背景:异基因造血干细胞移植(HSCT)受到急性非感染性毒性的挑战,包括正弦阻塞综合征(SOS),移植综合征(ES)和毛细血管渗漏综合征(CLS)等。这些并发症被认为是由功能失调的血管内皮引起的,但是病理生理机制还没有完全理解,诊断受到部分重叠的纯粹临床诊断标准的挑战,限制了在这一领域取得进展的可能性。有,然而,越来越多的证据表明,这些挑战可以通过诊断生物标志物的发展来解决,以提高致病性同源实体的诊断准确性,改善移植前风险评估和早期识别需要更多特定治疗的患者。可溶性血管内皮生长因子受体-1(sVEGF-R1)是创伤和脓毒症患者内皮损伤的重要生物标志物,但尚未在HSCT中进行研究。
目的:通过探索sVEGF-R1与SOS的关系,探讨sVEGF-R1作为小儿HSCT患者内皮损伤的标志物,CLS,ES,和急性移植物抗宿主病(aGvHD)。
方法:我们前瞻性纳入了113名接受清髓性HSCT的儿童,并在移植早期和移植后3个月每周获得的血浆样本中测量sVEGF-R1。
结果:全部,sVEGF-R1水平从移植输注后第7天开始显着增加,在第30天达到峰值,在接受白消安的患者中最为明显。被认为SOS风险增加并因此开始预防性去纤肽的患者在开始调理之前sVEGF-R1的水平显着升高(446pg/mL与281pg/mL,p=0.0035),与未接受去纤肽治疗的患者相比,这种治疗似乎稳定了sVEGF-R1水平.13名(11.5%)儿童在中位第8天(1-18天)符合修改后的西雅图SOS标准,在第14天sVEGF-R1水平显着升高(489pg/mL与327pg/mL,p=0.007)。相比之下。sVEGF-R1水平在更广泛的患者组(45.1%)符合EBMT-SOS标准,包括患有非常轻微疾病的患者,sVEGF-R1水平没有总体差异,但在需要利尿剂治疗的EBMT-SOS患者中sVEGF-R1水平较高.重要的是,sVEGF-R1水平与ES和CLS无关,但在III-IV级aGvHD患者中,sVEGF-R1水平在第30天显着增加(OR=4.2pr。四分位数,p=0.023)。
结论:发现出现SOS的儿科患者中VEGF-R1水平升高,反映发病率的严重程度。sVEGF-R1与CLS和ES均无关。应进一步探索sVEGF-R1作为SOS临床有用生物标志物的潜力,以改善移植前SOS风险评估。SOS-严重性分级,并指导治疗。
Allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT.
To investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD).
We prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant.
All over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1-18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023).
VEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.