D-dimer在非孕女性血栓傾向中的作用:指標解析與臨床意義

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研究發現,D-dimer可作為首個篩查不孕女性潛在血栓傾向的標誌物,特別是未解釋原因的不孕症患者。血栓傾向與不孕密切相關,透過早期檢測D-dimer,可加速診斷並提高治療效果。進一步研究將確認這一方法的廣泛應用潛力。

The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility

D-dimer 作為不孕女性血栓傾向的首要標誌:對血栓性不孕之病理生理與診斷的啟示

Di Micco P, D’Uva M, Strina I, et al. The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility. J Transl Med. 2004;2(1):38. Published 2004 Nov 9. doi:10.1186/1479-5876-2-38

https://pmc.ncbi.nlm.nih.gov/articles/PMC535536/

Abstract

Background

D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia.

Patients and Methods

We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient’s section of vascular medicine for suspected deep venous thrombosis.

Statistical analysis was based on χ2 test, differences were considered to be significant if p < 0.05.

Results

D-dimer was increased in 25/39 and 20/25 showed inherited/acquired thrombophilia while patients with normal d-dimer showed inherited/acquired thrombophilia in 7/14 (p: < 0.05, s).

Discussion

D-dimer is a well known marker of hypercoagulable state, in particular its high predictive negative value in case of suspected thrombosis has been recognised by several reports. Yet, increased d-dimer has been identified also for subclinical thrombophilia besides for vascular thrombosis. Our data, in fact, for the first time suggest an interesting role of d-dimer to identify women affected by unexplained primary or secondary infertility and thrombophilia. So, probably there is a role for d-dimer in these subjects for its predictive positive value. Of course, further data on large based population are needed to confirm our results, because these findings may speed up a diagnostic screening in these patients also for a good cost/effectiveness of this test.

Keywords: d-dimer, thrombophilia, alteration of haemostasis, sterility, recurrent fetal loss

摘要

背景

D-dimer 被視為高凝狀態及內源性纖維蛋白溶解的標誌,因此在血栓患者中可檢測到其升高。然而,多項研究顯示,不孕症,特別是因反覆流產導致的繼發性不孕,往往與血栓事件相關,尤其是攜帶遺傳性血栓傾向(如 MTHFR C677T、PTHR A20210G、Factor V Leiden 基因多型性,或遺傳性蛋白 C、蛋白 S、AT III 缺乏)或後天性血栓傾向(如原發性抗磷脂症候群、後天性蛋白 C、蛋白 S、AT III 缺乏,以及藥物引起的血栓傾向)的女性。此外,由於其在疑似血栓病例中具有高度陰性預測價值,升高的 d-dimer 常與亞臨床血栓傾向相關。本研究旨在探討 d-dimer 作為不明原因不孕女性血栓傾向首要標誌的作用,並進一步尋找 d-dimer 升高的原因,例如遺傳性和/或後天性血栓傾向。

病患與方法

我們選取了 79 名不明原因的原發性或繼發性不孕患者,排除 40 名患有輸卵管積水、子宮肌瘤、子宮畸形、內分泌及免疫疾病、黃體不足、細胞遺傳學異常的患者。其餘 39 名患者接受 d-dimer 檢測,分為兩組:A 組(25 名患者)血漿 d-dimer 水平升高,B 組包括 14 名血漿 d-dimer 水平正常的患者。隨後對這 39 名患者進行 MTHFR C677T、PTHR A20210G、Factor V Leiden 基因多型性、蛋白 C、蛋白 S、AT III、抗心磷脂抗體 IgM 和 IgG 以及狼瘡抗凝劑的篩查。同時,控制組包括 15 名年齡相符、無不孕問題且因疑似深部靜脈血栓而就診於我們血管醫學門診的女性。

統計分析基於 χ² 檢驗,當 p < 0.05 時,差異視為顯著。

結果

在 39 名患者中,25 人 d-dimer 升高,其中 20 人顯示遺傳性/後天性血栓傾向;而在 d-dimer 水平正常的患者中,14 人中有 7 人顯示遺傳性/後天性血栓傾向(p < 0.05,具有顯著性差異)。

