Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease

Abstract

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...

Cardiac involvement in sickle β-thalassemia

“…Various markers of hemolysis, such as plasma LDH concentration, reticulocyte count, plasma arginase activity and hemoglobin, have been correlated with pulmonary hypertension in those patients [40]. A recent study in SCD patients showed that pulmonary artery pressure and pulmonary vascular resistance were increased during vaso-occlusive crises in parallel to hemolysis and hemoglobin level drop [41].…”

Critical Reviews: How we treat sickle cell patients with leg ulcers

“…In a cohort of 20 SCD patients with leg ulcer who underwent right hearth catheterization for suspected pulmonary hypertension, 15 had confirmation of PAH (personal data, this cohort has been described in Mehari et al (2013) [24]. Both complications increase in prevalence with advancing age, and are associated with the most severe degree of hemolytic anemia among HbSS patients, characterized by the lowest hemoglobin levels and the highest serum levels of lactate dehydrogenase (LDH), a known biomarker of intravascular hemolysis, a process associated with impaired nitric oxide bioavailability [13,[29][30][31].…”

“…The association of SCD leg ulcers with biomarkers of vascular dysfunction and pulmonary hypertension has been a recurrent theme [30,32,33]. Both conditions are associated with elevated plasma level of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide (NO) synthase [34,35].…”

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

“…The increased ability of cell-free Hb to scavenge NO has been widely attributed to the hypertension, increased systemic and pulmonary vascular resistance, and morbidity and mortality associated with administration of hemoglobin-based oxygen carriers (HBOCs or "blood substitutes") [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. More recently, the importance of intravascular hemolysis on NO bioavailability in diseased states including hemolytic anemias like sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and cardiopulmonary bypass has been elucidated [17][18][19][68][69][70][71][72][73]. It had been thought that cell-free Hb in the blood was mainly present as metHb, but it is in fact mostly oxyHb [19,74].…”