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

Abstract

We analysed the clinical and hematological features in 41 patients of seven families, including 21 ET patients with a proven MPL S505N mutation and 20 relatives with thrombocythemia reported in the medical records. Out of the 41 MPL S505N mutated individuals 15 major thrombotic episodes in 14 members (34%) were reported as Budd-Chiari syndrome age 17 in 1, deep vein thrombosis leg age 41 in 1,ecclampsia and fetal in 1, stroke at ages 43, 72, 76 and 80 in 4 and myocardial infarction at ages between 31-81 years, median 52 years. Fourteen out of 21 well documented MPLS505N mutated ET patients had no splenomegaly and were free of major thrombosis during follow-up at ages between 2 and 76 years (mean 31 years). Eight MPL S505N mutated patients had myelofibrosis (MF) from grade MF1 in 5 to grade MF2 in 3 at ages between 28-80 years (mean 48 years), which was associated with mild to moderate splenomegaly (spleen length diameter 14.5 to 18 cm). Six anemic cases at hemoglobin levels between 10 and 11.9 g/dL had platelet counts between 317 and 963 × 10 9 /L. Among 15 family members 9 died from thrombosis in 3, hypocellular myelofibrosis (two of them at age 76 and 80 years) in 3, and cancer or undefined in 3 cases. The maximum life expectancy of MPL S505N family members with thrombocythemia was 50% at 80 years, and 90% at 80 years of non-affected family members without thrombocythemia. The clinical presentation in 30 ET patients with acquired MPL 505N mutation (9 males and 21 females, age 22-84 (mean 56 years of whom 18 had the W 515L and 12 the W 515K ) was featured by a high incidence of major arterial event in 23%, venous thrombosis in 10%, aspirin responsive microvessel disturbances in 60%, and major hemorrhage in 7%. The only abnormal laboratory finding in MPL mutated ET was increased platelet counts, 956+331 × 10 9 /L in all and slight splenomegaly in 5 (17%). Bone marrow histology from patients ET carrying the MPL 505N mutation consistently displayed a normocellular bone marrow with clustered small and large to giant megakaryocytes with hyperlobulated stag-horn nuclei and no features of polycythemia vera (PV) in blood and bone marrow.

<b><i>JAK2</i></b>^V617F, <b><i>CALR</i></b>, and <b><i>MPL</i></b> Mutations and Bone Marrow Histology in Patients with Essential Thrombocythaemia

“…MPL -mutated ET showed the lowest Hb level and the highest Plt count, in accordance with previous reports [7, 11, 12]. BM biopsies of MPL -mutated ET in our series showed the lowest marrow cellularity and the highest number of total, cloudy, and “staghorn” megakaryocytes, in line with a previous study [12], and also the greatest number of clusters of megakaryocytes and the lowest number of dysmorphic megakaryocytes. From a morphological point of view, MPL -mutated ET seems to be the group that mostly fits with the commonly accepted definition of ET [1].…”

“…These morphological features, in part, overlap those observed in pre-fibrotic/early primary MF, as defined in the revised 2017 WHO classification of haematological malignancies [10]. MPL -mutated ET showed the lowest Hb level and the highest Plt count, in accordance with previous reports [7, 11, 12]. BM biopsies of MPL -mutated ET in our series showed the lowest marrow cellularity and the highest number of total, cloudy, and “staghorn” megakaryocytes, in line with a previous study [12], and also the greatest number of clusters of megakaryocytes and the lowest number of dysmorphic megakaryocytes.…”

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

“…Liu et al [19] analysed in collaboration with the molecular genetic laboratory of Dr Skoda the large Polish and Dutch families with HET caused by the identical mutation C→G transversion in the splice donor [39]. There are at least four distinct variants of acquired ET in terms of molecular etiology: acquired clonal heterozygous JAK2 V617F positive ET, JAK2 wild type clonal ET carrying one of the MPL 515 or (CALR) mutations [35,39].…”

“…There are at least four distinct variants of acquired ET in terms of molecular etiology: acquired clonal heterozygous JAK2 V617F positive ET, JAK2 wild type clonal ET carrying one of the MPL 515 or (CALR) mutations [35,39]. All molecular variants of acquired clonal ET usually present with aspirin-responsive platelet sticky syndrome (ASPS) and frequently show evolution into myelofibrosis [35,40].…”

Bone marrow histology in CALR mutated thrombocythemia and myelofibrosis: results from two cross sectional studies in 70 newly diagnosed JAK2/MPL wild type thrombocythemia patients

“…The PVSG de ined primary myelo ibrosis (PMF) is the third Ph-negative MPD entity without previous PV or ML or ET ( Figure 1) [8]. In 1990 Georgii introduced the Hannover Bone Marrow classi ication of the Ph-negative MPD and revised the traditional 1975 PVSG and 1979 WHO classi ication of the MPDs by the introduction of bone marrow histology as a pathognomonic clue to each of MPD ET, PV and chronic primary megakaryocytic granulocytic myeloproliferation (CMGM/PMGM, (Figure 1) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The BRC/ABL negative ET, PV and PMGM constitute the three distinct benign Ph-negative MPD entities ET, PV and CMGM (Figure 1).…”