Inherited thrombophilia (IT) has a complex pathophysiology and is associated with recurrent miscarriage (RM) by causing placental insufficiency and inhibiting fetal development. However, thrombophilia screening in unexplained RM cases is still questionable. This study aimed to investigate the association between the common eight IT mutations and their combinations among Palestinian women with unexplained RM. This is an unmatched case-control study with 200 women (100 unexplained RM cases, 100 controls). Eight common IT mutations namely Factor V Leiden (FVL), prothrombin gene (FII) G202120A, Methylenetetrahydrofolate Reductase (MTHFR) gene (C677T and A1298C), B-fibrinogen gene − 455G > A, FV HR2 A4070G, Plasminogen activator inhibitor 1 (PAI1) 5G/4G and Factor XIIIA (FXIIIA) V34L; were analyzed. The first five mutations were analyzed by Restriction Fragment Length Polymorphism PCR and the other three mutations were analyzed using Amplification Refractory Mutation System PCR. The prevalence of the eight IT mutations among the control group was in the order PAI1 5G/4G (69%), MTHFR C677T (53%) and A1298C (47%), BFG − 455G > A (35%), FVL and FV HR2 (each 18%), FXIIIA V34L (16%) and FII G20210A (3%). Patients had a higher percentage of MTHFR A1298C (heterozygotes and mutant homozygote) compared to controls (p = 0.016). Frequencies of mutant alleles MTHFR A1298C (p < 0.001) and FXIIIA V34L (p = 0.009) were higher among patients compared to controls. No significant differences were observed for all other mutations or mutant alleles. Most patients (75%) and controls (75%) have 2–4 mutant alleles out of 8 mutant alleles studied, while 1% of patients and 2% of controls have zero mutant alleles. None of the combinations of the most often studied mutations (FVL, FII G20210A, MTHFR C1677T, and MTHFR A1298C) showed a significant difference between patients and controls. There was a significant association between unexplained RM and the mutant alleles of MTHFR A1298C and FXIIIA V34L. No significant association was observed between unexplained RM and the combination of both mutant alleles for the mutations studied. This study is the first Palestinian report that evaluates eight inherited thrombophilia mutations and their alleles’ combinations in unexplained RM cases.

中文翻译：

---

患有不明原因反复流产的巴勒斯坦妇女遗传性血栓形成倾向突变及其组合的关联

遗传性血栓形成倾向 (IT) 具有复杂的病理生理学，并通过导致胎盘功能不全和抑制胎儿发育而与复发性流产 (RM) 相关。然而，在不明原因的 RM 病例中进行血栓形成倾向筛查仍然值得怀疑。本研究旨在调查患有不明原因 RM 的巴勒斯坦妇女中常见的八种 IT 突变及其组合之间的关联。这是一项无与伦比的病例对照研究，涉及 200 名女性（100 名不明原因 RM 病例，100 名对照）。八种常见 IT 突变，即 V 因子 Leiden (FVL)、凝血酶原基因 (FII) G202120A、亚甲基四氢叶酸还原酶 (MTHFR) 基因（C677T 和 A1298C）、B 纤维蛋白原基因 − 455G > A、FV HR2 A4070G、纤溶酶原激活剂抑制剂 1 (PAI1) ) 5G/4G 和因子 XIIIA (FXIIIA) V34L；进行了分析。前五个突变通过限制性片段长度多态性PCR进行分析，其他三个突变通过扩增阻滞突变系统PCR进行分析。对照组中 8 种 IT 突变的发生率依次为 PAI1 5G/4G (69%)、MTHFR C677T (53%) 和 A1298C (47%)、BFG − 455G > A (35%)、FVL 和 FV HR2（各 18%）、FXIIIA V34L（16%）和 FII G20210A（3%）。与对照组相比，患者的 MTHFR A1298C（杂合子和突变纯合子）百分比较高 (p = 0.016)。与对照组相比，患者中突变等位基因 MTHFR A1298C (p < 0.001) 和 FXIIIA V34L (p = 0.009) 的频率较高。对于所有其他突变或突变等位基因，没有观察到显着差异。大多数患者 (75%) 和对照 (75%) 在研究的 8 个突变等位基因中具有 2-4 个突变等位基因，而 1% 的患者和 2% 对照具有零个突变等位基因。最常研究的突变（FVL、FII G20210A、MTHFR C1677T 和 MTHFR A1298C）的组合在患者和对照之间均未显示出显着差异。无法解释的 RM 与 MTHFR A1298C 和 FXIIIA V34L 突变等位基因之间存在显着关联。在无法解释的 RM 与所研究的突变的两个突变等位基因的组合之间没有观察到显着关联。这项研究是第一份巴勒斯坦报告，评估了不明原因 RM 病例中的八种遗传性血栓形成倾向突变及其等位基因组合。