This study firstly compared the allele and the genotype frequency for nine prothrombotic gene variants between patients with various forms of venous thrombosis and a large group of control subjects from the same geographical area.
Pulmonary embolism, DVT and SVT share a genetic predisposition represented by FVL, FVR2 and FII G20210A gene variants, whose frequency is significantly higher as compared to the GP. These data match with the current literature [5, 18-20]. Interestingly, the allele frequency of FVL and FVR2 resulted higher in males than in females with PE, DVT and SVT, although significantly only for PE subjects (while in the general population no sex difference was identified for all the variants examined). A sex difference in the allelic frequency of FVL and FII G20210A variants was previously found by our group in females with young AMI and for MTHFR C677T mutation in males with AMI [11]. Differently, most previous studies did not find (or did not assess) a sex difference for prothrombotic variants in patients with venous or arterial thrombotic disorders [21]. Only Farajzadeh M, et al [20] in an Iranian population with VTE, found a significantly higher frequency of the FII G20210A and PAI-1 4G allele in females. The sex difference in the allele frequency of prothrombotic variants in patients with venous thrombosis, once confirmed on larger populations, may impact on the strategies for care and prevention of these diseases, considering that the well known sex difference in the epidemiology of thrombotic diseases is due to mostly still unknown factors [7]. Moreover, the frequency of all other prothrombotic gene variants was not significantly different between patients with VTE and the GP. For some gene variants our data are in agreement with previous evidences: two studies excluded beta-fibrinogen -455 A>G [22, 23] and the FXIII V34L [24] as risk factors for VTE. Similarly, FXIII V34L, beta-fibrinogen -455, HPA-1, MTHFR C677T and A1298C variants and PAI-1 4G/5G alleles did not demonstrate a relationship with VTE [25]. While, differently from our study, MTHFR A1298C and C677T variants were found as risk factors for VTE [26]; and another study [27] revealed that only the MTHFR A1298C but not the C677T MTHFR variant was a risk factor for VTE. A significant increase of the PAI-1 4G allele frequency was found only in VTE patients that had also the FVL [28]. We did not confirm such data (data not shown).
In patients with portal vein thrombosis, FVL and FII G20210A variants resulted more frequent as compared to the GP in agreement to a previous study [4], while Parik et al. [29] excluded a major role of prothrombotic gene variants in portal thrombosis. The major limit of our study is that all cases with portal vein thrombosis had chronic liver disease and it is known that inflammation, fibrosis and alterations of local circulation are the main pathogenic basis of portal hypertension in such patients [3]. Interestingly, the frequency of FII G20210A is higher (although not significantly) in our females with PVT.
In patients with cerebral venous thrombosis we found only a significantly higher frequency of the FII G20210A variant respect to the GP, and such data match with two studies [2, 30]. While, our data exclude a role of MTHFR and FVL variants that in previous studies had been reported to be associated to a higher risk for the CVT [30, 31]. Interestingly, also in CVT (as we observed in PVT) the frequency of FII G20210A is higher in females than in males. Cerebral venous thrombosis is typical of young subjects and is about three times more frequent in females [2], and our results confirm this data supporting a role of hormones in its pathogenesis in addition to local risk factors [32]. However, a role of the FII G20210A, particularly in females with CVT, seems to be considered and confirmed in larger populations.
Finally, prothrombotic gene variants have a scarce role as risk factors for retinal vein thrombosis. It is well known that RVT has peculiar local risk factors different from those that act in other forms of VTE, while the potential role of thrombophilia (including FVL and G20210A) seems to be marginal [33]. Similarly, Janssen [4] found that FVL and G20210A and other prothrombotic gene variants have a minor role in the pathogenesis of RVT, being atherosclerosis the main cause [33, 34]. Thus, routine testing for prothrombotic variants must be considered not advisable in patients with RVT [33].
From all these observations, it may be concluded that prothrombotic gene variants have a relevant role in DVT, PE and SVT: about 40% of patients show a prothrombotic predisposition represented by at least one among FVL, FVR2 or FII G20210A variants. Such predisposition is significantly more pronounced in males confirming that sex-related risk factors act in VTE. All the other prothrombotic variants do not have a role, despite the ordering of tests for thrombophilia is strongly heterogeneous and still scarcerly respective of evidence-based data. While, portal and cerebral vein thrombosis seem to be less related to prothrombotic gene variants, and only FII G20210A seems to act as a risk factor, particularly in females, again confirming the existence of sex-related risk factors. Finally, retinal vein thrombosis is poorly related to prothrombotic risk factors, confirming the view that local vascular factors have a pivotal role in its pathogenesis. The evidence of a sex related difference in some prothrombotic variants is a relevant result that, once confirmed in larger populations, may help to address prevention of such diseases in a sex-specific way.
Conclusions: Our data indicate that only FVL, FVR2 and FII G20210A are related to vein thrombotic diseases while all the other gene variants, frequently ordered in the clinical context, do not have a role as risk factors. Finally, this work suggests that improving the appropriateness of laboratory test requests means a better benefit for the patient and a reduction of unnecessary costs for the National Health System.