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 dehydrogenase (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 hemolysisassociated 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 hemolysisassociated NO resistance, endothelial dysfunction, and end-organ vasculopathy. IntroductionPulmonary hypertension is an increasingly recognized complication of sickle cell disease and other chronic hereditary and acquired hemolytic anemias. Doppler echocardiography screening reveals a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or greater in 33% of adults with sickle cell disease, indicative of pulmonary hypertension. 1 Pulmonary hypertension in these patients is associated with a 10-fold increased risk for early mortality. Elevated pulmonary artery pressures in patients with sickle cell disease have been associated with low hemoglobin concentration, high levels of serum lactate dehydrogenase (LDH), elevated systolic systemic blood pressure, history of priapism, renal insufficiency, and markers of iron overload. Of the several independent epidemiologic factors associated with pulmonary hypertension, an elevated level of serum LDH has drawn particular interest and controversy. In addition to a link with pulmonary hypertension, we and others have observed a link between LDH and a generalized state of endothelial activation, reflected by elevated blood plasma levels of soluble adhesion molecules, especially vascular cell adhesion molecule (VCAM-1). 2-10 Both pathologic endothelial activation and pulmonary hypertension are associated with more severe hemolytic anemia, reflected by low hemoglobin levels and high reticulocyte counts. 1,2,8 These data begin to suggest that LDH elevation may be a marker of hemolysis-associated endothelial dysfunction and pulmonary hypertension.LDH has long been considered a useful c...

Pulmonary hypertension is prevalent in adult patients with sickle cell disease, and is strongly associated with markers of hemolysis, in particular serum lactate dehydrogenase (LDH), and early mortality. Intravascular hemolysis leads to a state of resistance to 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 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 nitric oxide consumption by plasma and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was statistically 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. Figure Figure Figure Figure

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV > 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P ‫؍‬ .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 1185.