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【杂志】妊娠期易栓症的胎盘病理变化 妊娠期易栓症的胎盘病理变化   贺晶 陈璐   作者单位:30006 杭州,浙江大学医学院附属妇产科医院产科   本文版权所有,欢迎分享;如需转载,请注明出处,谢谢!   易栓症(thrombophilia)是指由于抗凝蛋白、凝血因子、纤溶蛋白等遗传性缺陷或存在获得性危险因素而易于发生血栓的一种病理状态,高凝状态和血栓前状态也是对血栓形成潜在危险度增加这一病理状态的理论描述。   美国病理家学会(College of American Pathologists, CAP)关于易栓症的诊断指南及2004年意大利Carraro提供关于一级实验室检测遗传性易栓症循证指南[-2]指出,妊娠期妇女具有血栓形成倾向,这种血栓前状态不一定发生血栓性疾病,但可能因凝血-抗凝机制或纤溶活性失衡,子宫螺旋动脉或绒毛血管微血栓形成,导致胎盘灌注不良甚至梗死,从而发生不良妊娠结局。近年来研究表明系统性红斑狼疮、抗磷脂综合征、妊娠合并糖尿病、妊娠期糖尿病、妊娠合并肾病、子痫前期、胎儿生长受限、羊水过少、胎盘早剥、反复流产、死胎及妊娠期或产褥期深静脉血栓形成、肺栓塞等均与遗传性或获得性易栓症有关[3-5],并相应发生一系列胎盘病理变化。   一、易栓症的胎盘循环障碍   良好的妊娠依赖于胎盘循环足够的血液供应。蛋白C系统是维持正常妊娠所必须的抗凝因子,可直接作为滋养层细胞的生长因子并保护其不被凋亡(可能与阻止纤溶降解的作用有关)。胎盘滋养层细胞可表达凝血酶调节蛋白和组织因子受体,具有抗凝和促凝双重作用。正常妊娠时凝血酶原与凝血酶调节蛋白结合,激活蛋白C后活化细胞表面的蛋白酶激活体受体-,从而促进滋养层细胞的增殖;由于同时激活了凝血酶活化纤溶抑制物,减少了因纤维蛋白降解产物在胎盘绒毛间隙的沉积而导致细胞过度凋亡的可能[6]。胎盘蛋白C系统不仅具有抗凝作用,而且与胚胎的生发长育有关[7]。超声显示,孕妇妊娠8~0周后,卵黄囊动脉血流信号消失,而脐带-胎盘循环血流增加,胎盘开始替代卵黄囊成为胚胎供血的唯一途径,此时母体子宫螺旋动脉才能与胎盘绒毛间隙相互接触[8]。故母体抗凝因子缺陷在妊娠8周前对胚胎并不产生明显影响,不良妊娠多发生于妊娠8~0周之后。   成功的妊娠依赖于母体-胎儿-胎盘充足的血运,防止胎盘绒毛间隙的母血及绒毛内树状动静脉分支的胎儿血发生凝集是保证胎盘血循环通畅的重要条件。易栓症患者体内持续的、异常的高凝血状态可导致胎盘组织出现血栓形成倾向,其结果是引起胎盘绒毛间隙纤维蛋白的沉积和胎盘血管小血栓形成,蜕膜血管纤维素样坏死,胎盘灌注量下降,从而导致不良妊娠结局发生。妊娠期易栓症的胎盘病理变化与其他妊娠疾病伴有母体或胎儿血管系统慢性梗阻者极其相似,但缺乏特征性的胎盘病变。   二、母体血循环障碍引起的胎盘病变   妊娠期易栓症的胎盘病变主要是由于母体的血流灌注不足所致,也可能是妊娠使早已存在的病变加重,促发血栓形成加速、绒毛间隙缺氧,严重的长期灌注不足可导致远端绒毛发育不全、胎儿氧摄取量减少、绒毛间隙氧自由基蓄积。上述过程加速了凋亡与合体滋养细胞的转归,合体结节增加并最终脱落进入母体循环,合体结节和伴发的其他介质如微粒、细胞因子、作用于血管的配体,引起母体循环中系统性内皮损伤,胎盘可出现如下病理变化。