Subjects at risk for atherosclerosis may have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content in plasma. We considered whether efflux of excess cellular cholesterol to HDL from obese subjects is associated with impaired arterial endothelial function, a biomarker of cardiovascular risk. Fifty-four overweight (body mass index [BMI] 25 – 29.9 kg/m2) or obese women (BMI ≥ 30 kg/m2), age 46 ± 11 years, were enrolled in a worksite wellness program. HDL cholesterol averaged 57 ± 17 mg/dL and was inversely associated with BMI (r= −0.419, P= 0.002). Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Cholesterol efflux from 3H-cholesterol-labeled BHK cells transfected with the ATP-binding cassette transporter 1 (ABCA1) showed 8.2 to 22.5% cholesterol efflux over 18 hours when incubated with 1% serum and was positively correlated with FMD (P <0.05), especially in the 34 subjects with BMI ≥ 30 kg/m2 (r= 0.482, P= 0.004). This relation was independent of age, HDL or low-density lipoprotein cholesterol (LDL) concentrations in plasma, blood pressure or insulin resistance by stepwise multiple regression analysis (β= 0.31, R2= 0.21, P= 0.007). Nitration of apoA-I tyrosine residues (by sandwich ELISA) was significantly higher in women with BMI ≥ 30 kg/m2 and the lowest cholesterol efflux than in women with BMI 25 – 29.9 kg/m2 and the highest cholesterol efflux (P= 0.01). We conclude that decreased cholesterol efflux via the ABCA1 transporter is associated with increased nitration of apoA-I in HDL and is an independent predictor of impaired endothelial function in women with BMI ≥ 30 kg/m2. This finding suggests that functional measures of HDL may be better markers for cardiovascular risk than HDL cholesterol levels in this population.
Advances in computer-aided diagnosis (CAD) systems have shown the benefits of using computer-based techniques to obtain quantitative image measurements of the extent of a particular disease. Such measurements provide more accurate information that can be used to better study the associations between anatomical changes and clinical findings. Unfortunately, even with the use of quantitative image features, the correlations between anatomical changes and clinical findings are often not apparent and definite conclusions are difficult to reach. This paper uses nonparametric exploration techniques to demonstrate that even when the associations between two-variables seems weak, advanced properties of the associations can be studied and used to better understand the relationships between individual measurements.
This paper uses quantitative imaging findings and clinical measurements of 85 patients with pulmonary fibrosis to demonstrate the advantages of non-linear dependency analysis. Results show that even when the correlation coefficients between imaging and clinical findings seem small, statistical measurements such as the maximum asymmetry score (MAS) and maximum edge value (MEV) can be used to better understand the hidden associations between the variables.
Erythropoietin is being used more widely in the management of sickle cell disease (SCD, inclusive of homozygous sickle beta, SS, and compound heterozygous sickle beta thalassemia, Sβ0 thal), often in conjunction with hydroxyurea (HU). Herein, we summarize the published experience with erythropoietin use in SCD, including 39 patients (SS, n=30; Sβ0 thal, n=9) who were treated between 1990 and 1996; to which we add 13 patients with Sickle Syndromes (SS, n=12, compound heterozygous SC disease, n=1) who were treated with erythropoietin or darbopoietin (here cumulatively referred to as EPO) at the National Institutes of Health (NIH) since 2002. The dose range of erythropoietin for SCD in the published series, at a median of >200 Units/Kg/dose, is higher than is used in end-stage renal disease. The median duration of erythropoietin therapy in the published series was ≥3 months, with minimal reported side-effects. At the NIH, the median age of Sickle Syndrome patients who received EPO was 51 (24 to 70) years; 12/13 patient had sickle-associated pulmonary hypertension. 11/13 patients were treated with both HU and EPO for > 4 months (median of 11 months on EPO) without complication. 5/13 patients (all HbSS) with pulmonary hypertension were given EPO for reticulocytopenia (<100,000/μL) on HU; 5/13 patients (all HbSS), with pulmonary hypertension, were given EPO and HU concurrently, in light of an estimated glomerular filtration rate of <80 ml/minute. 3/13 patients (2 Hb SS, 1 HbSC) were treated with EPO for miscellaneous reasons. Hematologic responses, detailed herein, were promising. Our experience suggests that EPO may be safe in SCD, when used in conjunction with HU; EPO therapy could allow more aggressive HU dosing in high-risk SCD patients and in the setting of mild renal insufficiency, common to the aging sickle cell population. We outline our current therapeutic strategy for EPO use in SCD.
