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

DISCUSSION

The main objective of this study was to evaluate whether SNPs located in genes of platelet glycoprotein Ia/ IIa (c.807C>T), glycoprotein Ibα (VNTR; c.5T>C Kozak; c.5792 C>T), glycoprotein IIb/IIIa (PIA1/2), glycoprotein VI (c.13254T>C), vWF (c.24/1282A>G), coagulation FVII (c.-323P0/10), and β-fibrinogen chain (c.-148 C>T) could be associated with risk of thrombosis in patients with non BCRABL MPNs. The analysis of nine different SNPs provided evidence that the TT genotype (c.807C>T) of GP Ia/IIa, CT genotype (c.-148C>T) of β-fibrinogen chain and coagulation FVII (c.-323P0/10) SNP represent an additional risk factor for thrombosis in patients with non BCR-ABL MPNs. The c.807C>T SNP of GP Ia/IIa was also studied by Afshar-Kharghan et al. [16] in ET and PV patients. The investigators did not identify any associations between this SNP and thrombotic complications in a cohort of 86 ET and PV patients [16]. The homozygous state (TT genotype) of the above-mentioned polymorphism was identified as an additional risk factor for arterial thrombosis in patients with the antiphospholipid syndrome in the studies of Jimenez et al. [23] and Yonal et al. [24]. Our results suggest that the homozygous state of c.807C>T GP Ia/IIa SNP may increase the risk of arterial thrombosis in non BCR-ABL MPNs. A metaanalysis of 66,155 cases that was published by scientists from China did not show any significant relation between GP Ia/ IIa c.807C>T polymorphism and coronary artery disease [25]. In addition, German scientists revealed a modulatory effect of the aforementioned polymorphism on thrombosis development, which can be region- and race-dependent [26]. The impact of coagulation FVII c.-323P0/10 SNP has been recently reviewed by Buxhofer-Ausch et al. [18]. The investigators screened 105 patients with ET meeting the 2008 WHO criteria and 62 patients with early PMF. The c.-323P10 variant of the coagulation FVII showed a statistically significant association with total and arterial thrombosis in univariate as well as in multivariate analysis for patients with ET, but not for those with early PMF [18]. However, the investigators considered that solid data are lacking to explain the mechanism of the relation of c.-323P0 /P10 FVII polymorphism with thrombosis. The authors admit the importance of further experiments to evaluate the influence of the aforementioned SNP on the risk of thrombosis [18]. Our cohort of patients was smaller, but it also included a similar number of patients with ET. We also extended the non BCR-ABL MPN cohort to the whole WHO-confirmed non BCR-ABL MPN population. The majority of cases of the heterozygous variant of c.-323P0 /P10 FVII SNP were found in the ET cohort, compared to the PV cohort, which is in agreement with data published by Buxhofer-Ausch et al. [18]. We also observed a higher prevalence of this polymorphism in non BCR-ABL MPN patients with arterial and total thrombosis. However, the majority of cases of the c.-323P0/10 FVII SNP retained borderline significance on the multivariate analysis of our non BCR-ABL MPN patient cohort. Our study revealed that the coexistence of both heterozygous genotypes in c.-323P0/ P10 FVII and β-fibrinogen c.-148C>T SNP was related to arterial thrombosis in non BCR-ABL MPN patients with the OR of 6.93 and the relative risk of 2.19 for those who were double heterozygous in this study. To the best of our knowledge, a common effect of those two SNPs in non BCR-ABL MPN patients has never been analyzed before. Although the exact pathophysiological mechanism is unclear, we can only speculate that the simultaneous occurrence of two or more prothrombotic SNPs can activate the hemostatic cascade that further predisposes the development of thrombosis in non BCR-ABL MPNs. Our results showed a tendency of a higher frequency of the β-fibrinogen CT genotype (c.-148C>T SNP) in patients with total and arterial thrombosis than in non BCRABL MPN patients who did not experience vascular events. The effect of this SNP was evaluated in a large population of Chinese patients with ischemic stroke and cerebral infarction, but not in non BCR-ABL MPNs [27,28]. There was also evidence that β-fibrinogen c.-148C>T SNP is functional and associated with elevated plasma fibrinogen levels [29]. The carriers of the heterozygous genotype of this SNP showed a trend toward a higher risk of ischemic stroke in our cohort, although, considering the small number of patients, it was of borderline significance. This gave rise to a hypothesis that different single nucleotide poly-morphisms could be potential confounders in vascular-specific events. The age of non BCR-ABL MPN patients who experienced thrombotic events is already a well-known risk factor for thrombosis [2,30]. Our results also confirmed older age as a risk factor for thrombosis. We observed lower MCV and MCH indices in the thrombosis group compared to the thrombosis-free group. However, this difference could be due to the fact that three distinct non BCR-ABL MPN subtypes were studied in this cohort. Differently from Carobbio et al. [30], we were not able to reveal any cardiovascular risk factor as a predictor for thrombosis, probably due to the lower prevalence of cardiovascular risk factors in our cohort. The JAK2 p.V617F mutation is considered to be a risk factor for thrombosis in non BCRABL MPN patients. This was observed in many studies. JAK2 p.V617F mutation is also included in the International Prognostic Score of thrombosis in WHO-essential throm-bocythemia (IPSET-thromobosis) model for ET patients [31]. The results of our study also confirmed that this mutation was a risk factor for thrombosis in non BCRABL MPN patients. Conversely, Calreticulin mutation was associated with a decreased risk of thrombosis in ET and PMF patients in our cohort. Polymorphisms of the factor V Leiden (FVL) and the prothrombin gene G20210A were recognized as risk factors for venous thrombosis from 1994 [32]. They were also investigated in the thrombotic approach of myeloproliferative neoplasms. Ruggeri et al. [33] retrospectively investigated FVL in a cohort of 304 ET and PV patients. The study results revealed that the prevalence of FVL mutation in PV and ET patients was similar to that observed in the normal population. Moreover, the FVL mutation was not associated with arterial or venous thrombosis. However, the authors stated that the FVL mutation is associated with the risk of venous thrombosis recurrences [33]. Schwarz et al. [34] recognized the FVL mutation to be a significant additional risk factor in the occurrence of venous thrombosis in a prospective analysis of 1179 ET patients. De Stefano et al. [35] investigated MPN patients younger than 60 years of age. The study revealed that the risk of thrombosis was increased when FVL and prothrombin gene G20210A mutation coexists with the JAK2 p.V617F mutation in ET patients [35]. Similar results were demonstrated by Tevet et al. [32] in 192 patients with MPN. According to them, the thrombotic risk was higher in the JAK2 p.V617F mutation subgroup and it was further increased by the presence of the FVL mutation [36]. Unfortunately, we did not analyze the aforementioned mutations. However it would be interesting to investigate these thrombophilic factors in conjunction with our studied platelet receptor polymorphisms. Moreover, our study had a few limitations, such as small group size, the absence of controls, and non BCR-ABL MPN heterogeneity, as three types of the disease were analyzed. We also did not measure FVII or plasma fibrinogen levels in our patients. In conclusion, this study was focused on polymorphisms that were located in genes coding different players of the primary and secondary hemostatic system, which reflects several pathophysiological paths from platelet plug to fibrin formation. This study analyzed a large number of SNPs in non BCR-ABL MPN patients, bringing up-todate evidence of what platelet and coagulation factors can contribute to thrombotic complications. The coexistence of several different polymorphisms as well as vascularspecific event polymorphisms could be a clue for further investigations in order to delineate the pathophysiology of thrombosis in non BCR-ABL MPN patients.



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