Chapter 75: Hereditary and Reactive (Secondary) Thrombocytosis

INTRODUCTION

• The upper limit of a normal platelet count is usually between 350 × 10⁹/L and 450 × 10⁹/L depending on the clinical laboratory and specific method used.

• Table 75–1 presents the major causes of elevation of the platelet count above the normal limit.

FAMILIAL THROMBOCYTOSIS

• Most causes of familial thrombocytosis are due to inherited mutations in the gene for thrombopoietin (THPO), for its receptor (MPL), or for its signaling kinase (JAK2). Some pedigrees, but not all, are at risk for pathologic thrombosis.

• Several point mutations of MPL lead to chronic activation of the receptor, usually by altering the transmembrane domain of the receptor, although a polymorphism of the gene found in individuals of African-American heritage, MPL Baltimore, can lead to mild thrombocytosis when heterozygous but significant thrombocytosis when two alleles are present. Two other mutations lead to poor surface expression of the receptor, thereby reducing clearance of thrombopoietin (TPO) and, hence, thrombocytosis.

• Mutations in THPO lead to elevated TPO expression through an unusual route—altered translational efficiency of the primary transcript. Four mutations have been described in the 5′ untranslated region of the transcript that lead to alternate splicing or an alteration in TPO reading frame, each leading to far higher translational efficiency of the transcript and, hence, increased expression of TPO and thrombocytosis.

• Five germline mutations of JAK2 have been described associated with familial thrombocytosis, some but not all at position V617, the site of the most common acquired mutation of the kinase in patients with acquired myeloproliferative neoplasms. Like the acquired forms, the mutant JAK2 leads to hypersensitivity to TPO and expansion of megakaryopoiesis.

REACTIVE THROMBOCYTOSIS

• Reactive thrombocytosis may persist for prolonged periods and resolve only with resolution of the underlying disorder.

• Thrombocytosis after recovery from thrombocytopenia (“rebound”) usually peaks in 10 to 14 days.

• The platelet count after splenectomy may reach 1000 × 10⁹/L or more within the first week and usually returns to normal within about 2 months but may persist even for several years. Severe or persistent postsplenectomy thrombocytosis may be a result of persistent iron-deficiency anemia or unmasking of primary thrombocythemia.

• There is no convincing evidence that therapy to reduce the platelet count or interfere with platelet ...