血小板减少与早产儿视网膜病变的研究进展
Research Progress on the Association of Platelet Deficiency with Retinopathy of Prematurity
DOI: 10.12677/ACM.2023.13122617, PDF, HTML, XML, 下载: 102  浏览: 145 
作者: 程义明, 芦 起:重庆医科大学附属儿童医院新生儿诊疗中心,重庆
关键词: 早产儿视网膜病变血小板减少血管生成Retinopathy of Prematurity Platelet Deficiency Angiogenesis
摘要: 早产儿视网膜病变(retinopathy of prematurity, ROP)是发生在早产儿和低出生体重儿的视网膜血管增殖疾病,ROP的病理机制主要涉及视网膜血管发育不全和病理性新生血管形成。近年来研究发现血小板减少与严重早产儿视网膜病变的发生密切相关,本文针对血小板减少与早产儿视网膜病变的相关研究进展做一综述,为临床诊断与治疗ROP提供新的思考。
Abstract: Retinopathy of prematurity (ROP) is an abnormal proliferative disease of the retinal vasculature that occurs in preterm and low-birth-weight infants. The pathogenesis of ROP mainly involves reti-nal vascular hypoplasia and pathologic neovascularization. In recent years, it has been found that platelet deficiency is related to the severe retinopathy of prematurity. This review summarizes the current research on platelet deficiency and retinopathy of prematurity, and provides new insights for clinical diagnosis and treatment of ROP.
文章引用:程义明, 芦起. 血小板减少与早产儿视网膜病变的研究进展[J]. 临床医学进展, 2023, 13(12): 18617-18622. https://doi.org/10.12677/ACM.2023.13122617

1. 引言

早产儿视网膜病变(Retinopathy of prematurity, ROP)是全世界范围内儿童视力损伤和失明的主要原因 [1] [2] 。ROP是一种多因素疾病,早产和新生儿期氧疗是最常见的危险因素,此外,ROP的其他危险因素还包括支气管肺发育不良、脓毒症、脑室内出血等 [3] [4] [5] [6] 。目前关于ROP的病理生理机制研究尚未完全明确。血小板(Platelet)是血液循环中的重要组分,血小板是由骨髓发育成熟的巨核细胞合成并释放在外周循环中 [7] ,促进止血和伤口愈合,也在炎症、免疫反应和血管生成中发挥重要作用。血小板减少症是新生儿重症监护病房较常见的疾病,正常血小板计数为(100~300) × 109/L,当血小板计数低于100 × 109/L时称血小板减少症。研究发现,胎龄和出生体重越小,血小板减少症的发生率越高。据统计,出生体重 < 1000 g早产儿血小板减少症的发病率可达到73% [8] 。重度血小板减少症的发生会导致潜在出血风险增加,甚至引起严重并发症如颅内出血、肺出血等。近年来许多研究发现血小板减少在ROP的发展中有重要影响 [3] ,提示血小板减少可能在ROP的进展中发挥作用。本文拟就血小板减少与早产儿视网膜病变(ROP)相关研究进展综述如下。

2. 早产儿视网膜病变概述

早产儿视网膜病变(ROP)是一种玻璃体视网膜血管增生性疾病,由于早产儿(出生体重 < 1500 g,或孕周 < 32 w)视网膜血管化异常所致。近年来随着新生儿重症监护水平的不断提高,低胎龄早产儿存活率不断提高,严重ROP的病例也随之增加 [9] 。ROP的病理机制为视网膜血管发育不全和病理性新生血管形成,包括两个阶段:血管闭塞阶段和血管增生阶段。第一阶段发生在新生儿出生后至纠正胎龄32周,早产儿视网膜血管发育不成熟,生后暴露于宫外高氧环境,高氧抑制了视网膜生理性血管形成,视网膜血管生长受抑制,毛细血管退化、闭塞,导致视网膜缺血、缺氧;第二阶段为血管增生阶段,通常从纠正胎龄32周开始,视网膜组织代谢需求增加导致视网膜相对缺氧,未血管化的视网膜缺氧产生更多的VEGF,正常的血管生成被病理性血管生成替代 [10] [11] [12] 。

