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

Novel European Asiatic Clinical, Laboratory, Molecular and Pathobiological (2015-2020 CLMP) criteria for JAK2V617F trilinear polycythemia vera (PV), JAK2exon12 PV and JAK2V617F, CALR and MPL515 thrombocythemias: From Dameshek to Constantinescu-Vainchenker, Kralovics and Michiels

“…The JAK2 V617F dosage concept of Constantinescu & Vainchenkeris in line with the EEC bone marrow fi ndings in the UK study in Figures A and B [78]. A low level of JAK2 V617F kinase activity only activate the MPL (TPO) receptor and favors the ET phenotype in acquired heterozygous (Figure 2, Table 1), [8,27,60,76] and in dominant heterozygous JAK2 or TPO mutated ET (Figure 2, HET), [28]. A high level of JAK2 V617F activity in heterozygous/homozygous or homozygous mutated trilinear MPN is needed to activate the erythropoietin receptor (EPOR) and generate a PV-like phenotype (Figure 3), [8,21,31,32,57,59].…”

“…According to Dameshek,[2], Georgii, et al [11,12], and Michiels, et al [6,7,[14][15][16]21,[23][24][25][26][27][28][29][30][31][32][33][34][35][36] [5,16,27,31,32,43,44] (Figure 2, Table 3). Bone marrow histology of sequential stages in prodromal, overt and advanced PV is typically featured by increased cellularity due to increase erythrocytic megakaryocytic (EM), erythrocytic, megakaryocytic granulocytic (EMG), and predominant megakaryocytic granulcytic (MG) myeloproliferation (Figures 5,6 and Tables 4,5).…”

“…The JAK2 V617F allele burden in WHO-de ined advanced PV and post-PV myelo ibrosis(MF) patients ranged from 50% to 100% [63,67,[69][70][71]. According to the Vainchenker's "dosage" concept, heterozygosity for the JAK2 V617F mutation in acquired ET and autosomal dominant JAK2 or TPO mutated hereditary ET (HET) is enough to activate megakaryocytes to induce the ET clinical phenotype [8,21,27,28,36,60,72] (Figure 5, Table 1). Patients with dominant hereditary ET (HET) heterozygous for the JAK2 V617I and JAK2 R564Q germ line mutations have a clinical ET phenotype with normal values for Hb, Ht, erythrocytes, thrombopoietin (TPO), and erythropoietin (EPO) levels.…”

WHO Clinical Molecular and Pathological (WHO-CMP) Features of Congenital MPLS505N and the Acquired MPLW515l/K Mutated Essential Thrombocythemia and Myelofibrosis

“…Consequently, Vannucchi et al hypothesized that platelets from MPL W515L/K mutated ET patients present consitutively enhanced reactivity (hypersensitive) of the mutated platelets to explain the high incidence of aspirin responsive microvascular disturbances and major arterial thrombotic events in acquired MPL mutated ET [29]. The Dutch family with hereditary ET due to a gain of function mutation in the TPO gene had life-long increased plasma TPO levels and presented at young and adult age recurrent erythromelalgia complicated by acrocyanosis of a few toes followed by gangrene and amputation of toe, which typically responded to low dose aspirin but not by Coumadin [21] thereby preventing the occurrence of major thrombotic during lifelong follow-up.…”

“…This results in hyperproliferation of large mature megakaryocytes and platelet count complicated by plateletmediated microvascular complications. In a previous report we reviewed the presenting features and the natural history of two families with hereditary ET (HET) and secondary myelofibrosis caused by a gain of function mutation in the TPO gene [21]. In 2004 Ding et al described the first case of congenital ET in the pedigree of a Japanese family caused by a G to A nucleotide substitution at position 1073 in exon 10 of the MPL gene leading to the exchange os serine for asparaginase at position 505 (MPL S505N ) [22].…”