DISCUSSION
Reactive thrombocytosis is a common finding in SCD and may contribute to the pathogenesis of vaso-occlusion.5 Iron deficiency also results in thrombocytosis which improves with iron repletion.1,6 In SCD, iron deficiency may be difficult to detect, as serum ferritin may be elevated due to inflammation. Diagnosis of iron deficiency may be further complicated if microcytosis is obscured by hydroxyurea therapy. The absence of bone marrow iron stores was suggestive of iron deficiency in this patient, although it is not always predictive of iron deficiency.7
In cases of extreme thrombocytosis, etiologies other than reactive thrombocytosis must be considered, including myeloproliferative neoplasms (MPNs) such as essential thrombocythemia (ET), polycythemia vera, and primary myelofibrosis (PMF) as well as inherited thrombocytosis syndromes. The specific genetic testing selected for this patient served to assess for such conditions. The BCR/ABLtranslocation was tested to identify chronic myelogenous leukemia (CML). Among non-CML MPNs, the majority have the Janus kinase 2 gene (JAK2 ) V617F mutation, while JAK2 wild-type patients with ET and PMF commonly have mutations in exon 9 of the calreticulin geneCALR , and approximately 5% of adults carry MPL exon 10 mutations.8,9 Given that pediatric ET is rare and heterogenous, seldom involving the classic 3 MPN genes described above, we additionally explored less common genes associated with ET includingIDH1, IDH2 ,10 TET2 ,SRSF2 ,11 SF3B1 ,12CBL , CEBPA ,13 and AR encoding the androgen receptor. Mutations in the thrombopoietin gene (THPO ) are associated with autosomal dominant familial ET.14Serum TPO level is an important screening test for ET, particularly familial ET if markedly elevated above 1000 pg/mL.3TPO in this case was low normal, which suggests that inflammation was an unlikely driver for thrombocytosis. Though the genetic testing performed is not exhaustive and does not exclude other germline or somatic mutations in unidentified genes, our testing did exclude some of the most common reported genetic alterations causing extreme thrombocytosis. Patients with ET are prone for vascular complications, and SCD adds additional risk for stroke and thrombosis. Our patient did not experience thrombosis during his period of platelet count >2,000,000/µL, which may be partly attributed to the use of hydroxyurea and low-dose aspirin.
A consequence of severe thrombocytosis >1,000,000/µL may be acquired von Willebrand disease (VWD), as characterized by reduced VWF activity and loss of high MW VWF multimers, due to excessive binding of platelet GPIb receptors to circulating VWF.15,16 The VWF:GPIbM assay measures the binding of VWF with platelet GPIbα, providing a sensitive, functional assay of VWF activity that correlates with the VWF:RCoF assay but is not subject to falsely low levels seen in common polymorphisms of the ristocetin binding regions of VWF, such as the D1472H polymorphism.17,18 The VWF:GPIbM activity level in our patient during the time of extreme thrombocytosis remained above the level of probable bleeding risk identified by the National Heart Lung and Blood Institute Expert Panel report on VWD.19,20 The use of aspirin as an anti-platelet agent in our patient was carefully considered, weighing risks of thrombosis in SCD with risks of bleeding, and we recommend testing for acquired VWD in all patients with platelet count >1,000,000/µL.
Extreme thrombocytosis in a pediatric patient warrants special diagnostic evaluation, including testing for acquired VWD and VWF:GPIbM activity to assess for possible bleeding risk, radiographic evaluation for thrombosis, and evaluation for MPN which includes bone marrow biopsy and genetic testing. Pediatric patients with ET are less likely to have mutations in genes associated with adult ET (JAK2 , MPL , and CALR ), thus extended genetic testing should be considered. In this patient, hydroxyurea with aspirin and iron therapy were judiciously used balancing the associated risks of bleeding.