Pulmonary arterial hypertension (PAH) is emerging as a major complication and independent risk factor for death among adults with sickle cell disease (SCD). Using surface-enhanced laser desorption/ ionization time of flight mass spectrometry (SELDI-TOF MS), we searched for biomarkers of PAH in plasma specimens from 27 homozygous sickle cell anemia (HbSS) patients with PAH and 28 without PAH. In PAH patients, analysis consistently showed lower abundance of a 28.1-kDa peak (P < .001), identified by high-resolution mass spectrometry as the oxidant-scavenging protein apolipoprotein A-I (apoA-I), which correlated with clinical assays of apoA-I (r ؍ .58, P < .001) and high-density lipoprotein (HDL) levels (r ؍ .50, P ؍ .001). Consistent with endothelial dysfunction that may mediate this effect in PAH, HbSS patients with lower apoA-I levels also displayed impaired vasodilatory responses to acetylcholine (mean ؎ SEM, 189% ؎ 34% [n ؍ 13] vs 339% ؎ 51% [n ؍ 13], P < .001). As a group, patients with SCD demonstrated significantly lower apoA-I levels than African-American control subjects. The PAH cohort was further characterized by high levels of apolipoproteins A-II and B and serum amyloid A, and low levels of haptoglobin dimers and plasminogen. These results imply a relationship of apolipoproteins to the development of PAH vasculopathy in SCD, potentially involving an unexpected mechanistic parallel to atherosclerosis, another proliferative vasculopathy. (Blood. 2009;113:1122-1128) IntroductionPulmonary arterial hypertension (PAH) has emerged as a major complication and independent risk factor for sudden death among adults with sickle cell disease (SCD). A prospective study of 195 sickle cell patients revealed a PAH prevalence of 32% with a relative risk of mortality of 10.1 with tricuspid regurgitant jet velocity (TRV) higher than 2.5 m/s on transthoracic Doppler echocardiography, an indirect indicator of elevated pulmonary artery pressure. 1 This high prevalence and mortality rate are confirmed in other retrospective and prospective studies of PAH in SCD. [2][3][4][5][6][7] Markers that correlate significantly with PAH in SCD include increasing age, hemolysis, iron overload, renal dysfunction, and cholestatic liver dysfunction. 1,[6][7][8][9] Patients with SCD exhibit worse levels of exercise performance, maximal oxygen consumption, and mortality rates at milder elevations of pulmonary arterial pressures than do patients with idiopathic PAH. 2,10 These data indicate that PAH in SCD is associated with impaired cardiopulmonary function and early mortality.Recent epidemiologic, pathophysiological, and biochemical findings have linked PAH in SCD to a hemolysis-linked reduced bioavailability of nitric oxide (NO), a potent vasodilatory, antioxidant, and anti-inflammatory molecule produced endogenously in endothelium. PAH in these patients is further characterized by hemolysis-associated activation of platelets, 11 and variable activation of hemostatic proteins. 12 The only identified plasma marker of PAH in patient...
BackgroundAcute painful episodes are the clinical hallmark of sickle cell disease and have been linked to morbidity and mortality in the sickle cell population. Design and MethodsWe undertook exploratory proteomic studies on paired plasma samples collected from a cohort of 26 adult sickle cell patients during steady state and on the first day of an acute painful episode. We screened for changes in abundance of specific protein peaks via surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS), and confirmed the identify of candidate protein peaks by specific immunoassays. ResultsThe levels of hemoglobin, hematocrit, total protein, and albumin were lower and the levels of lactate dehydrogenase and absolute reticulocytes higher during acute painful episodes than during the steady state. Surface-enhanced laser desorption/ionization time of flight mass spectrometry spectral analysis consistently showed a mass-to-charge peak at 11.7 kDa with elevated intensities during acute painful episodes, which correlated significantly with the serum amyloid A immunoassay. Serum amyloid A levels were significantly elevated during acute painful episodes, especially in four patients with marked end-organ complications of such episodes. A second, recurring peak, less abundant during acute painful episodes, was present at 28.1 kDa; this peak was correlated significantly with immunoassay measurements of apolipoprotein A1. ConclusionsOn the average, plasma serum amyloid A rises and apolipoprotein AI falls during acute painful episodes. The serum amyloid A/apolipoprotein AI ratio increased in 81% of the patients during acute painful episodes, potentially making it a useful objective marker of such episodes. We propose that these protein alterations, known to contribute to endothelial dysfunction in other settings, might do likewise acutely in acute painful episodes and present a new target for therapeutic intervention in sickle cell disease. (ClincalTrials.gov Identifier: NCT00081523). 2010;95(9):1467-1472. doi:10.3324/haematol.2009 This is an open-access paper.Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease
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