Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria
Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria
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DOI：
10.1111/j.1365-2141.2010.08096.x
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发表时间：
2010-05-01
影响因子：
6.5
通讯作者：
Gladwin, Mark T.
中科院分区：
文献类型：
--
作者：
Hill, Anita;Rother, Russell P.;Gladwin, Mark T.
P>肺动脉高压（PH）是溶血性贫血的常见并发症。血管内溶血会导致一氧化氮 (NO) 消耗、内皮和平滑肌失调以及以进行性高血压为特征的血管病变。据报道，阵发性睡眠性血红蛋白尿 (PNH) 患者会出现 PH，这是一种危及生命的溶血性疾病。我们探讨了 73 名参加安慰剂对照 TRIUMPH（使用依库丽珠单抗治疗阵发性睡眠性血红蛋白尿症的输血减少疗效和安全性临床研究）研究的 73 名 PNH 患者的溶血、全身 NO、精氨酸分解代谢和 PH 测量值之间的关系。在基线时，血管内溶血与 NO 消耗升高（P < 0 中心点 0001）和精氨酸酶 1 释放（P < 0 中心点 0001）相关。试验中几乎一半患者的 N 末端脑钠肽前体 (NT-proBNP) 水平升高 (>= 160 pg/ml)，这是肺血管阻力和右心室功能障碍的标志物，之前表明可指示 PH。依库珠单抗治疗显着减少溶血（P < 0 中心点 001）、NO 消耗（P < 0 中心点 001）、血管舒缩张力（P < 0 中心点 05）、呼吸困难（P = 0 中心点 006），并在治疗 2 周内使 NT-proBNP 升高（P < 0 中心点 001）的患者比例减少 50%治疗。重要的是，呼吸困难和 NT-proBNP 水平显着改善，但贫血没有显着变化。这些数据表明，PNH 中的血管内溶血会产生 NO 分解代谢状态，从而导致 PH 症状，包括 NT pro-BNP 升高和呼吸困难，而通过依库丽单抗治疗可显着改善这些症状。
P>Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0 center dot 0001) and arginase-1 release (P < 0 center dot 0001). Almost half of the patients in the trial had elevated levels (>= 160 pg/ml) of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of pulmonary vascular resistance and right ventricular dysfunction previously shown to indicate PH. Eculizumab treatment significantly reduced haemolysis (P < 0 center dot 001), NO depletion (P < 0 center dot 001), vasomotor tone (P < 0 center dot 05), dyspnoea (P = 0 center dot 006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0 center dot 001) within 2 weeks of treatment. Importantly, the significant improvements in dyspnoea and NT-proBNP levels occurred without significant changes in anaemia. These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab.