Through bound apolipoprotein A-I (apoA-I), high density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD)have low apoA-I andendothelial dysfunction,we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C, and improves vascular function in SCD. Twenty-seven SCD patientswith HDL-C <39 mg/dL or apoA-I <99 mg/dL were randomized to 12 weeks of niacin-ER, increased in 500mg increments to a maximum of 1500mg daily, or placebo. The primary outcome was the absolute change in HDL-C after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C compared with placebo treatment at 12 weeks (5.1±7.7 vs. 0.9±3.8 mg/dL, one-tailed p=0.07), associated with significantly greater, improvements in the ratios of low-density lipoprotein to HDL-C (1.24 vs. 1.95, p = 0.003), and apolipoprotein B to apoA-I (0.46 vs. 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in three independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.
Sickle cell; niacin; high-density lipoprotein; endothelial function
Background: Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH.
Objectives: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization.
Methods: Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression.
Measurements and Main Results: Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05–2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09–3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP − pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23–3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14–2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09–1.89 per Wood unit increase; P = 0.009) as risk factors for mortality.
Conclusions: Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.
sickle cell; pulmonary hypertension; mortality; autopsy
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 serious complication of sickle cell disease (SCD), with a high risk of morbidity and mortality. Endothelin-1, a potent vasoconstrictor peptide known to be elevated in SCD, acts through two receptors: ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers approved for use in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk adult patients with SCD and pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and laboratory studies prior to starting ETR blocking agents. Six patients received bosentan and two ambrisentan as initial therapy. Six additional patients were already on sildenafil when ETR blocking agents were added. Over at least six months of therapy, sequential measurements of 6-min walk distance increased significantly (mean ± standard error baseline 357 ± 22 m, 1–2 months 367 ± 17 m, 3–4 months 387 ± 16 m, 5–6 months 398 ± 18 m, n=12, p<0.05, ANOVA with repeated measures). Nonsignificant downward trends were also observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in the three patients that had a repeat right heart catheterization from a mean of 44 to 38 mmHg, although this was not statistically significant. Adverse events while on ETR blocking therapy were similar to the ones reported on patients with primary PH: increase in serum alanine aminotransferase (2), increased peripheral edema (3), rash (4), and headache. Therapy was stopped in two patients, who were switched to the other ETR blocking agent, with resolution of symptoms. These data suggest preliminary evidence for benefit from the use of bosentan and ambrisentan and supports their use in pulmonary hypertension in SCD.
GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21–5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.
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
A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n = 661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta = 2.37, p = 0.02) and high hemolytic index (beta = 1.53, p = 0.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta = 3.21, p = 0.02), and with proteinuria (beta = 2.52, p = 0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.
Pulmonary hypertension (PH) in patients with sickle cell disease (SCD) is linked to intravascular hemolysis, impaired nitric oxide bioavailability, renal dysfunction, and early mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases (NOS), is associated with vascular disease in other populations. We determined the plasma concentrations for several key arginine metabolites and their relationships to clinical variables in 177 patients with SCD and 29 control subjects: ADMA, symmetric dimethylarginine (SDMA), NG-monomethyl L-arginine (L-NMMA), N-omega-hydroxy-L-arginine (NOHA), arginine and citrulline. The median ADMA was significantly higher in SCD than controls (0.94 vs. 0.31 μmol/L, p<0.001). Patients with homozygous SCD had a remarkably lower ratio of arginine to ADMA (50 vs. 237, p<0.001). ADMA correlated with markers of hemolysis, low oxygen saturation and soluble adhesion molecules. PH was associated with high levels of ADMA and related metabolites. Higher ADMA level was associated with early mortality, remaining significant in a multivariate analysis. Subjects with homozygous SCD have high systemic levels of ADMA, associated with PH and early death, implicating ADMA as a functional NOS inhibitor in these patients. These defects and others converge on the nitric oxide pathway in homozygous SCD with vasculopathy.
