification and treatment. This is not the case for pediatric patients, for whom there is neither a standard approach to workup nor any consensus regarding management. This review will discuss thrombocytosis in children, including causes of thrombocytosis in children, the limited knowledge we have regarding pediatric primary thrombocytosis, and our thoughts on potential risk stratification and management, and future questions to be answered by laboratory research and collaborative clinical study.

Figure 1.

Diagnostic algorithm for persistent elevated platelets. Figure 1 shows our groups’ proposed diagnostic algorithm for approaching patients with elevated platelets. Evaluation for secondary causes, such as iron deficiency or inflammatory or infectious disorders is conducted. Iron deficiency and other underlying causes are treated. If no secondary cause is found, or treatment of the underlying disorder does not remedy the platelet count, further evaluation is done to look for signs of essential thrombocytosis. Bone marrow evaluation is recommended at this point. Also, genetic studies are recommended, and if there is clinical suspicion then BCR-ABL testing should be done. If it is not tested for, or if it is negative, testing for JAK2V617F or MPLW5151K/L is done. Positive JAK or MPL testing, and/or diagnostic bone marrow findings, contribute to the diagnosis of an MPN. Specific criteria for ET (or if needed, PV or PMF) are evaluated to identify the correct MPN. Concurrently, a detailed family history should be obtained to evaluate the possibility of hereditary thrombocytosis. Testing for alternative THPO or MPL mutations is recommended in the setting of presumed hereditary thrombocytosis. Absence of the more common genetic mutation does not rule out diagnosis of an MPN, and if no other cause is identified genetic testing for additional MPL or THPO mutations should be considered and patients should be monitored for the continued possibility of MPN.

Figure 2.

Proposed treatment stratification for pediatric ET showing details of our group’s proposed treatment stratification for children with ET. Asymptomatic patients are observed with monitoring of blood counts. Patients with lower-risk symptoms such as organomegaly, erythromelalgia, or headache, or those with additional cardiovascular or thrombophilia risk factors (such as elevated cholesterol or Factor V Leiden mutation) are treated with aspirin and are monitored for change in symptoms. High-risk patients, including those with thrombosis or severe bleeding, those who failed aspirin therapy, or those who have persistent extreme thrombocytosis, are treated with cytoreductive therapy. Our current first line is hydroxyurea, followed by Interferon-alpha or anagrelide in certain patients. Ruxolitinib is not currently first-line therapy but is being studied in clinical trial for children with MPN and targeted inhibitors may some day become an important component of therapy for children with MPN.