討論

d-dimer 是一種已知的高凝狀態標誌,其在疑似血栓病例中具有高度陰性預測價值已被多篇報告確認。此外,d-dimer 升高除了與血管血栓相關外,亦被認為與亞臨床血栓傾向有關。我們的數據首次提出,d-dimer 在識別不明原因的原發性或繼發性不孕及血栓傾向女性中具有重要作用。因此,d-dimer 在這些患者中的預測陽性價值可能具有應用潛力。然而,仍需更大規模的數據進一步確認我們的研究結果,因為這些發現可加速此類患者的診斷篩查,並具有良好的成本效益比。

關鍵詞: d-dimer、血栓傾向、凝血異常、不孕症、反覆流產

引言

D-dimer 被視為高凝狀態與內源性纖維蛋白溶解的標誌,因此在動脈和/或靜脈血栓患者中可檢測到其升高現象 [1]。然而,多項研究也顯示,即便在無進行性血栓的亞臨床血栓傾向患者中,d-dimer 仍可能升高 [2]。此外,在其他臨床狀況中,例如慢性炎症(如感染性疾病,若合併敗血症,亦可作為彌散性血管內凝血的指標)、癌症、壞死、老齡化及懷孕等,也可能觀察到血漿 d-dimer 水平升高 [3-8]。因此,d-dimer 檢測通常用於臨床管理,特別是在疑似血栓的情況下(例如深部靜脈血栓,DVT),因其具有高度陰性預測價值 [9-11]。

然而,多項研究顯示,患有不孕症的女性(尤其是因反覆胎兒流失導致的繼發性不孕)常存在潛在的遺傳性和/或後天性血栓傾向 [12-20]。除了常見的血栓風險因子(如不良生活習慣:肥胖、不遵循地中海飲食、久坐不動),還有多種分子層面的血栓風險因子已被鑑定,包括遺傳性或後天性凝血抑制物缺乏(如蛋白 C、蛋白 S、抗凝血酶 III 缺乏)、遺傳性血栓傾向(如第 V 因子 Leiden 突變、凝血酶原 A20210G 突變)、原發性或繼發性高同型半胱氨酸血症、原發性或繼發性抗磷脂症候群,以及血漿第 VIII 因子水平升高 [21]。此外,這些分子異常在某些患者中可能同時存在,導致基因與基因間交互作用及/或基因與環境間交互作用 [22-24]。

因此,基於 Brenner 等人的研究數據 [24,25],考慮到這些患者中凝血異常的高發率,我們旨在探討 d-dimer 作為不孕女性血栓傾向首要標誌的作用,從而識別 d-dimer 升高的原因以及可能導致的不孕原因。

病患與方法

我們選取了 79 名因原發性或繼發性不孕(至少三次胎兒流失)而至不孕中心就診的女性患者。排除了 40 名患有輸卵管積水、子宮肌瘤、子宮畸形、黃體功能不足、無排卵、細胞遺傳學異常、感染性疾病、內分泌疾病(如糖尿病、垂體功能低下)及免疫性疾病(遺傳性和/或後天性免疫缺陷、類風濕性關節炎、系統性紅斑狼瘡、系統性硬化症、血管炎)的患者。

篩選後剩餘的 39 名患者中,12 名為原發性不孕,27 名為因反覆胎兒流失導致的繼發性不孕。這 39 名患者均接受了 d-dimer 檢測。d-dimer 的測量採用多種方法 [26],其中 31 名患者在卵巢月經週期的不同時期隨機測試,1 名患者於月經期進行測試,另有 7 名患者在接受荷爾蒙治療以促進卵巢超排卵(COH)期間進行測試。根據 d-dimer 檢測結果,患者分為兩組:A 組為 d-dimer 水平升高的 25 名患者,B 組為 d-dimer 水平正常的 14 名患者。同時選取 15 名年齡相匹配、病史中無不孕問題的女性作為對照組,這些女性因疑似深部靜脈血栓(DVT)而至血管醫學門診就診。