Sickle Cell Disease; ADMA; SDMA; NOHA; Arginine; Pulmonary Hypertension
Background & Aims
Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10–39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC.
SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated to length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE.
23 patients were evaluated (mean age=34.3 years, standard deviation=7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (p=0.01) and TRV (p=0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (p<0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (p=0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (p=0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (p=0.0037) and TRV (p=0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (p=0.041), lower albumin (p=0.046), hemoglobin/hematocrit (p<0.0021) but not TE.
TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC.
Transient Elastography; Sickle Cell Disease; Vaso-Occlusive Crisis; Hepatic Crisis; Liver Stiffness
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.
In addition to vaso-occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG-monomethyl-L-arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose-dependent manner, sodium nitrite infusion rates of 0·4, 4 and 40 µmol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0·0001) and stimulated forearm blood flow up to 77 ± 11% above baseline (P < 0·0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia-potentiated vasodilator and cytoprotective agent in the setting of ischaemia-reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD.
sickle cell; nitrite; blood flow; nitroprusside; vasodilation
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.
Mice genetically deficient in endothelial nitric oxide synthase (eNOS−/−) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. While the current paradigm holds that this bioactivity derives specifically from expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed.
Approach and Results
To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted WT and eNOS−/− mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NAME and repristinated by the NOS substrate L-Arginine, and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert 14C-Arginine into 14C-Citrulline in a NOS-dependent fashion.
These are the first studies to definitively establish a role for a blood borne eNOS, using cross transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.
Sleep disturbance and depression are commonly encountered in primary care. In sickle cell disease, depression is associated with pain, poor treatment compliance, and lower quality of life. The prevalence of sleep disturbance and its effect upon quality of life in adults with sickle cell disease is unknown. The goal of this study was to determine the prevalence of sleep disturbance and if it is associated with pain and depression in sickle cell disease.
Three hundred twenty eight adults with sickle cell disease enrolled on the Bethesda Sickle Cell Cohort Study were assessed using the Pittsburgh Sleep Quality Index and Beck Depression Inventory II screening measures as a cross-sectional survey. Scores greater than 5 (Pittsburgh Sleep Quality Index) and 16 (Beck Depression Inventory II) defined sleep disturbance and depression, respectively. Clinical and laboratory parameters were also assessed.
The mean Pittsburgh Sleep Quality Index score was 8.4 (SD ± 4.2) indicating a 71.2% prevalence of sleep disturbance. The mean Beck Depression Inventory II score was 8.0 (SD ± 8.9). Sixty five (20.6%) participants had a score indicating depression, and half of these (10.0%) had thoughts of suicide. Both Pittsburgh Sleep Quality Index and Beck Depression Inventory II scores were significantly correlated (p < .001). The number of days with mild/moderate pain (p = .001) and a history of headaches (p = .005) were independently associated with depression by multivariate regression analysis. Patients with sleep disturbance were older (p = .002), had higher body mass index (p = .011), had more days of pain (p = .003) and more frequent severe acute painful events (emergency room visits and hospitalizations) during the previous 12 months (p < .001).
More than 70 percent of adults with sickle cell disease had sleep disturbance, while 21 percent showed evidence of clinical depression. Sleep disturbance and depression were correlated, and were most common among those with more frequent pain. Providers caring for adults with sickle cell disease and frequent pain should consider screening for these common co-morbidities. Additional study is needed to confirm these findings and to determine if treatments for pain, depression or sleep disturbances will improve quality of life measures in this patient population.
ClinicalTrials.gov identifier: NCT00011648.
Sickle cell disease; Sleep disturbance; Depression; Chronic pain; Patient reported outcomes; Bethesda sickle cell cohort study
In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.†
sickle cell disease; stroke; nitric oxide; hemolysis; vascular disease
Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.
sickle cell disease; endothelial function; vascular biology; liver disease; adhesion molecules
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