血小板输注无效(三)
4 治疗与预防
血小板无效输注的治疗,可针对不同病因采用不同的方法,非免疫因素以治疗原发病为主,如抗感染,脾切除术,以及增加血小板的输入量来提高输注效果。免疫因素则以预防为主,可用去除白细胞制品,治疗方面可静脉输注免疫球蛋白,选择配合性血小板输注。
4.1 去除白细胞
血小板保存过程中,会产生活性物质如组胺、多种细胞因子,其主要来自于血小板中的白细胞,这些活性物质随保存时间延长而增多,随之发热反应的发生率也增高,降低血小板输注疗效。另外HLA抗原主要存在于白细胞上,以淋巴细胞膜表面浓度最高,去白细胞能有效防止初次同种免疫,避免HLA抗体的发生。应用白细胞滤器可将每单位血小板中混杂的白细胞数降至5×106以下。如果降低白细胞的输入数量,可减少HLA抗体同种免疫的发生。每次输入的血液制品中白细胞数量如能控制在(10—15)×104之内,则HLA抗体产生率可从40%—50%降至10%—20%。但是研究发现[21,22],白细胞滤除并不能减少HPA同种抗体的产生。血小板同种免疫的发生与HLA有直接关系。HPA诱导同种免疫主要有两种识别途径:直接途径是受者CD4+T细胞上的TCR直接识别供者抗原递呈细胞(APC)表面HLA?Ⅱ类分子槽沟里的供者抗原产生免疫应答,间接途径是受者抗原递呈细胞上的MHC?Ⅱ类分子识别供者抗原肽并呈递给受者CD4+T细胞刺激产生免疫应答。直接识别途径反应又快又强,可以激活5%的受者TCR,间接途径激活的CD4+T细胞比前者少100倍,但是仍然足够产生与直接识别途径同样效价的抗体。因此滤除白细胞可以降低直接途径引起的HPA免疫刺激,但是并不能消除间接途径的刺激。
4.2 减少患者接触同种异体抗原的机会
比较满意的方案是选择ABO同型、血小板HLA和HPA交叉配型均相合的单一供者的血小板输注,即相容性血小板输注[19],取代目前临床上比较普遍采用的随机性血小板输注。对于HLA同种免疫的患者,应选择HLA配合输注。若仅存HPA抗体,可以考虑在家庭成员中找到相配的血小板输注。两种抗体均有时,应选择两者相配合的血小板输注。Kekomaki等[28]经长期研究发现,输注HLA、HPA均相合血小板的患者,其血小板低于15×109/L的时间占整个病程时间的39%,而随机输入血小板的患者,其血小板低于15×109/L的时间占整个病程时间的75%。同时,最好要求ABO配合或者抗?A、B滴度较低的供者[37]。通过建立已知HLA、HPA分型信息血小板供者库,是为免疫性PTR患者选择适合性血小板输注的一种趋势。目前欧洲很多国家都已经建立了不同规模的供者库,而国内也已经开始这方面的研究。但是对于HLA同种免疫患者选择何种HLA配合程度的血小板至今没有统一的标准。对于HLA高致敏的患者要找到HLA完全一致的供者非常困难,而且研究发现[23]很大部分HLA配合性的血小板输注效果不佳,而“错配”的血小板输注效果不错,其原因仍不明确。Duquesnoy
[24]曾经依赖HLA血清学交叉反应组(CREG)来选择合适的供者,即选择与CREG内抗原错配的供者从而增加了找到合适供者的机会。Ashok等[25]应用一种新的基于计算机软件
HLA Matchmaker处理的氨基酸残基配型方案,
通过软件确定HLA分子抗体结合区氨基酸残基的免疫原性决定簇从而预测HLA配合性,基于这种方法的HLA配型方案扩大了供者范围,其配合程度可以很好的预测输注效果,但是仍然需要大量临床数据的验证。
4.3 大剂量丙种球蛋白静注 大剂量静注丙种球蛋白可提高60%以上自身免疫性血小板减少患者的血小板计数,缺点是仅可观察到患者血小板增加率的改善,而对严重同种免疫的患者很少有效。此法费用高,疗效时间短,不宜常规使用,但遇到危及生命的出血时可考虑。
4.4 紫外线照射 紫外线照射可灭活抗原递呈细胞(APC),在不严重影响血小板功能的照射剂量下,可抑制免疫反应。
4.5 去除血小板膜上的HLA抗原 常用氯喹或枸橼酸洗脱除去血小板膜上的HLA抗原,然而在减少血小板膜上HLA抗原的同时,血小板的质量也受到了影响,因此该法现在很少再用。
4.6 使用免疫抑制剂 应用免疫抑制剂对逆转同种免疫有一定效果,而抗体的减少发生在用药后至少2周,对要求血小板支持疗法即刻见效的患者不适宜。
4.7 血浆置换 对肾移植后产生免疫反应的患者进行血浆置换加免疫抑制联合治疗清除同种抗体已获成功,且用血浆加葡萄糖球菌蛋白A免疫吸附后,再输血小板,PTR状态将有所改善。
4.8 放射线照射 Dzik等[38]用剂量为5—15Gy的射线照射血小板,以破坏血小板表面HLA同种抗原,抑制免疫反应的发生,取得了比较满意的效果。目前一般认为血小板的γ?射线照射剂量以20—30Gy为宜[39]。
4.9 自体血小板的输注 若缺少合适的献血者,可考虑事先单采骨髓恢复期患者的血小板并加以冷冻保存,在血小板减少症发生时使用。
5 展望
实验室快速敏感的抗体筛查和鉴定对PTR的临床治疗至关重要。现在筛查抗体仍然采用新鲜或液氮冷冻保存的血小板谱,血小板冻干保存技术便于抗体筛查细胞的标准化制备,也许可以成为保存已知分型血小板的常规方法;可溶性重组HPA抗原用于抗体的检测目前存在敏感性低的缺点,如果应用新型检测平台如luminex xMAP磁珠技术有望解决该问题。血小板抗原分型已经从血清学迈向了基因分型时代,第五代芯片技术也许在不久的将来会成为常规分型方法,从而使筛查已知HPA型别的供者更快捷。
近年来使用血小板生成素或实验性血小板替代物来减少血小板的输注,但均没有获得完全成功。随机研究发现,对接受诱导和巩固化疗的AML患者,使用重组巨核细胞生长和发育因子,不能明显减少血小板输注或加快血小板恢复,而对外科性血小板减少则有很好的疗效[40,41]。也有报道使用重组活性因子Ⅶ治疗血小板减少取得了良好的疗效[42—44]。在可预见的将来,可行的血小板输注对止血仍然起着至关重要的作用,因此,同种异体免疫的治疗和预防将仍是重要的挑战。
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