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Chapter 69 Essential Thrombocythemia 1115

TABLE Conditions Associated With Thrombocytosis autosomal dominant. The thrombopoietin receptor in the Dutch
69.4 family was normal, yet there was a G-to-C transversion in the splice
donor site of intron 3 of the thrombopoietin gene. All of the affected
Primary Thrombocytosis members of the Dutch family were shown to have elevated throm-
Malignancies bopoietin levels. In this family, a point mutation in the thrombopoi-
Essential thrombocythemia etin gene was believed to lead to systemic overproduction of
Polycythemia vera thrombopoietin, leading to a familial form of thrombocytosis. This
Primary myelofibrosis was the first example of a human disease caused by increased efficiency
Chronic myeloid leukemia of mRNA production. Actually, the translation of full-length throm-
Refractory anemia with ringed sideroblasts and thrombocytosis bopoietin is almost completely inhibited by the presence in the 5′
Chronic myelomonocytic leukemia untranslated region of seven AUG codons, which create seven
MDS/MPN overlap upstream open reading frames (uORFs). These uORFs are potent
Familial thrombocythemia (inherited mutations in thrombopoietin or inhibitors of translation, and mutations in this area cause thrombo-
thrombopoietin receptor) cytosis by eliminating the normal physiological inhibition of throm-
Secondary (Reactive) Thrombocytosis bopoietin mRNA translation. Additional families with thrombocytosis
Blood loss or iron deficiency caused by a similar genetic mechanism have been identified.
Infection Hereditary mutations of MPL can either result in loss of function
Inflammation and thrombocytopenia, or in gain of function and thrombocythemia,
Disseminated malignancy and are important models to analyze the mechanism of c-Mpl
Hemolysis activity. Familial thrombocytosis has been attributed to germ-line
Drug therapy mutations of MPL (MPL-S505N, MPL-K39N, and MPL-P106L).
Hyposplenism MPL-S505N was first described in a Japanese pedigree of familial
Cytokine administration thrombocytosis that is inherited in an autosomal dominant fashion.
Spurious Thrombocytosis This disorder has been attributed to a dominant-positive activating
Schistocytes mutation of the cellular receptor of MPL. Eight additional Italian
Cytoplasmic fragmentation of neoplastic cells families with thrombocytosis and MPL-S505N have been identified.
Cryoglobulinemia In these individuals hematopoiesis is polyclonal. Etheridge and
Bacteria coworkers recently described a novel, autosomal dominant germ-line
mutation that causes familial ET resulting from a single-nucleotide
MDS, Myelodysplastic syndrome; MPN, myeloproliferative neoplasm. substitution, generating the mutant kinase JAK2R564Q. Their data
indicate that this mutation leads to isolated thrombocytosis. Mild
thrombocytosis was observed as well as polyclonal hematopoiesis.
Furthermore, increased activation of JAK2 was confirmed in the
Clinical and Laboratory Features Helpful in platelets of JAK2R564Q-positive family members compared with
TABLE Distinguishing Essential Thrombocythemia From
69.5 Reactive Thrombocytosis a those without the mutation
A polymorphism of the thrombopoietin receptor (MPL Baltimore,
MPL-K39N) that is accompanied by thrombocytosis has also been
Feature ET RT
described. This germ-line polymorphism is caused by a single-
Chronic platelet increase + − nucleotide substitution that results in a lysine-to-asparagine (K39N)
Known causes of RT − + substitution in the ligand-binding domain of MPL. The polymor-
Thrombosis or hemorrhage + − phism occurs exclusively in African–Americans and appears to have
an autosomal dominant pattern of inheritance with incomplete
Splenomegaly + − penetrance because some heterozygotes have normal platelet counts
BM reticulin fibrosis + − while others have thrombocytosis. Approximately 7% of African–
Americans are heterozygous for MPLK39N. The mutation in the
BM megakaryocyte clusters + −
homozygous state is associated with extreme thrombocytosis with a
Abnormal cytogenetics + − reduced expression of platelet MPL, which has been proposed to
Increased acute phase reactants − + affect the receptor’s ability to bind thrombopoietin, resulting in its
Spontaneous colony formation b + − reduced clearance and increased stimulation of megakaryocytopoiesis.
MPL-P106L is another germ-line mutation associated with throm-
JAK2V617F mutation + − bocytosis that has been found in 3.3% of Arabs. It leads to severe
a Acute phase reactants include C-reactive protein and fibrinogen. thrombocytosis in homozygotes and occasionally to mild thrombo-
b Erythroid colonies. cytosis in heterozygotes. In the families described with this germ-line
BM, Bone marrow; ET, essential thrombocythemia; RT, reactive thrombocytosis. mutation, extreme thrombocytosis was associated with homozygosity
Modified from Tefferi A, Hoagland HC: Issues in the diagnosis and
management of primary thrombocythemia. Mayo Clin Proc 69:651, 1994. and the mode of inheritance is regarded as being autosomal recessive
with possible mild manifestations occurring in heterozygotes.
Subjects with familial forms of thrombocytosis are characteristically
diagnosed at earlier ages than patients with ET, and appear to have
is polyclonal. An abnormality of thrombopoietin production or of similar risks for thrombotic and hemorrhagic complications. These
the thrombopoietin receptor has been documented to be the basis disorders were initially considered to be associated with a benign
of these inherited disorders leading to thrombocytosis. Because the clinical course, but follow-up of such families for longer periods of
median age of diagnosis of patients with these familial forms of time has corrected this misperception. Overall, 23 members of a
thrombocytosis is 17 years, these disorders should be carefully con- Dutch and a Polish family with a form of thrombocytosis attributed
sidered in all JAK2V617F-, MPLW515L-, and MPL515K-negative to excessive thrombopoietin production were shown to have similar
children with multiple family members with thrombocytosis. thrombotic and hemorrhagic complications as individuals with ET.
Several different mutations have been reported in families in Also, these family members experienced vasomotor symptoms, includ-
which excessive thrombocytosis has been attributed to increased ing erythromelalgia and Raynaud phenomena, which responded to
8
thrombopoietin production. A Dutch family with 11 family members aspirin therapy but not hydroxyurea therapy. Furthermore, many of
and a Japanese family with eight family members were reported with these patients developed splenomegaly as well as BM histopathologic
a hereditary form of thrombocytosis that was inherited as an findings that resemble an MPN, including BM hypercellularity,