The PAI-I gene 4G/5G Polymorphism and Deep Vein Thrombosis in Patients with Inherited Thrombophilia

Abstract

Genetic and acquired factors may influence phenotypic expression of inherited thrombophilia. Hypofibrinolysis due to excess PAI-1 can be found in patients with deep vein thrombosis (DVT) and 4G/5G polymorphism of the PAI-1 gene may modulate the inhibitor's synthesis. In 149 patients with inherited thrombophilia, the possible thrombotic contribution of both 4G/5G polymorphism and PAI-1 plasma levels was evaluated. Sixty-seven patients with idiopathic DVT and 98 normal subjects were also studied. By comparison with controls, a significantly higher prevalence of 4G/4G genotype was seen in idiopathic DVT and in thrombophilia patients, although in this latter group the difference only remained significant in cases symptomatic for thrombosis (p = 0.01). The 4G/4G genotype was associated with a greater risk of thrombosis both in symptomatic thrombophilia patients (OR 2.85, 95% CI 1.26-6.46) and in idiopathic DVT patients (OR 3.1, 95% CI 1.26-7.59). The greater frequency of 4G allele in symptomatic thrombophilia patients with respect to controls was statistically significant (p = 0.04). Compared to healthy subjects, PAI-1:Ag levels were higher in symptomatic thrombophilia patients and related to the 4G/5G polymorphism, with significantly higher values in the 4G/4G carriers. In conclusion, PAI-1 4G/5G polymorphism may influence PAI-1 expression and thrombotic risk in patients with inherited thrombophilia.

Contraception-Related Deep Venous Thrombosis and Pulmonary Embolism in a 17-Year-Old Girl Heterozygous for Factor V Leiden, Prothrombin G20210A Mutation, MTHFR C677T and Homozygous for PAI-1 Mutation: Report of a Family with Multiple Genetic Risk Factors and Review of the Literature

“…Data obtained in a recent meta-analysis suggest that PAI-1 4G/5G polymorphism is probably a mild risk factor for VTE. However, the 4G allele appears to increase the risk of VTE, particularly in subjects with other genetic thrombophilic defects [7,8,[31][32][33] .…”

“…PAI-1 polymorphism is not considered an independent risk factor for VTE, and some literature data suggest an additional role of this polymorphism in VTE occurrence in subjects who are carriers of genetic or acquired thrombophilic factors. High plasma levels of PAI-1 have been associated with an increased risk of initial and recurrent DVT in Caucasians as well as with a 4G/5G insertion/deletion polymorphism in the promoter region of the PAI-1 gene [7][8][9] . Numerous other proposed causes of thrombophilia have been tested in a small number of patients, and none of them have gained widespread acceptance as risk factors for thrombosis [6,7,10] .…”

“…It has been established that abnormalities of the anticoagulant mechanisms in plasma such as antithrombin (AT), protein C (PC), and protein S (PS) deficiencies are related to VTE accidents. Besides, the presence of activated PC (APC) resistance, a phenomenon mostly attributable to the presence of a factor V Leiden (FV Leiden) mutation [6][7][8] , and the prothrombin gene mutation G20210A (FII 20210A) are also associated with an increased VTE risk [3,6] . These mutations are more prevalent than the deficiency of the anticoagulant proteins AT, PC, and PS, accounting for a much higher population-attributable risk in Caucasians.…”

Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism

“…It is plausible that increased production of PAI-1 induces a prothrombotic state by inhibiting tPA-dependant plasmin production and, thus, fibrinolysis. Indeed, susceptibility to thrombosis has been confirmed in the setting of meningococcal septicemia, trauma, and deep vein thrombosis (1)(2)(3). Additionally, there are clinical data associating deficiencies in PAI-1 production with an increased likelihood of hemorrhagic events (4 -6).…”

Polimorfismos genéticos relacionados à hemostasia e a sua relação com abortos espontâneos recorrentes

“…Bem como, o alelo 4G foi encontrado em maior frequência em indivíduos com TVP do que em controles, embora haja divergência na sobre esse dado na literatura (Sartori et al, 2003;Chen et al, 2005;Coulam et al, 2008;Akhter et al, 2010).…”