Sickle Cell Trait (HbAS), the heterozygous state for the sickle hemoglobin beta globin gene is carried by as many as 100 million individuals including up to 25% of the population in some regions of the world (World Health Organization, Provisional agenda item 4.8, EB117/34 (22 December 2005) or World Health Organization, Provisional agenda item 11.4 (24 April 2006)). Persons with HbAS have some resistance to falciparum malaria infection in early childhood (Piel FB, Patil AP, Howes RE, et al., Nat Commun 2010;1104:1–7 and Aidoo M, Terlouw DJ, Kolczak M, et al., Lancet 2002;359:1311–1312) and as a result individuals with HbAS living in malarial endemic regions of Africa have a survival advantage over individuals with HbAA. Reports from the US emphasize possible health risks for individuals with HbAS including increased incidence of renal failure and malignancy, thromboembolic disorders, splenic infarction as a high altitude complication, and exercise-related sudden death. The National Heart, Lung, and Blood Institute, National Institutes of Health convened a workshop in Bethesda, Maryland on June 3–4, 2010, Framing the Research Agenda for Sickle Cell Trait, to review the clinical manifestations of HbAS, discuss the exercise-related sudden death reports in HbAS, and examine the public health, societal, and ethical implications of policies regarding HbAS. The goal of the workshop was to identify potential research questions to address knowledge gaps.
Priapism is a familiar problem to hematologists, well known for its association with sickle cell disease. It also occurs in a variety of other hematological illnesses, nearly all forms of congenital hemolytic anemia, including other hemoglobinopathies and red blood cell membranopathies and enzymopathies.
Provide urologists with a comprehensive review of priapism in sickle cell disease, with an emphasis on the perspective of a practicing hematologist.
Medline searches through July 2010 were conducted using the terms priapism, erectile dysfunction, and sickle cell.
Main Outcome Measure
Expert opinion was based on review of the medical literature related to this subject matter.
In men with sickle cell disease, large epidemiological studies have linked the risk of priapism to clinical markers of the severity of intravascular hemolysis. Extracellular hemoglobin and arginase released during hemolysis has been implicated in reducing nitric oxide bioavailability, although the relevance of hemolysis to vascular dysfunction has been challenged by some scientists. Consistent with the role of impairment of the nitric oxide axis, mice genetically deficient in nitric oxide production have also been shown to develop priapic activity. Provocative new data indicates that hemolysis-linked dysregulation of adenosine signaling in the penis contributes to priapism in sickle cell mice. Serious questions have arisen regarding the efficacy of mainstays of textbook dogma for treatment of acute severe priapism, including intravenous fluids, alkalinization and exchange transfusion, and there is increasing acceptance for early aspiration and irrigation of the corpus cavernosum.
For sickle cell patients with recurrent priapism, there is very limited evidence for a medical prophylaxis role for hydroxyurea, etilefrine, pseudoephedrine, leuprolide, sildenafil, and other agents. Recent publications have highlighted nitric oxide and adenosine signal transduction pathways as worthy of additional research. Research and clinical management of sickle cell priapism is strengthened by multidisciplinary collaboration between hematologists and urologists.
Priapism; Ischemic Priapism; Stuttering Priapism; Erectile Dysfunction; Sickle cell; Hematology and Priapism
Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident α-thalassemia (OR = 0.95, 95% CI = 0.46 – 1.94, P = NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (Odds Ratio [OR] = 0.18, 95% confidence interval [CI] = 0.06 to 0.51, P = 0.0005) or Sβ+ thalassemia (OR = 0.25, 95% CI = 0.06 to 1.16, P = 0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of follow-up (Hazard Ratio=8.20, P=0.0057).
Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular hemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in SCD vs. ethnically-matched healthy controls. Several cholesterol parameters correlate significantly with markers of anemia, but not endothelial activation or PH. More importantly, serum triglyceride levels are significantly elevated in SCD compared to controls. Elevated triglyceride levels correlate significantly with markers of hemolysis (lactate dehydrogenase and arginase; both p<0.0005), endothelial activation (soluble E-selectin, p<0.0001; soluble P-selectin, p=0.02; soluble vascular cell adhesion molecule-1, p=0.01), inflammation (leukocyte count, p=0.0004; erythrocyte sedimentation rate, p=0.02) and PH (amino-terminal brain natriuretic peptide, p=0.002; prevalence of elevated tricuspid regurgitant velocity (TRV), p<0.001). In a multivariate analysis, triglyceride levels correlate independently with elevated TRV (p=0.002). Finally, forearm blood flow studies in adult patients with SCD demonstrate a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (p<0.05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.
