Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease
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DOI：
10.1182/blood-2005-06-2373
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发表时间：
2006-03-15
期刊：
影响因子：
20.3
通讯作者：
Gladwin, MT
中科院分区：
文献类型：
--
作者：
Kato, GJ;McGcwan, V;Gladwin, MT
肺动脉高压在患有镰状细胞病的成年患者中普遍存在，并且与早期死亡率和溶血标志物（特别是血清乳酸脱氢酶（LDH））密切相关。血管内溶血导致一氧化氮（NO）的生物利用度受损，通过血浆氧合血红蛋白清除NO和血浆精氨酸酶降解精氨酸介导。我们假设血清LDH可能代表血管内溶血和NO生物利用度的便利生物标志物，表征溶血相关血管病变的临床亚表型。在213例镰状细胞病患者的队列中，我们发现稳态LDH与血红蛋白和结合珠蛋白水平低以及网织红细胞、胆红素、血浆血红蛋白、天冬氨酸转氨酶、谷胱甘肽酶和可溶性粘附分子水平高之间存在统计学显著相关性。LDH同工酶分馏证实了LD1和LD2（红细胞内的主要同工型）的优势。在一个亚组中，LDH水平与血浆无细胞血红蛋白密切相关，加速血浆NO消耗，并损害对NO供体的血管舒张反应。值得注意的是，这种简单的生物标志物与镰状细胞病患者的肺动脉高压、腿部溃疡、阴茎异常勃起和死亡风险的临床亚表型相关。我们认为LDH升高是溶血相关的NO抵抗、内皮功能障碍和终末器官血管病变综合征的标志。
Pulmonary hypertension is prevalent in adult patients with sickle cell disease and is strongly associated with early mortality and markers of hemolysis, in particular, serum lactate dehydrogenese (LDH). Intravascular hemolysis leads to impaired bioavailability of nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysis-associated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of steady-state LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysis-associated NO resistance, endothelial dysfunction, and end-organ vasculopathy.