Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia

Gladwin, Mark T.; Kato, Gregory J.

doi:10.1182/asheducation-2005.1.51

Cited by 99 publications

(80 citation statements)

References 63 publications

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“…Prior studies of PH in Hb-SS have revealed an association of PH with a history of renal dysfunction and an elevation in ALT (28,38). In addition, platelets appear to have an important role pathogenically in the development of PH, both as mediators of serotonin metabolism and in their role in thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Pulmonary Function in Adults with Sickle Cell Anemia

Klings

Wyszynski

Nolan

et al. 2006

Am J Respir Crit Care Med

187

166

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Rationale: Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. Objectives: PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DL CO ]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Methods: Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DL CO , or normal. The association between laboratory data of patients with decreased DL CO Sickle cell anemia (Hb-SS) results from homozygosity for a point mutation in the ␤-globin gene (HBB; Glu6Val) causing the resultant sickle hemoglobin (Hb S) to be less soluble when deoxygenated than normal hemoglobin (1). Even with improved treatment, including the early use of prophylactic antibiotic regimens, judicious transfusions, and the administration of hydroxyurea in selected patients, mortality remains high for this population. The median age at death is 42 yr for males and 48 yr for females with Hb-SS. Pulmonary complications, including acute chest syndrome (ACS), pulmonary hypertension (PH), and pulmonary fibrosis, account for 20-30% of deaths in the Hb-SS population and are often underrecognized by the health care community (2, 3).Dyspnea is a frequent complaint amongst patients with sickle cell disease, the etiology of which is unclear and likely multifacto- 5). Studies of lung function to date in this population have been of modest size, often involving fewer than 50 patients (4, 6-11) and largely inconclusive. Their results have yielded a spectrum of abnormalities, including restrictive lung disease, abnormal diffusion capacity for carbon monoxide (Dl CO ), obstructive disease, and hypoxemia (4,6,7,9,12). No definitive profile for pulmonary function in sickle cell disease has emerged. As a result, clinicians find pulmonary function tests (PFTs) difficult to interpret in this population and their clinical utility for directing further investigation and therapy has not been well evaluated.Of growing concern is the link between obstructive lung disease and ACS, particularly in children (7,13,14). The few published studies suggest that obstructive lung disease, in some cases, plays a role in the pathogenesis of ACS (7,13,15). Moreover, obstructive lung disease could be a long-term sequela of recurrent episodes of ACS (6, 9). Larger scale studies are necessary to elucidate more clearly the interaction between lung function and ACS. In addition, certain findings on PFTs might be a marker of other complications of sickle vasculopathy. For example, isolated decreased Dl CO is a well-established finding associated with PH (16, 17). However, its role as a marker or predictor of PH in the Hb-SS population is unknown. The purpose of this study is to evalua...

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Section: Discussionmentioning

confidence: 99%

Abnormal Pulmonary Function in Adults with Sickle Cell Anemia

Klings

Wyszynski

Nolan

et al. 2006

Am J Respir Crit Care Med

187

166

View full text Add to dashboard Cite

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“…64 A PH prevalence of 60% to 75% has been reported in both thalassemia intermediate and major, 10 and occurs in nearly every form of hereditary or acquired hemolytic anemia. 8,55 PH has been definitively linked to hemolytic rate and low NO bioavailability in both human and sickle cell transgenic mouse studies. 8 Hsu and colleagues have dem- Figure 4.…”

Section: Vascular Phenotypes Of Sickle Cell Diseasementioning

confidence: 99%

“…As such, LDH represents a convenient biomarker of intravascular hemolysis and NO bioavailability associated with mortality that Kato and colleagues found helpful in identifying the clinical subphenotypes of hemolysis-associated vasculopathy ( Figure 5). 54 PH is the best characterized clinical complication of acute and chronic hemolysis 55 and occurs in about one third of adults 7,22,56 and children [57][58][59][60][61] with SCD. A Doppler echocardiogram measured tricuspid regurgitant jet velocity (TRV) of 2.5 m/sec or greater, suggesting PH is currently the strongest predictor for early death in SCD, with approximately 10-fold increased risk of early mortality 7,62,63 and a 40% mortality risk within 3 years of diagnosis.…”

Section: Vascular Phenotypes Of Sickle Cell Diseasementioning

confidence: 99%

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Morris¹

2008

Hematology

162

214

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Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

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“…Intravascular hemolysis (1/3 of SCD hemolysis) and extravascular hemolysis are driven by HbS polymerization and HbS instability respectively (Bensinger and Gillette, 1974;Hebbel, 2010). Recent evidence suggests that chronic intravascular hemolysis is associated with a state of progressive vasculopathy, characterized by reduced nitric oxide (NO) bioavailability, prooxidant and pro-inflammatory stress, coagulopathy, pulmonary hypertension, stroke, leg ulcers, and priapism (Gladwin and Kato, 2005;Gladwin et al, 2004;Kato et al, 2007;Morris et al, 2008;Reiter et al, 2002).…”

Section: Hemolytic Crisismentioning

confidence: 99%