Protection From Pregnancy Loss in Women With Hereditary Thrombophilia When Associated With Fibrinogen Polymorphism Thr331Ala.

Abstract

Thrombophilia such as protein C (PC), antithrombin (AT), or protein S (PS) deficiency can cause either fatal or frequent venous thromboembolism (VTE); however, Japanese individuals have few factor V Leiden or prothrombin mutations. The a-fibrinogen (FGA): p.Thr331Ala polymorphism occurs in a region that is important for FXIII-dependent cross-linking, and it may therefore affect the clot structure or degree of rigidity. A significant association has been observed between FGA: p.Thr331Ala and poststroke mortality in participants with atrial fibrillation, and this fibrinogen polymorphism has also been reported to be associated with VTE; the genotype distribution of patients with pulmonary embolism (TT 1⁄4 49%, TA 1⁄4 36%, AA 1⁄4 15%) differed significantly from healthy control participants (TT, wild type 1⁄4 60%, TA, heterozygous 1⁄4 34%, AA, homozygous 1⁄4 6%). The frequency of the FGAThr312Ala polymorphism was reported to be 46.5% in Japanese individuals and 29.9% in Europeans. A previous report suggested that FGA: p.Thr331Ala may cause early pregnancy loss. Therefore, FGA: p.Thr331Ala polymorphism was examined in 27 pregnant women without early pregnancy loss and 26 those with more than 1 experience of suffering early pregnancy loss, including 14 patients with thrombophilia according to a genetic analysis (4 with hereditary AT deficiency, 9 with hereditary PC deficiency, and 1 with hereditary PS deficiency) and 8 patients with hypofibrinogenemia (less than 1.5 g/L vs normal range 1.8-2.8 g/L). Of 14 patients with hereditary thrombophilia, 12 patients experienced VTE and 5 patients experienced pregnancy loss. All patients with AT deficiency were diagnosed during pregnancy, but 9 patients with PC deficiency and 1 with PS deficiency were diagnosed after delivery. The diagnosis of AT, PC, or PS deficiency was reported previously. Thirtyseven cases of thrombophilia (14 with AT deficiency, 16 with PC deficiency, and 7 with PS deficiency) with VTE were diagnosed at Mie University Hospital. The Japanese birth rate was 8.0 per 1000 in 2015, and the pregnancy loss rate varied with age. Early pregnancy loss was defined as an unknown cause, and more than 1 abortion before 10 weeks of pregnancy occurred. Early pregnancy loss was found to be associated with 8 (57.1%) of 14 women demonstrating homozygous FGA: p.Thr331Ala polymorphism, in 17 (54.8%) of 31 women with heterozygous FGA: p.Thr331Ala polymorphism and in 1 (12.5%) of 8 women with FGA: p.Thr331. The rate of pregnancy loss was 1 in 10 cases, 2 in 9 cases, 3 in 6 cases, and 8 in 1 case, respectively. Although FGA: p.Thr331Ala polymorphism was found to increase the risk of early pregnant loss, thrombophilia reduced the risk of early pregnant loss (Table 1). The risk of early pregnancy loss was significantly higher in women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in women with FGA: p.Thr331 (Odds ratio: 8.84, P < .05). Although the risk of early pregnancy loss tended to be low in the thrombophilic women with either homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women, it was significantly higher in the nonthrombophilic women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women (odds ratio: 4.85, P < .01). These findings suggest that thrombophilia might provide some advantage for preserving pregnancy in women with an abnormal fibrinogen function, but thrombophilia causes thrombosis in pregnant women. As our analysis was small and there may have been some bias in the selection of samples, further investigation is therefore required. In conclusion, although FGA: p.Thr331Ala polymorphism increased the risk of early pregnant loss, thrombophilia reduced the incidence of early pregnant loss in women with FGA: