Inherited and Acquired Thrombophilia in Children and Young Adults with Bcr-Abl Negative Chronic Myeloproliferative Disorders.
Authors: Giona Fiorina , Palumbo Giovanna , Pignoloni Patrizia , Amendola Angela , Chistolini Antonio , Testi Anna Maria , Moleti Maria Luisa , Foa Robert , Mazzucconi Maria Gabriella 
Published: April 2020

Abstract
Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (MPD), mostly essential thrombocythemia (ET) and polycythemia vera (PV), but sporadic data are available in younger patients (pts). In order to define coagulation abnormalities in very young pts, we evaluated thrombophilic parameters in MPD pts aged &lt;20 years (yrs) at diagnosis. Prothrombin time (PT), activated partial thromboplastin time (aPTT), lupus anticoagulant (KCT and dRVVT), functional protein C (PC), free protein S (PS) antigen, functional antithrombin (AT), homocysteine (HCY), factor V Leiden (FVL) mutation, factor II (FII) G20210A mutation and methylentethrahydrofolate reductase (MTHFR) C677T polymorphism were investigated. Thirty-two MPD pts (16 males and 16 females) with a median age of 166/12 yrs (range: 3mo-1911/12 yrs) diagnosed at the study Institution between March 1980 and February 2005 were tested after informed consent of pts or parents. Twenty-five had a diagnosis of ET (7 familial forms) and 5 had PV, according to the criteria of the PV Study Group; in 2, a diagnosis of MPD with thrombocytosis and erythrocytosis was made. Cytogenetic and molecular studies were normal in all cases. At diagnosis, median platelet count for ET and MPD pts was 1,184 x 109/L (range 611–2,640); median hematocrit level for PV and MPD pts was 54% (range 52–72%). Among the ET cohort, 6 asymptomatic pts received no treatment, 4 were treated with aspirin alone and 15 received cytoreductive therapy. PV and MPD pts were phlebotomized to maintain a hematocrit level &lt;50%. Median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo – 24 yrs ). No thrombotic events occurred. Four female ET became pregnant and had 4 children, 1 of them being affected by familial thrombocythemia. At the time of the coagulation study, median platelet count for ET and MPD pts was 695 x 109/L (range 325–1,120); the median hematocrit level for those with PV and MPD was 53% (range 52–60.5%). Increased PT and aPTT ratios (n.v. &lt;1.14 and &lt;1.16) were observed in 8/32 (20%) and 16/32 (50%) pts, combined in 7. KCT ratio (n.v. &lt;1.31) was increased in 4/31 (13%) pts, while the dRVVT ratio was normal in 31/31 tested pts. Functional PC and free PS levels were decreased in 3/30 (10%) and 3/31 (10%) tested pts, respectively. AT levels were normal in all pts (32/32). An increased HCY level was found in 1 PV pt. Of the 27 pts investigated for FVL, FII G20210A mutations and MTHFR C677T polymorphism, 1 ET pt was heterozygous for both the FVL and FII G20210A mutations, 1 ET pt was heterozygous for both MTHFR C677T polymorphism and FII G20210A mutation. One ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphism in the MTHFR gene revealed that 18 pts (66.5%) were heterozygous, 15 of them affected by ET (7 with the familial form). In our MPD population of children and young adults, the frequencies of heterozygosis of FII G20210A mutation (3/27 pts = 11%) and MTHFR C677T polymorphism (66.5%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Larger multicenter studies are required to further extend these observations.