The Influence of Hemostasis Genetic Features on Thrombosis Rates in Patients with Polycythemia Vera
Authors: Shikhbabaeva Dzhariyat , Shuvaev Vasily , Kapustin Sergey , Martynkevich Irina , Udaleva Vera , Golovchenko Regina , Zamotina Tatyana , Fominykh Mikhail , Zotova Irina , Polushkina Lyubov , Abdulkadyrov Kudrat 
Published: October 2019

Abstract
Background. Thrombotic complications are the main cause of disability and mortality in Polycythemia Vera (PV) patients. Thrombosis in PV is a result of both inherited (genetic) and acquired predisposition under the external factors influence. Effective personalized prophylactic antithrombotic therapy is a key factor to save quantity and quality of life in PV patients.
Objective. The objective of study was to assess the prevalence of hereditary thrombophilia genetic markers in PV patients in overall and groups with or without thrombotic complications.
Materials and methods. 104 PV patients (60 females, 44 males, median age 58 years, range 31-82) were researched. Blood probes were examined by PCR for the presence of nucleotide polymorphisms in the following genes: FV (Leiden mutation), FII (prothrombin), methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). We studed the overall hereditary thrombophilia markers rate and the statistical significance between PV patients groups with (Thr+) or without thrombosis (Thr+). We used the next statistical methods: descriptive statistics, the significances of differences by gender and genes frequencies in the groups were evaluates with Fisher exact test, differences in age at the time of diagnosis were assessed with Mann-Whitney U test.
Results. Thrombotic complications occurred in 20 (19.2%) of patients (16 arterial and 5 venous thrombotic episodes, 1 patient had both arterial and venous thrombotic episodes). Myocardial infarction was found in 7 (6.7%), cerebrovascular accident in 9 (8.7%) patients. The general PV population thrombophilia markers frequencies were: heterozygous (G/A) Leiden mutation in 4 (3,8%) patients; heterozygous mutation in prothrombin gene (G20210-A) in 4 (3,8%) patients; homozygous (T/T) mutation in MTHFR in 8 (7,7%) patients, heterozygous (C/T) mutation in 43 (41,3%) patients; homozygous (A/A) mutation in FI gene in 4 (3,8%) patients, heterozygous (G/A) mutation in FI gene in 43 (41,3%) patients; combination of mutations in FI and MTHFR was registered in 23 (22,1%) patients; homozygous (4G/4G) mutation in PAI-1 gene was revealed in 35 (33,7%) patients, heterozygous (4G/5G) mutation in 49 (47,1%) patients; mutation frequencies in GPIIIA gene were as follows: homozygous (A2/A2) in 5 (4,8%) patients, heterozygous (A1/A2) in 26 (25%) patients. The markers of hereditary thrombophilia was not identified only in one patient (1%).Characteristics and difference significances in the frequency of detection of thrombophilia genes between groups of patients with thrombosis (Thr+) and without their presence in history (Thr-) are shown in table 1.
Table 1. Characteristics of PV patients with (Thr+) or without (Thr-) thrombotic complications. Thr+ (n=20) Thr- (n=84) p Age, median (range) 63 (36-73) 58 (32-82) 0.75 Gender, male/female 9/11 35/49 0.81 Factor V Leiden mutation, GA/GG 2/18 2/82 0.17 Prothrombin gene (G20210A) mutation, GA/GG 1/19 3/81 0.58 MTHFR mutation, (TT+CT)/CC 14/6 37/47 0.05 FI mutation, (AA+GA)/GG 6/14 41/43 0.14 PAI-1 mutation, (4G/4G+4G/5G)/(5G/5G) 17/3 67/17 0.76 GPIIIA mutation, (A2A2+A1A2)/A1A1 1/19 30/54 0.01
Conclusions. Various hereditary thrombophilia gene mutations were present in almost all PV patients. PV patients with and without thrombotic complications were significantly (p≤0.05) differed in frequencies of mutations in methylenetetrahydrofolate reductase gene (MTHR) and platelet fibrinogen receptor type IIIA (GPIIIA). We also observed statistical trends (p≤0.30) in differences of mutations frequencies in fibrinogen (FI) gene and Factor V Leiden mutation, for the confirmation of which the further research is required.

Disclosures
No relevant conflicts of interest to declare.