3. 血小板减少与早产儿视网膜病变的相关研究

3.1. 临床研究

Vinekar等 [13] 首次报告了1例重度血小板减少症(血小板计数:21 × 109/L)合并急进型后极部ROP (AP-ROP)患儿(胎龄28周,出生体重960 g),产后18天发现AP-ROP,在72 h内纠正血小板减少后,急进型后极部ROP (AP-ROP)症状自发缓解,并且不需要接受手术治疗。同一研究对10例AP-ROP病例和21例对照组的病例进行回顾性分析后发现:病例组的平均血小板计数(82.9 × 109/L)明显低于对照组(178.3 × 109/L) (P = 0.0002),此外,发生血小板减少症的病例组(50%)高于对照组(4.8%) (P = 0.007)。Jensen等 [14] 的一项1:1病例匹配对照研究中发现,血小板减少症的发生与严重ROP (Early Treatment of ROP)发生密切相关,血小板减少症是独立于胎龄、出生体重、脓毒症和坏死性小肠结肠炎等混杂变量的独立危险因素。随后的多项回顾性研究发现,视网膜血管发育阶段(纠正胎龄 < 35周),血小板减少症发生与严重ROP的发生密切相关 [15] 。

一些回顾性研究同时分析了血小板其他参数与ROP的相关性。血小板平均体积(MPV)是反映血小板活化功能的指标,较大体积的血小板具有更强的代谢活性。Tao [16] 等发现激光治疗术前1周内,1型ROP患儿的平均血小板体积(MPV)高于对照组,并具有统计学意义。但在另一项研究中,研究者发现ROP组与对照组平均血小板体积(MPV)差异无统计学意义 [17] 。血小板分布宽度(PDW)也被发现与ROP的发生存在相关性 [18] ,生后第一天及诊断ROP一周内血小板分布宽度(PDW)较高。

目前尚无临床研究可以证实血小板输注可减轻或者预防严重ROP的发生,Lundgren等 [19] 发现,血小板输注总天数和血小板输注量(ml/天)与AP-ROP呈正相关。然而,Sancak等 [20] 的研究则发现血小板输注与I型ROP的发生无相关性。由于相关研究均属回顾性研究,尚不清楚输血本身是否增加严重ROP发生的风险,未来仍需更进一步的研究证实预防性血小板输注对ROP结局的影响。

3.2. 实验研究

Bertan Cakir的一项小鼠氧诱导视网膜病变模型(OIR)实验研究表明:血小板的α颗粒可以释放抗血管生成刺激,抗血管生成刺激通过下调VEGF-A转录物的视网膜表达,从而抑制早产儿视网膜病变第2阶段视网膜新生血管形成,从而对血管内皮细胞发挥局部抗血管生成作用。与对照组(含氧量正常)相比,小鼠模型在生后17天(新生血管阶段)的血小板计数较低,血小板的耗竭增加了新生血管形成,同时增加了VEGF-A转录物的视网膜表达。小鼠模型在生后15天、16天时血小板输注可以抑制新生血管形成并降低VEGF-A转录物的视网膜表达 [21] 。作者同时研究了具有完整颗粒的静息血小板和凝血酶激活的脱颗粒血小板,发现完整颗粒的静息血小板可以减少新生血管形成,而凝血酶激活的脱颗粒血小板则不能,这也证实:血小板颗粒的成分参与抑制新生血管形成的过程,而不是血小板与内皮的相互作用,血小板减少可以促进新生血管生成 [21] 。

4. 血小板减少与早产儿视网膜病变的可能机制

4.1. 血小板与血管生成

血管生成在人体许多生理及病理过程中起非常重要的作用,任何器官系统功能的正常运转都依赖于正常的血管生长及血液供应。新生血管的生成由多种血管生成因子释放局部驱动,血小板已被证实参与新生血管生成,活化的血小板具有存储、运输、传递血管生成调节因子的功能 [22] [23] [24] 。血小板和巨核细胞的α颗粒亚群中存在促进和抑制血管生成两种活性因子,不同理化因素的刺激下,可以通过激活蛋白酶激活受体1(PAR1)、蛋白酶激活受体4 (PAR4)刺激α颗粒选择性的释放,激活蛋白酶激活受体1 (PAR1)可以刺激促血管生成物质VEGF的释放并抑制内皮抑素的释放,发挥促血管生成作用;激活蛋白酶激活受体4 (PAR4)会刺激内皮抑素的释放并抑制VEGF的释放,发挥抑制血管生成的作用 [25] ,促血管生成因子和抗血管生成因子的正确平衡保证了新生血管生成的精准过程。

