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.