必须强调这些病理变化也可见于子痫前期、胎儿生长受限、死胎等疾病的胎盘,无论有无血栓形成倾向基础,胎盘的病变可能仅代表一种早已存在的母体灌注不足的恶化。   (一)胎盘梗死   由于母体全身性或局部性血管病变导致蜕膜螺旋动脉痉挛、狭窄或闭塞,使进入绒毛间隙的母体血流被阻断,引起局部缺血性绒毛坏死。梗死灶常为多发性,直径从数毫米至数厘米不等,切面边界清晰,呈颗粒样质地坚硬的圆形实质区,常与底板相连,很少延伸至绒毛膜板。如胎盘梗死灶呈深红色,又称为红色梗死,镜下见绒毛互相紧密挤压,绒毛间隙几乎完全消失,绒毛毛细血管扩张、充血。如胎盘陈旧性梗死,则呈黄白色,又称为白色梗死,镜下见大量挤压的绒毛,绒毛的合体滋养层细胞有不同程度的退变,毛细血管闭塞甚至消失。胎盘梗死面积0%时,可能对胎儿造成威胁。显然,易栓症背景下的胎盘以红色梗死表现为主。有学者报道易栓症背景下发生单一或多发梗死灶的发生率分别为72%和44%,而正常妊娠组的发生率分别为39%和4%,两者差异具有统计学意义[9]。   (二)绒毛周围大量纤维蛋白沉积   易栓症易导致胎盘绒毛周围纤维蛋白沉积。一项对32例易栓症患者胎盘进行病理分析的研究报道,胎盘绒毛周围纤维蛋白沉积发生率为62%[9],而在正常足月胎盘中其发生率报道不一,为22%~33%[9-0]。有学者比较了早发型重度子痫前期和无妊娠合并症的早产患者的胎盘病变,发现在合并早发型重度子痫前期的患者中,胎盘梗死、纤维蛋白沉积的发生率显著升高[]。少量的纤维蛋白沉积肉眼不易发现,广泛的纤维蛋白沉积可形成肉眼可见的斑块,形态不规则或卵圆形,质硬,切面呈灰白色、颗粒状或光滑无结构,与周围组织界限清楚,多位于胎盘的边缘。斑块由纤维蛋白及其所包裹的绒毛构成,被包裹的绒毛有不同程度的退变,并可累及绒毛膜板、远端绒毛血管树和绒毛底板。   (三)其他胎盘病理改变   对于易栓症胎盘病理的研究多数为回顾性的小样本研究,缺乏大规模的循证医学证据支持,较为一致的结论支持易栓症可导致胎盘梗死和绒毛周围纤维蛋白沉积的发生率升高。事实上,易栓症的胎盘病理改变并非单一,诸如细胞滋养层增生、纤维蛋白样坏死、绒毛膜下纤维蛋白沉积、绒毛膜下及绒毛间血栓形成、底蜕膜或边缘蜕膜血肿、螺旋动脉粥样硬化及胎盘早剥等病理改变,但由于样本量较小或仅为个例报道,无法证实胎盘病理改变与易栓症最终导致不良妊娠结局存在相关性,多为理论推理。   .绒毛膜下纤维蛋白沉积:在正常足月胎盘中发生率约为20%,对胎儿的生长发育无不良影响,在易栓症病例中亦可观察到。纤维蛋白可沉积于羊膜与绒毛膜之间,在胎盘胎儿面绒毛膜下呈灰白色斑块,质硬,形态不规则,切面为层状,与周围组织间界限清楚。斑块由分层的纤维蛋白组成,其内无绒毛成分,与正常非绒毛膜板附着甚紧。当然,易栓症者绒毛膜下纤维蛋白沉积比例增加,胎盘功能不良发生率增加。   2.绒毛膜下血栓:绒毛膜下血栓中的血液来自母体,易栓症背景下母体全身或局部的血流动力学改变可能引起绒毛间隙血流动力学的改变,使流经绒毛间隙的血流速度突然明显变慢并导致血栓形成。血栓将绒毛膜板与其下的绒毛隔开,成层纤维蛋白黏附于绒毛间隙顶部,即绒毛膜的细胞滋养细胞及其周围的纤维蛋白。小的绒毛膜下血栓呈红色或黄白色,散在的绒毛膜下小血栓对胎儿无明显影响,常被漏诊或忽视。大的绒毛膜下血栓呈红色结节状或肿块状,突出于胎盘的胎儿面,也可形成光滑肿块伸入胎盘实质中。巨大绒毛膜下血栓影响胎儿与母体血液间的气体及物质交换,严重者可危及胎儿生命,造成死胎。