在完成 d-dimer 檢測後,為確定可能的遺傳性和/或後天性血栓傾向,所有患者接受了以下篩查:亞甲基四氫葉酸還原酶 C677T 基因多型性(MTHFRC677T)、第 V 因子 Leiden 基因多型性(FVL)、凝血酶原 A20210G 基因多型性(PTHRA20210G)、蛋白 S 缺乏、蛋白 C 缺乏、抗凝血酶 III(AT III)缺乏、狼瘡抗凝劑,以及 IgM 和/或 IgG 抗心磷脂自體抗體 [22,27]。

此外,對於 d-dimer 升高的患者,進一步檢測 β-人絨毛膜促性腺激素(β-HCG),以排除早期妊娠,並結合下肢超音波血管檢查和壓縮超音波(CUS),以排除下肢深部靜脈血栓(DVT)。這兩種情況均為已知會導致 d-dimer 升高的狀況 [4,9-11]。

最後,對比 A 組(25 名患者)和 B 組(14 名患者)的遺傳性和/或後天性血栓傾向的分子標誌是否存在差異。

統計分析採用 χ² 檢驗,當 p < 0.05 時,差異視為具有顯著性。

結果

在 A 組中,80% 的患者具有血栓傾向;在 B 組中,50% 的患者具有血栓傾向。綜合 A 組(不孕且 d-dimer 升高的女性)與 B 組(不孕但 d-dimer 正常的女性),39 名患者的總血栓傾向比例為 65%(表 1,「見附加文件 1」)。

A 組中 25 名不孕且 d-dimer 升高的患者中,有 20 人(80%)顯示遺傳性和/或後天性血栓傾向,包括:6 人為 MTHFRC677T 同型合子,4 人為 FVL 異型合子,5 人為 PTHRA20210G 異型合子,3 人為遺傳性蛋白 S 缺乏;另有 2 人顯示複合缺陷(1 人為 MTHFRC677T 同型合子伴蛋白 S 缺乏,1 人為 MTHFRC677T 同型合子伴 FVL 異型合子);無蛋白 C 缺乏、AT III 缺乏、狼瘡抗凝劑陽性或抗心磷脂抗體(IgM 和/或 IgG)升高的病例(表 2,「見附加文件 2」)。

A 組中其餘 5 人未顯示分子血栓傾向,但病史中有與後天性血栓傾向相關的潛在因素,包括:1 人接受卵巢超排卵治療,1 人處於月經期間,1 人為早期妊娠,1 人有流產史,1 人無明顯原因;其中 2 人為 MTHFRC677T 異型合子。此外,A 組中 2 名攜帶 FVL 異型合子且 d-dimer 升高的患者,其病史中顯示曾發生深部靜脈血栓(DVT)及隨後的肺栓塞。

B 組中 14 名患者中有 7 人(50%)顯示遺傳性和/或後天性血栓傾向,包括:1 人為 MTHFRC677T 同型合子,1 人為 FVL 異型合子,5 人為 PTHRA20210G 異型合子;無蛋白 S 缺乏、蛋白 C 缺乏、AT III 缺乏、狼瘡抗凝劑陽性或抗心磷脂抗體(IgM 和/或 IgG)升高的病例(表 2,「見附加文件 2」)。B 組其餘 7 名患者均為 MTHFRC677T 異型合子。無患者顯示既往有 DVT 或肺栓塞。

C 組(對照組)15 名患者中有 5 人(33.3%)顯示 d-dimer 升高,且經超音波血管檢查與壓縮超音波(CUS)證實為進行性近端 DVT;此外,這 5 人均顯示潛在的遺傳性和/或後天性血栓傾向,其中 3 人為 MTHFRC677T 同型合子,1 人為蛋白 S 缺乏,1 人為複合血栓傾向(FVL 異型合子伴蛋白 S 缺乏)(表 2,「見附加文件 2」)。

在所有組別中,均未發現抗心磷脂抗體或狼瘡抗凝劑陽性,無法模擬原發性抗磷脂症候群(APS)。

如表 3 所示(「見附加文件 3」),d-dimer 升高的女性中,血栓傾向的發生率顯著較高;而在 d-dimer 正常的患者中,這種相關性較低,且差異達統計學顯著性(p < 0.05)。此外,A 組的血栓傾向發生率顯著高於 C 組(對照組),且差異具有統計學顯著性(p < 0.05)。最後,B 組的血栓傾向發生率高於 C 組,但差異未達統計學顯著性(p = 0.08,無顯著性)。

