Impact of Inherited Thrombophilia Factors On Thrombotic Risk in Patients with Newly Diagnosed BCR- Abl (-) Myeloproliferative Disorders; Finally a Role of MTHFR- C677T Polymorphism?

Myeloproliferative Neoplasms (MPN) are commonly associated with thrombotic complications, which constitute the major cause for morbidity and mortality in these patients. While the pathogenesis of Thrombosis is not yet fully elucidated, the impact of inherited thrombophilia on MPN patients is unknown. MTHFR-C677T polymorphism is a usual variation of the MTHFR gene and exerts weak, if any, prothrombotic role mainly through increased homocysteine levels. Up to date there are no specific guidelines for treatment of thrombotic events in MPN patients.

The purpose of our study is to determine the impact of inherited thrombophilia factors on thrombotic risk in patients with newly diagnosed BCR- abl (-) myeloproliferative neoplasms. We also tried to assess the role of the MTHFR- C677T polymorphism in thrombotic risk in our MPN patients.

Our study population consisted of 68 patients diagnosed with BCR- abl (-) myeloproliferative neoplasms in the Hematology Department of our Hospital during the period 2005– 2008. Diagnosis was set according to the World Health Organization and Updated European Clinical and Pathological criteria for the Diagnosis, Clasification and Staging of the Philadelphia chromosome (-) chronic myeloproliferative disorders. Age, Sex, Platelet count, serum homocysteine levels, presence of Jak-2 mutation, together with genetic polymorphisms of Factor V-Leiden and FII- G121120A prothrombin mutations, and MTHFR- C677T polymorphism were assessed. Among our patients, whose median age was 65 years (range 21– 83), 40 were male and 28 female. 41 patients were diagnosed with essential thrombocythemia (ET), 22 with Polycythemia Vera (PV), 3 with essential myelofibrosis and 2 with Unclassified Chronic bcr- abl (-) MPN. Statistical analysis was conducted with SPSS 20. 0. At first a monovariate statistical model was used with significant level set at p= 0. 05. For the multivariable statistical analysis model we used all variables with p<0, 05 from the previous model and those mentioned at recent medical literature as significantly related with thrombotic risk.

From our patients, 31 suffered a thrombotic event (arterial or venous thrombosis, microvascular disorders). Regarding their thrombophilia profile patients were found to be: 4 carriers of the FVL mutation, 4 carriers of the FII- G121120A and 13 were carrying the MTHFR- C677T polymorphism. Moreover, 56 patients were tested for Jak-2V617F, and 42 of them were found to be positive (100% patients with P. V., 79% ET patients). We tried to define whether the following variables are high risk factors for thrombotic events in our population: Platelet count, serum homocystein levels, presence of Jak-2 mutation, Factor V-Leiden and FII- G121120A, mutations, and MTHFR- C677T. Surprisingly, the presence of MTHFR- C677T reached statistical significance on the monovariate analysis (p= 0. 001), while published data on general thrombosis population don't show any correlation of the MTHFR- C677T with thrombotic events. Jak-2 mutation was studied in a subgroup of patients, which didn't include patients with PV and was found to be statistically significant thrombosis risk factor in the monovariate analysis. Multiple regression analysis revealed MTHFR- C677T genetic polymorphism as independent risk factor concerning thrombotic events in patients with BCR- abl (-) MPNs (p= 0. 01, Exp (B)= 39. 227, 95%CI: 2. 41 –638. 547). The mean concentration of serum homocystein and the mean platelet count didn't show any statistically significant difference between patients carying MTHFR- C677T polymorphism and MTHFR- C677T negative patients. So serum homocystein levels and platelet count were not found to be confounding factors. In addition the co- existence of MTHFR- C677T with either G121120A or FVL mutations was detected in 4 patients, and all of them suffered from thrombotic events.

Our study is the first to demonstrate a prothrombotic role of MTHFR- C677T polymorphism in a MPN population. Thrombophilia studies are needed in MPN patients in order to better assess the thrombotic risk for the patients but foremost to properly tailor anticoagulant treatment after a thrombotic episode.

No relevant conflicts of interest to declare.