Autosomal Dominant Hereditary Essential Thrombocythemia due to a Gain of Function Mutation in the Thrombopoietin (TPO) and JAK2 Gene as the Cause of Congenital Aspirin-Responsive Sticky Platelet Syndrome: Personal Experiences and Review of the Literature

Abstract

Autosomal dominant hereditary Essential Thrombocythemia (ET) due to the gain of function mutation CG transversion in the splice donor of intron 3 in the TPO gene on chromosome 3q27 in a Dutch and Polish family is associated with marked increased TPO levels and Aspirin-responsive Sticky Platelet Syndrome (SPS). SPS is featured by typical clinical manifestations of aspirin responsive microvascular circulation disturbances including erythromelalgia and atypical transient ischemic attacks. Increase of large platelets in blood smears and large mature megakaryocytes with hyperploid nuclei in a normal cellular bone marrow were diagnostic for autosomal dominant hereditary ET (HET). The spectrum of platelet-mediated thrombophilia in HET is comparable to the aspirin responsive SPS in acquired JAK2 V617F positive ET. The affected members of the Dutch and Polish HET families showed no endogenous erythroid colony (EEC) formation. The first generation of the Dutch HET family, two females and one male had stable increased platelet counts, no features of PV, no splenomegaly during life-long follow-up. Three of four elderly family members in the Dutch HET family developed pancytopenia due to myelofibrosis at the age of 71 and 73 years in two, and evolution in acute myeloid leukemia at age 60 in one. These 3 HET patients were on long-term low dose aspirin to prevent SPS manifestations and not treated cytoreductive agents indicating that evolution of ET into myelofibrosis (MF) and leukemia belong to the natural history of TPO-induced HET. In the congenital HET caused by gain of function mutation in the TPO and the JAK2 gene ( JAK2 V617I and JAK2 R564Q ) the responses of mutated CD33 and CD34+ cells to TPO are increased, but the responses to EPO were normal thereby explaining why HET caused by heterozygous germline TPO and JAK2 mutations are associated with the biological characteristics of ET without PV features.