The contribution of hereditary thrombophilia to increasing the frequency of thrombosis in patients with Ph negative myeloproliferative neoplasms, including the victims from the Chornobyl accident. / VNESOK SPADKOVOÏ TROMBOFILIÏ V ZBIL'ShENNIa ChASTOTY TROMBOZIV U KhVORYKh NA Ph NEGATYVNI MIIeLOPROLIFERATYVNI NOVOUTVORENNIa, VKLIuChAIuChY POSTRAZhDALYKh VNASLIDOK AVARIÏ NA ChORNOBYL'S'KIY̆ ATOMNIY̆ ELEKTROSTANTsIÏ.

OBJECTIVE: The definition of a contribution of the carriage of the G1691A allele of thecoagulation factor V gene and the G20210A allele of the coagulation factor II gene in the development of thrombosis in Ph negative myeloprolifer ative neoplasms (MPN) patients, who were irradiated in the dose range 0,001 0,99 Gy and who were not. MATERIALS AND METHODS: The clinical and molecular genetic characteristics of patients with radiation associated and spontaneous polycythemia vera (PV), essential trombotsytemiya (ET) and primary myelofibrosis (PMF) were ana lyzed. The group of radiation associated PV, ET and PMF represented by 35, 10 and 22 patients respectively, and the cohort of spontaneous PV, ET and PMF - 149, 111 and 78 patients respectively. RESULTS AND CONCLUSIONS: The carriage of any of the two molecular genetic markers of hereditary thrombophilia at spontaneous PMF increases the frequency (3 of 6 vs 8 of 72; p = 0.033) and risk (RR = 6.09; 95 % CI = 1.40-26.43) of thrombosis. The presence of the G1691A allele of the proaccelerin gene in patients with PMF, who were not exposed to ionizing radiation, causes increase the likelihood of venous thrombosis at 10.14 times (95 % CI = 1.67-61.33). At spontaneous and radiation associated Ph negative MPN (in individuals exposed to doses in the range 0,001-0,99 Gy), the higher rate of the occurrence of venous, arterial and any thrombosis was observed in carriers of the G1691A allele the coagulation factor V gene, than in those, whose have the wild type allele. In particular, the G1691A allele of the proaccelerin gene carriers, that are belonged to the group of patients with radiation associated PV, have at 33.33 person years bigger rate of any thrombosis (95 % CI = 0.22-100.00, p = 0.048) and venous vascular events (95 % CI = 12.50-50.00; p = 0.003).In PMF patients with a radiation anamnesis were found the difference (20.00 person years; 95 % CI = 1.51-50.00, p = 0.035) between the ratio of any thrombosis and arterial vascular events, which was calculated for the G1691A allele of the proaccelerin gene and for those, who have the wild type allele. The carriers of the G20210A nucleotide variant of the coagulation factor II gene with spontaneous ET and PMF, compared with patients with the wild type allele, have a higher rate of venous thrombosis per 100 patient years.

Specifics of the course and the clinical pictures of essential thrombocythemia depending on the JAK2V617F status of the patients. / OSOBLYVOSTI PEREBIGU TA KLINIChNOI KARTYNY ESENTsIAL'NOI TROMBOTsYTEMII ZALEZhNO VID JAK2V617F STATUSU KhVORYKh.

OBJECTIVE: The purpose of the study was to analyze the specific features of the relationship between the JAK2 V617Fmutation and clinical presentation, and risks of thrombosis in patients with spontaneous and radiation associated essential trombocitemia (ET). MATERIALS AND METHODS: Clinical, laboratory hematological, molecular genetic characteristics of ET patients were analyzed. The group of patients with radiation associated ET was represented by 10 individuals and the cohort of spontaneous ET represented by 111 persons. RESULTS: The JAK2V617F positive mutation status in patients with spontaneous ET is the predictor of the increase of distribution of thrombosis (23.0 % vs. 6.0 %), risk of its development (relative risk = 1.5; 95 % confidence interval = 1.3-1.8), and the decrease of survival without thrombosis. It has been proved that presence of the JAK2V617F mutation increases the probability of venous thrombosis (relative risk = 1.5; 95 % confidence interval = 1.30-1.7) in spontaneous ET patients. The use of the JAK2V617F mutation status of patients with spontaneous and radiation associated ET (AUC = 0.62 and AUC = 0.68 respectively) complies with the average power marker for the prediction of thrombosis. The carriage of the JAK2V617F mutation in patients with spontaneous and radiation associated ET is characterized by a higher (93.9 % and 100 % accordingly) indicator of predictive value of a negative result to deter mine of the risk of thrombosis. ET patients with the JAK2V617F mutation were found to have a higher average value of erythrocytes, hemoglobin, mean corpuscular volume and lower erythrocyte sedimentation rate in their peripher al blood, when compared to those without the mutation. Trepanobioptat samples of JAK2V617F positive ET patients exhibited a prevalence of moderate hypercellularity of bone marrow, large and giant forms of megakaryocytes, reti culin fibrosis and microcirculation disorders compared to individuals without the mutation. A greater number of average quantities of leukocytes in JAK2V617F positive patients with radiation associated ET were found compared to JAK2V617F negative persons.

Molecular characterization of Ph-negative myeloproliferative neoplasms in Ukraine.

AIM: The aim of this study was to examine the JAK2 V617F, the G1691A allele of factor V, and the G20210A prothrombin gene mutation status, and their predictive value for thrombosis in patients with Ph-negative myeloproliferative neoplasms (MPN) in Ukraine, with special emphasize to patient exposed to ionizing radiation due to the Chernobyl accident. MATERIALS AND METHODS: There were 198 patients with Ph-negative MPN included in the study. Of these, 45 patients had experienced radiation exposure due to the Chernobyl accident. The JAK2 V617F mutation, the G1691A of factor V and the G20210A of prothrombin were detected by allele-specific polymerase chain reaction. RESULTS: The polycythemia vera and essential thrombocythemia patients in unexposed group and Chernobyl patients were comparable in terms of the JAK2 V617F mutation prevalence with the frequency of anomaly corresponding well to the published data on unselected cases of these types of Ph-negative MPN. The JAK2 V617F mutation was less common on the border of statistical significance (p = 0.08) in Chernobyl primary myelofibrosis (PMF) patients than in non-exposed patients. JAK2 V617F positive patients had higher level of leukocytes (p = 0.03), hemoglobin (p =0.04) and splenomegaly (p = 0.04) than those without mutation. The JAK2 V617F mutation was strong predictor for thrombosis in essential thrombocytemia patients (relative risk=3.1, 95% CI = 1.7-16.4, p = 0.03). In PMF, the association with thrombosis was found for the G1691A allele of factor V (p = 0.03). The risk of thrombosis associated with the inherited thrombophilia in PMF patients was 7.0-fold (95% CI = 1.41-33.1, p = 0.03) higher than in polycythemia vera patients. The inherited thrombophilia increased risk of thrombotic complication 5.4-fold (95% CI = 1.41-18.17, p = 0.01) in overall cohort of Ph-negative myeloproliferative neoplasms patients. This trend continued in Chernobyl patients (p = 0.02), but not in unexposed cases. CONCLUSIONS: Our findings confirm previous results of other studies reporting that the JAK2 V617F mutation significantly and independently influences on a disease phenotype in Ph-negative MPN. The inherited thrombophilia is important risk factors of the thrombosis development in overall cohort primary myelofibrosis patients, and especially in disease developed following radiation exposure.