Circulating Protein Disulfide Isomerase Is Associated with Increased Risk of Thrombosis in JAK2-Mutated Myeloproliferative Neoplasms.
Circulating Protein Disulfide Isomerase Is Associated with Increased Risk of Thrombosis in JAK2-Mutated Myeloproliferative Neoplasms.
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DOI：
10.1158/1078-0432.ccr-21-1140
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发表时间：
2021-10-15
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血栓栓塞症(TE)是骨髓增生性肿瘤(MPN)最常见的并发症。包括患者年龄和突变状态在内的临床参数被用来对MPN患者进行风险分层，但缺乏真正的TE风险生物标志物。蛋白质二硫键异构酶(PDI)是一种对蛋白质折叠至关重要的内质网蛋白质，也具有重要的细胞外功能，包括调节血栓的形成。药物PDI抑制可防止血栓形成，但PDI病理性增加是否会增加TE风险仍不清楚。与健康对照组相比，我们评估了一组确诊为真性红细胞增多症(PV)或原发性血小板增多症(ET)的MPN患者的血浆PDI水平与TE风险的相关性。在登记时测量血浆PDI，并对受试者进行前瞻性跟踪以了解TE的发展。与对照组相比，一组患者，主要是JAK2突变的MPN，血浆PDI水平显著升高。血浆PDI在功能上是活跃的。PDI水平与通常用于MPN患者风险分层的临床参数之间没有关联。那些PDI水平高于2.5 ng/ml的患者发生TE的风险是后者的8倍。来自JAK2突变的MPN患者的循环内皮细胞，而不是血小板，显示PDI释放增加，这表明内皮激活是MPN血浆PDI增加的一个来源。观察到JAK2突变MPN患者血浆PDI水平与TE风险增加之间的关联具有预后和治疗意义。
Thromboembolic events (TE) are the most common complications of myeloproliferative neoplasms (MPN). Clinical parameters including patient age and mutation-status are used to risk-stratify patients with MPN, but a true biomarker of TE risk is lacking. Protein disulfide isomerase (PDI), an endoplasmic reticulum protein vital for protein folding, also possesses essential extracellular functions, including regulation of thrombus formation. Pharmacologic PDI inhibition prevents thrombus formation, but whether pathologic increases in PDI increase TE risk remains unknown. We evaluated the association of plasma PDI levels and risk of TE in a cohort of patients with MPN with established diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET), compared to healthy controls. Plasma PDI was measured at enrollment and subjects followed prospectively for development of TE. A subset of patients, primarily JAK2-mutated MPN, had significantly elevated plasma PDI levels as compared to controls. Plasma PDI was functionally active. There was no association between PDI levels and clinical parameters typically used to risk-stratify patients with MPN. The risk of TE was 8-fold greater in those with PDI levels above 2.5 ng/ml. Circulating endothelial cells from JAK2-mutated MPN patients, but not platelets, demonstrated augmented PDI release, suggesting endothelial activation as a source of increased plasma PDI in MPN. The observed association between plasma PDI levels and increased risk of TE in patients with JAK2-mutated MPN has both prognostic and therapeutic implications.