討論

本研究首次探討 d-dimer 在不孕患者診斷篩查中的作用,為該臨床領域提供了創新數據。

d-dimer 是纖維蛋白降解的產物,通常用於疑似血栓或肺栓塞患者的篩查 [9]。雖然血漿 d-dimer 升高對深部靜脈血栓(DVT)和/或肺栓塞具有陽性預測價值,但由於 d-dimer 升高也出現在與血栓無關的多種情況(如惡性腫瘤、慢性炎症、感染、急性冠狀動脈綜合症、壞死、老齡化)[3-9],其更重要的臨床價值在於其陰性預測價值 [9]。此外,據報導,在無進行性血栓但具有血栓傾向的患者(如遺傳性和/或後天性血栓傾向)中,也可觀察到 d-dimer 升高 [2,23]。

本研究結果顯示,A 組 d-dimer 升高的患者中,80% 存在已知與高凝狀態相關的分子異常(表 2,「見附加文件 2」),該比例在統計學上顯著高於 B 組和 C 組(表 3,「見附加文件 3」)。此外,A 組中有 5 名患者未顯示遺傳性或後天性血栓傾向,但深入病史調查和臨床評估發現,4 人的 d-dimer 升高與以下因素相關:早期妊娠、早期流產、卵巢超排卵治療或月經期,均為已知與高凝狀態相關的情況;剩餘 1 人的原因可能與未明確診斷的血栓傾向或其他狀況相關 [34]。

此外,B 組雖然 d-dimer 水平正常,但仍有 50% 的患者存在血栓傾向(表 1,「見附加文件 1」),進一步確認了血栓傾向與不孕之間的密切關聯。B 組患者未顯示 d-dimer 升高的原因可能包括實驗室誤差、血栓傾向的暫時性或隱性表現等,這些患者在自然病程中可能因其他誘因(如後天性血栓傾向)而進入高凝狀態。

在我們的研究群體中,與反覆流產相關的血栓傾向(如蛋白 C、蛋白 S、AT III 缺乏)的發生率相對較低,而其他血栓傾向(如 FVL 基因多型性、MTHFRC677T 同型合子、PTHRA20210G 基因多型性)則更為普遍,這與文獻中報導的趨勢一致 [12-20]。FVL 和 MTHFRC677T 的異常在 A 組和 B 組中均有較高比例,這進一步支持其在不孕症病理生理中的重要性。此外,PTHRA20210G 的高發率可能與南歐人群的基因特徵有關 [44,45]。

有趣的是,我們的研究未發現抗磷脂症候群(APS)的病例,這可能與我們的排除標準相關,因為我們排除了免疫病理性疾病患者,進而排除了次級 APS 的常見病因 [46]。

結論

本研究結果明確證實血栓傾向在不孕患者中的重要作用,並顯示 d-dimer 升高在這些患者中的顯著診斷價值。基於 d-dimer 水平的不孕女性血栓傾向篩查,不僅快速且具成本效益,還能有效懷疑血栓傾向,但仍需考量其他可能導致 d-dimer 升高的因素。在 d-dimer 水平升高的情況下,可進一步調查高凝狀態的原因(例如遺傳性和/或後天性血栓傾向),這一方法不僅有助於不孕症的鑑別診斷,亦有助於早期診斷血栓傾向所致的不孕症。

第一步評估 d-dimer 後,應繼續分析 d-dimer 升高的原因,以便及時展開潛在抗凝治療。雖然少數 d-dimer 水平正常的患者也可能存在血栓傾向,但若排除其他不孕原因,仍應對血栓傾向進行篩查。

因此,我們強烈建議將 d-dimer 作為不孕患者潛在血栓傾向的初步篩查工具,幫助早期識別血栓傾向的原因並及早治療。然而,我們的研究結果需要進一步基於大規模人群的研究來加以驗證。

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