The breakdown of senescent or defective red blood cells releases red cell contents, especially hemoglobin, which scavenges nitric oxide (NO) and decomposes to heme and free iron. These are potent oxidants, all of which have promoted the evolution of inducible and vasculoprotective compensatory pathways to rapidly clear and detoxify hemoglobin, heme and iron. Chronic hemolytic red cell disorders as diverse as sickle cell disease, thalassemia, unstable hemoglobinopathy, cytoskeletal defects and enzymopathies have been linked to a clinical constellation of pulmonary hypertension, priapism, leg ulceration and possibly cerebrovascular disease and thrombosis. Besides free hemoglobin, hemolysis has been associated with extracellular arginase that limits substrate availability to NO synthase, endogenous inhibitors of NO synthase activity, and inappropriate activation of hemostatic pathways. This article reviews the hemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that hemolysis mediates some of the vascular complications of inflammation and diabetes.
Sickle cell disease; Thalassemia; Vasculopathy; Hemolysis; Nitric oxide
Non-invasively assessed pulmonary pressure elevations and left ventricular diastolic dysfunction (LVDD) are associated with increased mortality in adults with sickle cell disease (SCD), but their relationship to exercise intolerance has not been evaluated prospectively.
Methods and Results
Echocardiography, six-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the US and UK Walk-PHaSST study. Tricuspid regurgitation velocity (TRV), which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/sec (mean±SD 2.8±0.1) in 26% of the subjects and ≥3.0 m/sec (3.4±0.4) in 11%. LV lateral E/e′ ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in SCD, was significantly higher in the groups with TRV ≥2.7 m/sec. Increased hemolysis (P<0.0001), LV lateral E/e′ ratio (P=0.0001), BUN (P=0.0002) and erythropoietin (P=0.002) were independently associated with an increased TRV. Further, female gender (P<0.0001), older age (P<0.0001), LV lateral E/e′ ratio (P=0.014), and TRV (P=0.019) were independent predictors of a shorter six-minute walk distance.
Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e′ ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LVDD will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered.
sickle cell anemia; pulmonary hypertension; left ventricular diastolic dysfunction; echocardiography; six-minute walk
Pulmonary artery systolic hypertension is common and associated with increased mortality among adult sickle cell disease (SCD) patients in the United States. While the prevalence of SCD is highest in sub-Saharan Africa, the frequency of pulmonary artery systolic hypertension and the risk factors for the development of pulmonary hypertension have not been reported from Africa. We studied 208 hydroxyurea naïve Nigerian SCD patients at steady state and 94 healthy controls. Pulmonary artery systolic hypertension was defined prospectively as tricuspid regurgitant jet velocity ≥2.5 meters per second. Results were compared with a previously published US prospective SCD cohort. Only 7% of Nigerians compared to 46% of US adults with SCD were >35 years. Tricuspid regurgitant jet velocity was ≥2.5 m/second in 25% of Nigerian SCD patients. Higher jet velocity was associated with greater serum globulin (P=0.002), blood urea nitrogen (P=0.019) and lactate dehydrogenase concentrations (P=0.026) and with inability to walk >300 meters in six minutes (P=0.042). Compared to the US cohort, Nigerian patients had more hemolysis as indicated by lower hemoglobin and higher lactate dehydrogenase concentrations (P ≤0.003). Pulmonary hypertension is common among Nigerian SCD patients. The public health implication of this finding is significant considering the potential number of individuals at risk for this complication. Better understanding of the long term outcome of pulmonary hypertension and causes of death in SCD and the institution of preventive measures are major public health challenges for Africa. The inclusion of African sites in sickle cell pulmonary hypertension clinical trials should be encouraged.
Pulmonary hypertension; sickle cell disease; Nigeria
Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160 ng/l was present in 27.6 % of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0.001), high lactate dehydrogenase (P<0.001), and high total bilirubin levels (P<0.007). A NT-proBNP level ≥160 ng/l was an independent predictor of mortality (RR 6.24, 95% CI 2.9–13.3, P<0.0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population.
Sickle cell disease; pulmonary hypertension; brain natriuretic peptide; biomarkers; survival
Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC).
To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care.
Design, Setting and Participants
Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home.
Inhaled NO gas versus inhaled nitrogen placebo.
There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite.
Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.
Nitric oxide; sickle cell disease; vaso-occlusive pain crisis; acute chest syndrome
The inheritance of genetic disease depends on ancestry that must be considered when interpreting genetic association studies and can provide insights when comparing traits in a population. We compared the genetic profiles of African Americans with sickle cell disease to those of Black Africans and Caucasian populations of European descent and found that they are less genetically admixed than other African Americans and have an ancestry similar to Yorubans, Mandenkas and Bantu.
sickle cell disease; genetic ancestry; admixture; genetic association
Hemoglobin (Hb) is crucial to the function of the red blood cell. However, when it is released during intravascular hemolysis from the cell into blood plasma, it produces a state of NO depletion, oxidant stress, and vascular dysfunction, including hypertension. In their study reported in this issue of the JCI, Boretti and colleagues used canine and guinea pig models to demonstrate that pharmacological doses of glucocorticoid can increase the plasma levels of haptoglobin (Hp), the principal plasma-binding protein for free Hb (see the related article beginning on page 2271). Hp prevented Hb-induced hypertension and the generation of oxidant damage to the kidney. Neutralization of free Hb appears to be part of the downstream antiinflammatory properties of glucocorticoid.
