Is there a relationship between factor V Leiden and type 2 diabetes?

Background Diabetes is well known risk factor for thrombotic events. The association between diabetes and venous thromboembolism is still matter of debate. However, during diabetes an acquired thrombophilia is present and is due to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state. A possibile relationship between the presence of FVL gene variant in type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings. Patients and methods Retrospectively we analysed nearly 7000 patients referred to our Thrombosis Center for venous thromboembolism (VTE) then we selected 115 patients underwent to the screening for inherited thrombophilia. All selected patients were divided in 2 groups: the first group (group A) included 64 patients with previous VTE and carriers of factor V Leiden, while the second group (group B) included 51 patients with previous VTE and evetually carriers of thrombophilic defects other than factor V Leiden. Patients of group B acted as control group. 75 g oral glucose tolerance Test (OGTT) recommended by WHO was perfomed to all subjects in the study in order to screen subjects with glucose reduced tolerance or subjects with inducible diabetes. Statistical analysis was performed with STATA 6 with Student t test for unpaired data, with χ2 test or with Fisher exact test where appropriated; differences were considered to be significant if p < 0.05. Results We did not find sifferences between glycaemia at baseline and after OGTT between patients with VTE carriers of FVL compared to non-carriers of FVL. We found a relevant increase in the prevalence of IGT and diabetes between patients with VTE carriers of FVL compared to non-carriers of FVL although this increase did not raise statistical significance. Discussion our data pointed out an interesting aspect of the linking between FVL gene variant, diabetes and atherothrombosis and other vascular complications, although data on larger population are needed; this aspect may be another relevant topic of research based because also a link between the pathogenesis of venous thrombosis and atherothrombosis has been recently reported in the Literature.


Background
Diabetes is well known risk factor for thrombotic events [1]. In particular, since Framingham Study has been published diabetes is recognised as one of the more common risk factor for atherothrombosis [2]. Both type 1 diabetes (i.e. insulin dependent) and type 2 diabetes (i.e. not-insulin dependent) are associated to vascular events, in particular if glycated haemoglobin is higher than 7.0% [3]. Actually, in fact, vascular complications of diabetes represent the more common cause of morbidity and mortality of diabetic patients [4,5]. On the other sides the association between diabetes and venous thromboembolism (VTE) is still matter of debate [6,7]. Some Author did not find an association between diabetes and VTE [6], but recently several Authors showed that atherosclerosis and traditional atherosclerotic risk factor as diabetes should be considered also as risk factor for VTE, in particular for idiopathic VTE [8].
Of course, during diabetes an acquired hypercoagulability is present and is due to several factors as to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state [9,10]. This acquired thrombophilia may be added in any case to a possible inherited thrombophilia if such patients is carrier of such thrombophilic gene variant (e.g. A1691G of factor V and\or prothrombin A20210G) or other thrombotic risk factor.
Factor V Leiden (FVL) is a well known inherited thrombophilic condition both in heterozygosity or in homozygosity. The association between FVL and VTE has been frequently described [11], while the association between FVL and atherothrombosis is still matter of discussion in particular for patients with early onset of vascular atherothrombosis [12,13].
A possibile relationship between the presence of FVL gene variant and type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings [14][15][16].
The aim of our retropspective study is to find a possible association between factor V Leiden gene variant and type 2 diabetes in a population of patients with previous VTE.

Patients and methods
We performed a retrospective analysis of nearly 7000 patients referred to our Thrombosis Center for one or more episode of thrombotic disorders. After a first screening we analysed only patients with previous VTE and in this population, we selected subjects that perfomed the screening for inherited thrombophilia after one or more episodes of VTE; so, we selected 115 patients underwent to the screening for inherited thrombophilia.

Inclusion criteria
All selected patients were divided in 2 groups: the first group (group A) included 64 patients (33 males and 31 females, mean age 54 ± 9 years) with previous VTE and carriers of factor V Leiden as inherited thrombophilic defect, while the second group (group B) included 51 patients (26 males and 25 females, mean age 51 ± 9 years) with previous VTE and carriers of thrombophilic defects other than factor V Leiden. Patients of group B acted as control group.

Exclusion criteria
We excluded all patients affected by thrombotic disorders other than VTE, and younger than 40 years and with already personal history of diabetes.

Factor V Leiden identification
Whole blood samples were collected by venipuncture in order to screen the presence of factor V Leiden gene variant.
DNA was extracted using an automated procedure (MagNA PURE, Roche, Italy). Patients were screened for the G1691A gene variant of factor V Leiden using PCR amplification with specific primers and Light Cycler apparatus (Roche, Milan, Italy).

Latent diabetes or reduced glucose intolerance identification
75 g oral glucose tolerance Test (OGTT) recommended by WHO was perfomed to all subjects in the study. According to the WHO and National Diabetes Data Group (NDDG) guidelines, we diagnosed diabetes if glycaemia after 2 hours from OGTT was higher than 199 mg\dL and reduced glucose tolerance, if glycaemia after 2 hours from OGTT was higher than 139 mg\dL but lower than 199 mg/dl

Results
We did not find significant difference between glycaemia at baseline and two hours after OGTT

Discussion
The association between FVL and VTE is well known [11], while the association between FVL and atherothrombosis is still matter of discussion [12]. On the other hand, the association between diabetes and atherothrombosis is well known [9] while the association between diabetes and VTE has not been recognised by data available in the Literature [7]. However, it is already not known why such patients with diabetes develop more vascular complications both as atherothrombosis (of any district) as VTE and other patients with diabetes do not develop vascular complication. In previous years several research suspected a relationship between diabetes and FVL gene variants both for type 1 or type 2 diabetes but not univocal data were found [14][15][16]. Krekora et al. in fact suspected also a possible genetic co-segregation for both inherited disorders (i.e. type 2 diabetes and factor V Leiden gene variant) [16].
Our data revealed that there is relationship between latent diabetes in patients carriers of FVL with previous VTE, compared to controls although these data did not raise statistical significance. However, an increase of IGT and diabetes in the group A was found versus group B, so inducing the suspect that a relationship between diabetes and FVL may be looked for in larger population. From a methodological point of view, we may suppose that the number of selected patients should be increased in order to have a more appropriate dimension of the problem and this is actually may represent a study limitation; yet, based on the fact that we performed the study on a retrospective analysis we may speculate that our results are of great interest from a clinical point of view, although at this moment did not raise a statistical significance. Furthermore, from a clinical point of view, in fact, these data may explain better the personal and familial trend to develop thrombotic events of such diabetic community, being type 2 diabetes a disease that show multiple gene-gene interactions.
Moreover, a relevant aspect is related to the recent data present in the Literature that are linking more and more the pathophysiology of arterial and venous thrombosis: actually, in fact, it is not known because during the natural history of type 2 diabetes such diabetic patient present a significant number of atherothrombotic events or venous thrombosis or both type of vascular complications or none of them. Our results underline, in fact, that this clinical aspect could be typical of any community and nor for all type 2 diabetic patients because the inherited trend to develop type 2 diabetes is related to a multivariate genegene interaction and gene-enviromental interaction.

Conclusion
So, our data pointed out again an interesting aspect of the linking between FVL gene variant, diabetes and athero- This aspect, in fact, may be another relevant topic of research based on recent data from the Literature that are frequently linking the pathogenesis of venous thrombosis and atherothrombosis.