Thrombocythemia 3
A number sign (#) is used with this entry because thrombocythemia-3 (THCYT3) is caused by heterozygous germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p24.
DescriptionThrombocythemia-3 is an autosomal dominant hematologic disorder characterized by increased platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic episodes, such as cerebrovascular events or myocardial infarction (summary by Mead et al., 2012).
For a discussion of genetic heterogeneity of thrombocythemia, see THCYT1 (187950).
Clinical FeaturesMead et al. (2012) reported a 3-generation family with autosomal dominant inheritance of thrombocythemia. The proband presented at age 53 years with an ischemic cerebrovascular event associated with long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5 additional family members with thrombocytosis, including 1 with a myocardial infarction at age 46 and another with a myocardial infarction at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow biopsy showed megakaryocyte hyperplasia without fibrosis. In addition, none of the patients had splenomegaly or evidence of leukemic transformation.
InheritanceThe transmission pattern of thrombocythemia in the family reported by Mead et al. (2012) was consistent with autosomal dominant inheritance.
Molecular GeneticsGermline Mutation in the JAK2 Gene
In affected members of a family with thrombocythemia, Mead et al. (2012) identified a germline heterozygous gain-of-function mutation in the JAK2 gene (V617I; 147796.0004). Examination of peripheral blood cells showed normal baseline STAT3 (102582) activity and lack of cytokine-independent colony formation. However, after stimulation with granulocyte colony-stimulating factor (GCSF; 138970), V617I-containing CD33+ myeloid and CD34+ stem cells showed a marked increase in STAT3 levels, particularly in response to low levels of GCSF, suggesting that the mutation causes limited constitutive activation with a reduced threshold for cytokine-induced activation.
Somatic Mutation in the JAK2 Gene
Baxter et al. (2005) and Kralovics et al. (2005) found that 57% (29 of 51) and 23% (21 of 93) of patients with essential thrombocytopenia, respectively, carried a somatic mutation in the JAK2 gene (V617F; 147796.0001).
In a 45-year-old man with no cardiovascular risk factors who presented in cardiogenic shock and was found to have coronary occlusion, myocardial infarction, and multiple myocardial microthrombi, Lata et al. (2010) identified at least 1 mutated V617F JAK2 allele on a peripheral blood smear. The patient, who had a platelet count of 529,000 per cubic millimeter, died in irreversible asystole after multiple percutaneous transluminal coronary angioplasties, stenting, and intracoronary fibrinolysis. Considering this to represent a fulminant initial presentation of occult essential thrombocythemia, Lata et al. (2010) stated that screening for the JAK2 mutation would likely be of value in selected patients with otherwise unexplained coronary ischemic events and mild thrombocytosis.