4.2. 血小板减少与血管内皮生长因子(VEGF)

血管内皮生长因子(VEGF)是一类糖蛋白,可以特异性的促进血管内皮细胞分裂生长,发挥诱导血管生成的作用 [3] ,VEGF是在ROP生理性视网膜血管发育和病理性新生血管中发挥主导作用的血管生长因子 [26] 。各种应激反应,如缺氧、炎症均可以上调VEGF的基因表达,其中缺氧是VEGF表达的强烈诱发因素,短时间缺氧(3 h)可使VEGF的表达量增加3~4倍。临床研究发现血小板减少与1型ROP发生密切相关,且主要影响一区ROP病变,一区ROP则提示着更大范围的视网膜无血管区,血小板可能通过调控VEGF的视网膜表达参与新生血管的形成,在ROP的进展中发挥作用 [21] 。

4.3. 血小板减少与胰岛素样生长因子-1 (IGF-1)

胰岛素样生长因子-1 (IGF-1)是参与胎儿组织(包括大脑和血管)生长和发育的主要因子 [27] [28] 。IGF-1可以上调视网膜色素上皮细胞VEGF-mRNA表达和蛋白水平,正常情况下,血管内皮生长因子(VEGF)刺激的视网膜血管生成需要足够水平的胰岛素样生长因子-1 (IGF-1) [29] [30] [31] 。在子宫内,血清IGF-1水平随胎龄的增加而增加,早产儿由于母体来源缺乏和内源性分泌不足导致血清IGF-1的水平较低 [32] [33] ,尽管存在VEGF,但出生时较低的IGF-1的水平抑制了ROP第一阶段视网膜血管形成的正常生长。动物实验发现,IGF-1基因缺乏小鼠的视网膜血管变现出明显的发育迟滞,表明生后早期视网膜血管生成抑制可能与血清IGF-1水平不足相关 [29] 。Jensen等的临床研究也证实,低浓度的IGF-1与生后早期血小板减少症发生相关,并与随后发生严重ROP相关 [14] ,早期恢复IGF-1水平可能预防ROP的进展 [29] 。IGF-1可由血小板α颗粒释放,血小板减少可能通过影响IGF-1的传递,进而在ROP的进展中发挥作用,这提示或许通过预防性血小板输注改善早产儿血小板减少水平,维持血清IGF-1的水平,可能会降低ROP发展的风险 [34] 。

4.4. 血小板减少与血小板衍生生长因子(PDGF)

血小板衍生生长因子(PDGF)最初从血小板中分离,由血小板α颗粒释放,随后研究发现其也存在于血管内皮细胞中,PDGF是普遍存在的有丝分裂原 [35] ,通过对周细胞对内皮细胞的调控,在血管生成和伤口愈合中发挥重要作用 [36] 。Hammes等 [37] 研究了PDGF-β受体缺陷的氧诱导增值性视网膜病变小鼠模型,以研究糖尿病视网膜病变的增殖期,发现与对照组小鼠相比,PDGF-β受体缺陷的小鼠在产后早期周细胞数量显著减少,无细胞毛细血管数量显著增加,暴露于高氧环境后,PDGF-β受体缺陷小鼠的新生血管对缺氧的反应几乎加倍,周细胞可能在促进内皮细胞存活和限制内皮细胞增生方面发挥作用。在ROP的增殖阶段,在高VEGF水平下,血小板减少会导致循环PDGF水平降低,导致周细胞活性不足,可能导致新生病理性血管生成反应加剧,在ROP中发挥作用。

5. 未来展望

血小板具有广泛的生物活性,参与机体的各项病理生理机制,血小板储存、传递、释放血管生成活性因子可能作为一种重要的血管生成调节机制,在早产儿视网膜病变的发生、发展中发挥重要作用,血小板减少可能作为ROP严重程度的预测因素之一。血小板减少及预防性血小板输注与ROP的相关机制研究尚不完全明确,未来有待进行更深入的研究探索。

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