Inherited and Acquired Thrombophilic Abnormalities in Patients Aged &lt;20 Years with Bcr-Abl Negative Chronic Myeloproliferative Disorders
Authors: Giona Fiorina , Amendola Angela , Palumbo Giovanna , Pignoloni Patrizia , Chistolini Antonio , Moleti Maria Luisa , Foà Robert , Mazzucconi Maria Gabriella 
Published: April 2020

Abstract
Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (CMD), mostly in essential thrombocythemia (ET) and polycythemia vera (PV), while only sporadic data are available in younger patients (pts). In order to identify coagulation abnormalities in very young pts with a diagnosis of CMD, we evaluated different thrombophilic parameters in CMD pts aged &lt;20 years (yrs) at the time of diagnosis. 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 polymorphisms were investigated. Thirty-four CMD pts (18 M and 16 F) with a median age at diagnosis of 168/12 yrs (range: 3mo-1911/12 yrs), followed at the study Institution, were tested. According to the criteria of the PVSG or WHO, 17 pts had a diagnosis of ET, 8 of PV and 9 of hereditary thrombocythemia (HT). Among the ET cohort, 3 pts were treated with aspirin alone and 14 received cytoreductive therapy. Among the HT cohort, 2 patients received cytoreductive therapy. PV pts were phlebotomized to maintain a hematocrit (Ht) level &lt;50%. The median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo-24 yrs). No thrombotic events occurred. Five females with ET or HT became pregnant and had 5 children, 1 of them being affected by HT. At the time of the study, the median platelet (plt) count was 649 × 109/L (range 325–1,712) for ET pts and 1,000 × 109/L (range 602–2,142) for HT pts; the median Ht level for pts with PV was 53% (range 52–60.5%). The KCT ratio (n.v. &lt;1.31) was increased in 5/33 (15%) pts, 4 of them with PV (1 with high dRVVT ratio). Functional PC and free PS levels were decreased in 4/34 (11.7%) pts tested. An increased HCY level was found in 3/8 pts (37.5%) with PV. Of the 34 pts investigated for FVL, FIIG20210A mutations and MTHFRC677T polymorphisms, 1 ET pt was heterozygous for both the FVL and MTHFRC677T mutations and one ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphisms in the MTHFR gene revealed that 22/34 pts (64.7%) were heterozygous, 9 of them affected by ET and 8 by HT. In our CMD population of children and young adults, the frequencies of heterozygosis of FIIG20210A mutations (4/34 pts = 11.7%) and MTHFRC677T polymorphisms (64.7%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Our data demonstrate that an accurate thrombophilic screening is important in young CMD pts in order to better manage this particular category of patients.
Coagulation parameter All pts ET pts HT pts PV pts Median KCT ratio (range) No. of pts with increased ratio 0.89 (0.26–1.49) 5/33 (15%) 0.86 (0.26–1.21) 0/16 1.22 (0.77–1.49)&gt; 1/9 (11%) pan lang=”EN-US”&gt;1.31 (0.9–1.41)4/8 (50%) Median dRVVT ratio (range) No. of pts with increased ratio 0.64 (0.26–1.15) 1/34 (2.9%) 0.78 (0.26–0.99) 0/17 0.75 (0.54–0.98) 0/9 0.72 (0.55–1.6) 1/8 (12.5%) Median PC level (range) No. of pts with reduced levels 97 (58–137) 4/34 (11.7%) 97 (62–137) 0/17 (0%) 91 (62–133) 2/9 (22%) 101 (58–116) 2/8 (25%) Median PS level (range) No. of pts with reduced levels 85 (48–113) 4/34 (11.7%) 82 (49–113) 1/17 (5,8%) 84 (63–95) 1/9 (11%) 106 (60–112) 2/8 (25%) Median antithrombin level (range) No. of pts with reduced values 100 (87–197) 0/34 100 (88–197) 0/17 99 (88–197) 0/9 97 (87–100) 0/8 Median HCY level (range) No. of pts with increased levels 9.20(4.6–34.06)/span&gt; 3/34 (8,8%) d&gt; 8.7 (4.6–14.1) 0/17 5.7(4.6–13.5) 0/9 9.8 (4.5–34.06) 3/8 (37.5%) FVL (allele frequency) mutations 1/34 (2.9%) 1/17 (5.8%) 0/9 0/8 FIIG20210A mutations (allele frequency) 4/34 (11.7%) 1/17 (5.8%) 3/9 (33%) 0/8 MTHFRC677T polymorphisms (heterozygosis) 22/34 (64.7%) 9/17 (52.9%) 8/9 (89%) 5/8 (62.5%)