GENETIC POLYMORPHISMS OF HEMOSTATIC FACTORS AND THROMBOTIC RISK IN NON BCR-ABL MYELOPROLIFERATIVE NEOPLASMS: A PILOT STUDY
Dambrauskienė R1,*, Gerbutavičius R1, Ugenskienė R2, Jankauskaitė R2, Savukaitytė A2, Šimoliūnienė R3, Rudžianskienė M1, Gerbutavičienė R4, Juozaitytė E1
*Corresponding Author: Rūta Dambrauskienė, Department of Oncology and Hematology, Institute of Oncology, Lithuanian University of Health Sciences, Eivenių str. 2, LT-50009 Kaunas, Lithuania. Tel.: +370-3732-6303. Fax: +370-3732-6413. E-mail: ruta.dambrauskiene@gmail.com
page: 35

RESULTS

In total, 108 patients were analyzed. The main clinical characteristics of patients with non BCR-ABL MPNs in our population are depicted in Table 2. Patients with thrombosis were older [mean age 66.98 years (SD = 13.42) vs. 60.17 years (SD = 15.58) p = 0.016], and had a lower median value of MCV and MCH at the time of diagnosis [83.00 (range 70-100) vs. 87.00 (range 65-101), p = 0.021, and 27.0 (range 17-34) vs. 28.0 (range 23-33), p = 0.048, respectively]. In the non BCR-ABL MPN thrombosis group, patients were predominantly female (54.8 vs. 45.7%), and more patients were positive for the JAK2 p.V617F mutation (52.6 vs. 47.4%, p = 0.002). Concerning patients with ET and PMF, 11.1% of them were CALRpositive in the thrombosis group compared to 88.9% of the thrombosis-free patients (p = 0.033). Other clinical characteristics were similar. Arterial thrombosis was more frequent in the ET/ PMF group than in the PV group (73.5 vs. 26.5%, p = 0.03) (Table 3). Forty-five (42.6%) patients had experienced an arterial thrombotic event, 10 (9.3%) patients had experienced a venous event, and four (3.7%) patients had both arterial and venous thrombosis. Genotype distributions and allele frequencies of the studied polymorphisms in patients with thrombotic complications according to the type of thrombosis are summarized in Table 4. Our data showed a higher prevalence of GP Ia/IIa c.807C>T polymorphism of the TT genotype than the CC wild-type or the heterozygous CT genotype in MPN patients with arterial thrombosis (65.0 vs. 38.2 vs. 42.6%, p = 0.09), respectively. The analysis of the c.807 C>T polymorphism TT genotype separately showed that it was significantly more frequent in the MPN patient group with arterial thrombosis compared to the MPN group of thrombosis-free patients [26.5 vs. 11.5%, p = 0.049; odds ratio (OR) 2.68; 95% confidence interval (95% CI) 1.017.38]. The CT genotype of the β-fibrinogen (c.-148C>T polymorphism) in MPN patients with arterial and arterial and venous thrombosis occurred significantly more frequently compared to the CC wild-type or the homozygous TT genotype (57.7 vs. 40.0 vs. 12.5%; p = 0.027) and (64.7 vs. 44.4 vs. 25.0%, p = 0.032), respectively. The carrier state for the c.-323P10 variant of FVII SNP (summation of P10/10 and P0/10) was significantly more frequent in MPN patients with arterial and venous thrombosis compared to wild-type genotype carriers (71.4 vs. 43.4%, p = 0.049; OR 3.26; 95% CI 1.01-11.31). It maintained a borderline significance when analyzed in the arterial thrombosis subgroup only (69.2 vs. 38.2%, p = 0.06). The coexistence of both heterozygous genotypes of β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP in creased the risk of arterial thrombosis in MNP patients (21.1 vs. 3.7%, p = 0.008; OR 6.93; 95% CI 1.38 – 34.80). In the univariate analysis, no statistically significant association was found between the remainder of the tested polymorphisms and thrombosis. In the multivariate analysis performed on arterial thrombosis considering TT genotype of c.807C>T GP Ia/ IIa, CT genotype of β-fibrinogen c.-148C>T, a carrier state for c.-323P10 variant of FVII (summation of P10/10 and P0/10) SNPs, MCV, and age, two of three SNPs (TT genotype of c.807C>T GP Ia/IIa and CT genotype of β-fibrinogen c.-148C>T) as well as MCV and age, retained statistical significance (Table 5). A test of the full model against a constant only model was statistically significant, indicating that the predictors as a set reliably distinguished between MPN patients with arterial thrombosis and those without thrombosis (ζ2 = 21.82, p <0.001 with df = 4). Nagelkerke’s R2 was 0.33. The overall prediction success was 72.4% (62.2% for thrombosis and 80.0% for no thrombosis). Separate analyses of different arterial thrombotic events showed more frequent CT genotype of β-fibrinogen c.-148C>T SNP in MPN patients with ischemic stroke compared to other arterial vascular events; however, the results were of borderline significance (75.0 vs. 50.0%, p = 0.06). The c.-323P0/10 plus c.-323P10/10 genotype of FVII SNP was statistically significantly more frequent in the ischemic stroke group compared to the thrombosis-free group (33.3 vs. 12.2%, p = 0.04).



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