A hemolysis-linked subphenotype of sickle cell disease (SCD), characterized by pulmonary hypertension, stroke, priapism and leg ulcers, is associated with decreased nitric oxide bioavailability and vasculopathy. Vasculopathy appears to have a multifactorial etiology, including mechanisms primarily that involve deficient nitric oxide (NO) signaling, but also involving altered function of NO synthase related to substrate availability and cooperating factors such as apolipoproteins. Improved understanding of the vascular pathophysiology of SCD has led to new vascular targets for translational research in SCD. This growing vascular therapeutics field in SCD is complementary to the ongoing efforts to reduce the morbidity of vaso-occlusive pain crisis. This presentation will review the current biology and translational clinical development of novel small molecules targeting sickle cell vasculopathy. Strategies targeting the heme-oxygenase-carbon monoxide pathway, the arginine-NO synthase-cGMP-phosphodiesterase 5 pathway, the nitrate-nitrite-NO pathway, and the apolipoprotein A-I pathways will be reviewed. In this context, current clinical trials of inhaled NO, CO, nitrite, sildenafil and apoA-I mimetics will be discussed.
Elevated pulmonary arterial systolic pressure is strongly associated with mortality in patients with sickle cell disease (SCD). A tricuspid regurgitant velocity (TRV) of 2.5 m/s or greater by trans-thoracic echocardiogram is a key marker of risk [1–3]. The pathophysiologic mechanism involves release from the red cell during intravascular hemolysis of cell-free plasma hemoglobin and arginase . Hydroxyurea is the only drug approved by the Food and Drug Administrations specifically for SCD. It acts by increasing levels of fetal hemoglobin, which inhibits sickling, and has been shown to reduce the incidence of vaso-occlusive crisis (VOC), and prolong survival in patients with sickle cell disease [5,6]. Because fetal hemoglobin also reduces the rate of hemolysis in SCD, hypothetically, hydroxyurea might also reduce the severity of hemolysis-linked vascular dysfunction and pulmonary hypertension. Herein, we describe five patients with sickle cell disease having elevated pulmonary arterial systolic pressure who exhibited improvement in their baseline laboratory parameters of hemolysis, accompanied by reduced TRV, during treatment with hydroxyurea. Hydroxyurea may have a role in the management of selected patients with elevated TRV.
A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor L-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists. This article reviews the pathophysiology of sickle vasculopathy and the results of preliminary clinical trials of novel small-molecule therapeutics directed at abnormal vascular biology in patients with sickle cell disease.
Chronic leg ulcers are a debilitating complication of sickle cell disease, associated with increased morbidity and perhaps mortality that affect 8 to 50% of patients. We evaluated the characteristics of SCD patients with a history of leg ulceration, including hemolytic rate, estimated pulmonary artery systolic pressure, and other parameters in a cohort of 505 adults with SCD.
Ninety four subjects (18%) had either active ulcers at enrollment or history of leg ulceration. Patients affected were older and predominantly had homozygous SS, lower body mass index, and pulse oximetry, higher tricuspid regurgitation velocities, markers of hemolysis, serum uric acid and serum NT-proBNP, when compared to subjects without such history.
In this prospective cohort of adults with SCD, we confirm that leg ulcers are still frequent and are associated with elevated TRVand markers of hemolysis. We describe a novel association of leg ulcer with hyperuricemia and oxygen desaturation and suggest potential implications for uric acid as a marker of vascular dysfunction.
Sickle Cell Disease; Leg Ulcer; Pulmonary Hypertension; Hemolysis; Uric Acid
Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.
sickle cell; thalassemia; pulmonary hypertension; nitric oxide; arginase
Secondary pulmonary hypertension (PH) is emerging as one of the leading causes of mortality and morbidity in patients with hemolytic anemias such as sickle cell disease (SCD) and thalassemia. Impaired nitric oxide (NO) bioavailability represents the central feature of endothelial dysfunction, and is a major factor in the pathophysiology of PH. Inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate arginine during the process of intravascular hemolysis. Rapid consumption of NO is accelerated by oxygen radicals that exists in both SCD and thalassemia. A dysregulation of arginine metabolism contributes to endothelial dysfunction and PH in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and pulmonary arterial hypertension. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, or use of NO donors represent potential therapeutic strategies for this common pulmonary complication of hemolytic disorders.
Pulmonary hypertension; sickle cell disease; thalassemia; hemoglobinopathies; arginine; nitric oxide; arginase; hemolysis