Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria.

Abstract

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 < 0.0001) and arginase-1 release (P < 0.0001). Almost half of the patients in the trial had elevated levels (> or =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 < 0.001), NO depletion (P < 0.001), vasomotor tone (P < 0.05), dyspnoea (P = 0.006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0.001) 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.

• Authors: Anita Hill, Russell P Rother, Xunde Wang, Sidney M Morris Jr, Kerry Quinn-Senger, Richard Kelly, Stephen J Richards, Monica Bessler, Leonard Bell, Peter Hillmen, Mark T Gladwin
• Journal: British journal of haematology (Br J Haematol) Vol. 149 Issue 3 Pg. 414-25 (May 2010) ISSN: 1365-2141 [Electronic] England
• PMID: 20230403 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Biomarkers
• Hemoglobins
• Peptide Fragments
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Nitric Oxide
• eculizumab

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Biomarkers (blood)
• Blood Pressure (drug effects)
• Dyspnea (drug therapy, etiology)
• Female
• Hemoglobins (metabolism)
• Hemoglobinuria, Paroxysmal (blood, complications, drug therapy)
• Hemolysis (drug effects, physiology)
• Humans
• Hypertension, Pulmonary (drug therapy, etiology, physiopathology)
• Male
• Natriuretic Peptide, Brain (blood)
• Nitric Oxide (deficiency)
• Peptide Fragments (blood)
• Treatment Outcome