发生易栓症时,巨大的绒毛膜下血栓形成罕见,小的绒毛膜下血栓形成可能与胎儿宫内生长受限等不良围产结局相关。   3.绒毛间血栓:绒毛间血栓系绒毛间隙内的凝血块,不含绒毛成分,常发生于合体或细胞滋养层细胞退变的背景上。病灶大多位于胎盘的中央部,呈圆形或卵圆形,常为多个血栓并存,一个胎盘可有20余个大小不等、形成时间不同的血栓。新鲜的血栓质软,色暗红,由红细胞组成,数天后红细胞溶解,血栓的中央部分常可见到胆红素、含铁血黄素及吞噬了红细胞的巨噬细胞。随着时间的延长、红细胞的退变及纤维蛋白的沉积,血栓的质地逐渐变硬,形成白色、边界清楚的层状斑块。目前绒毛间血栓的发病机制尚不完全清楚,多数学者认为绒毛间血栓是母亲和胎儿的红细胞混合构成,而且在多数情况下,胎儿血仅为血栓中的一小部分,母体发生易栓症时形成绒毛间血栓的病因及构成亦尚未清楚。   4.胎盘早剥:胎盘早剥的主要病理变化是底蜕膜出血,在胎盘底板和子宫壁间形成血肿。底蜕膜血肿大小不等,一般为椭圆形,新鲜的血肿质软,鲜红色,易于胎盘分离,陈旧的血肿呈棕褐色,质较硬,与胎盘不易分离,剥离血肿后在胎盘母体面可见压痕。孕妇血管病变是最常见的相关因素,包括子痫前期、子痫、慢性高血压或慢性肾脏疾病,这类疾病引起全身血管痉挛和硬化,子宫蜕膜螺旋小动脉也发生痉挛或硬化,引起远端毛细血管缺血坏死而破裂出血形成血肿。一项回顾性队列研究分析了0年间247例胎盘早剥病例,认为妊娠期高血压和子痫前期为其独立高危因素,其相对风险值分别为7.4和2.9[2]。有文献报道,单纯易栓症胎盘早剥发生率并未升高[9],而在易栓症合并严重妊娠并发症如重度子痫前期的患者,胎盘早剥的发生率升高,这一定程度反映了母体血管破坏的程度。   5.底蜕膜血肿:是胎盘早剥的结果,也称为胎盘后血肿,其发生率约为4.5%。底蜕膜血肿大小不等,小者直径为~2 cm,大者可占据整个胎盘的母体面。血肿一般为椭圆形,新鲜的血肿质软、鲜红色,易与胎盘分离,多是分娩时形成,对母胎无特殊不良影响。陈旧的血肿呈棕褐色,质较硬,与胎盘粘连不易分离,剥离血肿后在胎盘母体面可见压痕。镜检可见边界清晰的纤维蛋白网状结构中有皱缩的红细胞聚集,附近的蜕膜及滋养细胞有含铁血黄素,周围有白细胞浸润,底板的细胞结构可完全破坏,并有明显的退行性变。底蜕膜血肿形成后,影响胎儿血供,可导致胎儿窘迫甚至死胎,母亲可因子宫卒中导致子宫收缩不良和产后出血。   6.螺旋动脉急性粥样硬化:镜检显示螺旋动脉子宫肌段甚至蜕膜小动脉缺乏妊娠生理性变化,血管壁呈纤维蛋白样坏死,管壁中有许多嗜脂质细胞,血管周围有不等量的淋巴细胞和浆细胞浸润。这种病变只发生于未重铸的螺旋动脉,与早发型子痫前期的病变相似,可导致绒毛梗死或胎盘剥离[0]。   三、胎儿血液循环障碍引起的胎盘病变   胎盘分有母体和胎儿两个血液循环,其中胎儿的血液循环障碍主要导致胎儿血管的血栓形成(fetal vessel thrombosis)和胎儿的血栓性血管病变(fetal thrombotic vasculopathy)。此外,一些其他胎儿循环的微血管病变亦可导致胎盘病变,可能与供应绒毛组织的胎儿循环丧失有关。其病变机制尚不清楚,可能由于易栓症时血管壁暴露于一些特殊的细胞因子或胎儿循环的凝血级联异常,破坏了早期胎儿、胎盘的脉管系统,导致胎盘病变。   (一)胎儿血管血栓形成   胎儿血管中的血栓多发生于胎盘浅表的血管及干绒毛的血管中,更常见于胎盘胎儿面的静脉和胎盘内的静脉中,有时胎儿血管中的血栓是由脐带的血栓伴发的。胎儿血管血栓形成基本上可分为闭塞性和非闭塞性两种,闭塞性血栓对胎儿的危害更严重,而非闭塞性的胎儿血栓性血管病变在干绒毛或胎儿面的血管中表现为附壁血栓、内膜垫等,当血栓形成很久时,血管也可以完全闭塞,发展为闭塞性血栓,表现为没有管腔的圆形纤维肌性的结构[3]。   绒毛膜板上一根大的胎儿动脉或一根较小的胎儿干动脉闭塞,可导致退行性变,最后远端较小的血管和毛细血管消失,闭塞血管的下游有成簇的无血管的绒毛,此即称为胎儿的血栓性血管病变。由于许多血栓累及较小的血管,远端纤维化的无血管绒毛往往是很小的,仅在显微镜下才可辨认。当一根较大的胎儿血管闭塞时,肉眼可见在胎盘上形成一个界限清楚的无血管绒毛区,病灶呈灰白色,多为三角形,基底部朝向底板。镜下可见无血管绒毛沿绒毛树分支分布,其血管和间质基本萎缩,间质通常呈粉红色、玻璃样变,因绒毛间隙仍正常开放,间隙中仍有母血灌注,合体滋养细胞可存活,不过合体结节会增多,血栓远端较大的胎儿干血管有分隔现象。有血栓的血管,其中层过度增生和内膜的增生形成纤维肌性的硬化症特征,最后管腔闭塞。单条干绒毛动脉血栓形成时,受累的绒毛面积不到胎盘的5%,对胎儿的影响不大。当多条干绒毛动脉受累,形成多发性血栓,使受累绒毛面积达30%以上时,可因血供不足导致胎儿窘迫甚至死亡。   正常足月胎盘中单条干绒毛动脉血栓的发生率约为5%,糖尿病患者胎盘干绒毛动脉血栓的发生率高达0%,死胎胎盘约4%有多发性干绒毛动脉血栓[0]。既往认为胎儿的血栓性血管病变是继发于血液流经受损的脐带,但随后的研究发现血栓形成也可见于伴有母体或胎儿的血栓形成倾向者。虽然缺乏易栓症患者干绒毛动脉血栓发生率的统计数据,但有学者对3例遗传性易栓症伴不良围产结局(如死胎、严重胎儿生长受限、新生儿脑瘫及子痫前期)的患者进行胎盘病理检查,7例发生干绒毛动脉血栓,例发生胎儿血栓性病变,这8例患者均为死胎或严重胎儿宫内生长受限,提示易栓症时胎儿血管血栓形成可能与胎儿预后不良密切相关[4]。另一项回顾性队列研究比较了54例病理检查证实有胎儿血栓性血管病变与00例无该病变的孕妇的临床资料,发现存在胎儿血栓性血管病变的病例中,妊娠期并发症包括妊娠期高血压、子痫前期、急产、剖宫产、胎儿宫内生长受限、死胎、胎心率异常及血栓栓塞性疾病的发生率均较对照组升高[5]。   (二)其他胎儿血管病变   除了上述胎儿血管血栓形成,还存在一些其他类型胎儿血管异常,可能协同引起胎盘的胎儿循环障碍。出血性血管内膜炎多继发于近端血管闭塞,末端绒毛的血流突然停止导致血管退行性变。慢性血管周炎可累及胎盘近端胎儿的血管,并合并慢性绒毛炎,导致血管闭塞和(或)血栓形成,可伴有胎儿的血栓形成倾向。绒毛膜血管病和绒毛膜血管瘤病病变则位于终末绒毛毛细血管,引起末梢循环阻力增加和血流停滞[3]。   虽然妊娠期易栓症缺乏特征性的胎盘病理改变,但目前的胎盘病理研究支持该疾病所伴发的胎盘病变多是母体血管闭塞和绒毛灌注不足所致。因此,对胎盘病理的研究有助于我们识别易栓症和了解易栓症导致不良妊娠结局的机制。由于妊娠期易栓症胎盘的病变与其他妊娠并发症或合并症的胎盘病变相类似,故病理诊断时应多部位取材,结合临床资料和典型的胎盘病理做出诊断。   参 考 文 献(略)   贺晶, 陈璐. 妊娠期易栓症的胎盘病理变化[J/CD]. 中华产科急救电子杂志,204,3(2):86-89.
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