Decanucleotide Insertion Polymorphism of F7 Influences Significantly the Risk of Thrombosis in Patients with Essential Thrombocythemia

Abstract 1730

Thrombosis is one of the main complications observed in patients with myeloproliferative neoplasm (MPN). The underlying mechanisms of thrombosis are not entirely clarified. The incidence of, and risk factors for, thrombosis appear to differ in distinct and accurately diagnosed sub-entities of MPN. Similar incidences have been reported for essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (PMF) diagnosed according to the WHO 2008 criteria. However, the two sub-entities differ in terms of their risk factor profiles (Carobbio et al, Blood 2011; Buxhofer-Ausch et al, Am J Haematol 2012). A gain of function in procoagulant pathways is believed to be the reason for an inherited hypercoagulable state (Anderson et al, Crit Care Clin 2011). There is strong evidence indicating that certain thrombophilic single nucleotide polymorphisms account for increased risk of thrombotic complications (Di Castelnuovo et al, Thromb Res 2000; Shimasaki et al, J Am Coll Cardiol 1998; Elbaz et al, Stroke 2000; Mollaki et al, J Thromb Haemost 2004). Data concerning the impact of an inherited risk in patients with underlying MPN are scarce (Shetty, Thromb Res 2011). We aimed to investigate the influence of three pre-selected thrombophilic single nucleotide polymorphisms (SNPs) on the risk of thrombosis in patients diagnosed with ET or prefibrotic PMF according to the WHO 2008 criteria.

In 167 patients with a valid consensus diagnosis of ET (n= 105) or prefibrotic PMF (n= 62), the thrombophilic SNPs of NOS3 (Glu 298 Asp), F7 (10 nucleotide insertion-deletion) and FCGR2A (His 131 Arg) were determined by AS-PCR or sequencing. These variables and certain disease-specific and laboratory parameters were correlated with the incidence of major arterial and venous thrombosis by using Cox-regression analysis. The latter was performed in the entire population as well as separately for ET and prefibrotic PMF.

The frequency of SNPs of F7, NOS3 and FCGR2A did not differ significantly in ET and prefibrotic PMF. Notably, the homo- or heterozygous insertion variant of F7 was found to be a significant (multivariate analysis) risk factor for total thrombosis and arterial thrombosis in the entire population (HR 3.06, p= 0.0082 and HR 3.94, p= 0.0007, respectively) as well as on separate analysis of those patients with ET (HR 5.94, p= 0.001 and HR 9,47, p= 0.00024, respectively). The homozygous 298 Asp NOS variant was significantly (univariate analysis) associated with total thrombosis in the entire population (HR 3.29, p= 0.0257) as well as on separate analysis of the ET cohort (HR 4.739, p= 0.0161). These significances were lost on multivariate analysis. No significant associations were established with any of the tested thrombophilic SNPs and the risk of thrombosis in the prefibrotic PMF cohort.

Our data show that the risk of thrombosis in ET diagnosed according to WHO 2008 is increased many-fold by the inherited insertion polymorphism of F7. This is very interesting because, in patients without an underlying pathological condition, this polymorphism appears to protect the organism against thrombosis by reducing FVII activity (Humphries et al, Thromb Haemost 1996). Moreover, the different impact of thrombophilic SNPs in ET compared to prefibrotic PMF might provide further evidence of the presumed difference in risk profiles between these two sub-entities of MPN. These data emphasize the importance of considering the inherited as well as acquired hypercoagulable state in patients with MPN. Larger studies are needed to confirm these findings. If proven true, we would be able to more accurately define the risk of thrombosis in an individual patient and subsequently tailor treatment and anticoagulation strategies.