FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 350:886-895 February 26, 2004 Number 9 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Vichinsky, E. P. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown.

Methods We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [±SD] age, 36±12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up.

Results Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model.

Conclusions Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Methods

Patients

To avoid tertiary care referral bias, we recruited 195 patients from the community through multimedia advertisements, community outreach, and regional clinics. All evaluated patients were screened by means of history taking and physical examination, laboratory studies, and transthoracic echocardiography. All patients provided written informed consent. The advertisements and protocol were approved by the institutional review boards of the National Heart, Lung, and Blood Institute and Howard University.

Patients with sickle cell hemoglobinopathy documented by high-pressure liquid chromatography were eligible for the study. Only outpatients in stable condition were included; patients who had had a vaso-occlusive crisis within the previous two weeks or an episode of acute chest syndrome within the previous four weeks were evaluated at a later time. Patients receiving transfusions were not excluded. In addition, 41 black control subjects, with age and sex distributions similar to those of the patients, were evaluated for race-based comparisons of laboratory and echocardiographic data.

Echocardiography

Transthoracic echocardiography was performed in all patients with the use of the Acuson Sequoia (Siemens) and Sonos 5500 (Philips) systems. Cardiac measurements were performed according to the guidelines of the American Society of Echocardiography.¹⁶ Transmitral flow, Doppler determinations of the severity of valvular regurgitation, and left ventricular stroke volume were assessed and graded as previously described.^17,18,19 Peak velocities of the E wave and A wave, the ratio of the E wave to the A wave, and the deceleration time were measured in a standard manner.²⁰ Isovolumic relaxation time was measured as the time from aortic-valve closure to the start of mitral inflow.

Tricuspid regurgitation was assessed in the parasternal right ventricular inflow, parasternal short-axis, and apical four-chamber views, and a minimum of five sequential complexes were recorded. Continuous-wave Doppler sampling of the peak regurgitant jet velocity was used to estimate the right-ventricular-to-right-atrial systolic pressure gradient with the use of the modified Bernoulli equation (4 x [tricuspid regurgitant jet velocity]²).²¹ For the purpose of analysis, we prospectively defined pulmonary hypertension as a peak tricuspid regurgitant jet velocity of at least 2.5 m per second. Since most patients with clinically significant pulmonary hypertension have measurable tricuspid regurgitation,²¹ we assumed that pulmonary-artery pressures were normal in patients with trace or no tricuspid regurgitation.

Pulmonary-artery systolic pressure was quantitated by adding the Bernoulli-derived pressure gradient to the estimated mean right atrial pressure. The mean right atrial pressure was calculated according to the degree of collapse of the inferior vena cava with inspiration: 5 mm Hg for a collapse of at least 50 percent and 15 mm Hg for a collapse of less than 50 percent.²²

Right Heart Catheterization

Right heart catheterizations were performed in 18 consenting patients with a tricuspid regurgitant jet velocity of at least 2.5 m per second.

Statistical Analysis

When tricuspid regurgitant jet velocity was analyzed as a continuous variable, undetectable values were assigned a value lower than any actually measured (1.3 m per second).²¹ We used t-tests and Wilcoxon rank-sum tests to compare continuous variables between patients with sickle cell disease and control subjects and the normal-approximation test to compare dichotomous variables, with no correction for continuity. For patients with sickle cell disease, associations between tricuspid regurgitant jet velocity and continuous variables were assessed by separate linear regression of each variable on tricuspid regurgitant jet velocity, defined as a categorical variable: 0 for values of less than 2.5 m per second, 1 for values of 2.5 to 2.9 m per second, and 2 for values of at least 3.0 m per second. Associations with dichotomous variables were assessed by means of the Armitage chi-square statistic for trend.

We used logistic-regression analysis of low values for tricuspid regurgitant jet velocity (less than 2.5 m per second) and high values (2.5 m per second or more) to obtain a set of variables that were independently associated with increasing jet velocity. Using both forward and backward selection methods in a stepwise procedure, we derived a model in which all variables had a calculated P value of less than 0.05 when they were added to the other variables in the model. We used proportional-hazards regression to assess variables that could be associated with an increased risk of death in patients with sickle cell disease. All regression analyses were performed with the use of log-transformed values (on a base 10 scale) for laboratory measurements in order to reduce the influence of extremely high values. Calculations were made with the use of Number Cruncher Statistical Systems software.

Results

Clinical Characteristics

The base-line characteristics of all 195 patients who were evaluated and the 41 black control subjects are shown in Table 1. The information for the patients is further categorized according to the values for tricuspid regurgitant jet velocity (less than 2.5 m per second, 2.5 to 2.9 m per second, and 3.0 m per second or more) in Table 2. The genotype on the basis of hematologic and hemoglobin characteristics was hemoglobin SS in 132 patients (69 percent), hemoglobin SC in 35 (18 percent), and hemoglobin S–thalassemia (⁰ or ⁺) in 23 (12 percent). Data on genotype were missing for five patients.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Patients with Sickle Cell Disease and Control Subjects.

 

View this table: [in this window] [in a new window]   Table 2. Characteristics of Patients with Sickle Cell Disease According to the Tricuspid Regurgitant Jet Velocity.

 
Prevalence and Severity of Pulmonary Hypertension

Values for pulmonary-artery systolic pressure as estimated by Doppler echocardiography accurately predicted pulmonary-artery systolic pressures measured during right heart catheterization (25 catheterizations performed in 18 patients) (r=0.77, P<0.001) (Figure 1C). The patients with sickle cell disease had significantly higher mean values for tricuspid regurgitant jet velocity than did the controls (P=0.003) (Figure 1A and Figure 1B and Table 1). Thirty-two percent of patients with sickle cell disease had elevated pulmonary-artery systolic pressures, as defined by a tricuspid regurgitant jet velocity of at least 2.5 m per second (an estimated pulmonary-artery systolic pressure of at least 30 mm Hg). Nine percent had pulmonary hypertension with the use of the more conservative cutoff value for tricuspid regurgitant jet velocity of at least 3.0 m per second (an estimated pulmonary-artery systolic pressure of at least 41 mm Hg) (Figure 1A). Of the 18 patients with a tricuspid regurgitant jet velocity of at least 2.5 m per second who underwent right heart catheterization, 17 had a mean pulmonary-artery pressure of more than 25 mm Hg (the definition of pulmonary hypertension used in the National Institutes of Health registry²³).

View larger version (24K): [in this window] [in a new window]   Figure 1. Distribution (Panel A) and Frequency Distribution (Panel B) of Tricuspid Regurgitant Jet Velocity in 195 Patients with Sickle Cell Disease and 41 Black Control Subjects and the Association between Right Ventricular Systolic Pressure Measured by Doppler Echocardiography and Pulmonary-Artery Systolic Pressure, Measured during Catheterization (Panel C). In Panel A, the percentages of patients with sickle cell disease and tricuspid regurgitant jet velocity values of less than 2.5 m per second, 2.5 to 2.9 m per second, and at least 3.0 m per second are shown. Patients in whom tricuspid regurgitant jet velocity was undetectable were assigned a value of 1.3 m per second. The solid vertical line in Panel B shows the cutoff value of 2.5 m per second used to define pulmonary hypertension. Panel C shows the regression of pulmonary-artery systolic pressure as measured by right heart catheterization and the estimated pulmonary-artery systolic pressure as measured by Doppler echocardiography. The dashed lines in Panel C indicate the 95 percent confidence interval.

 
Effect of Pulmonary Hypertension on Ventricular Size and Function

Higher values for tricuspid regurgitant jet velocity were associated with increased cardiac-chamber sizes (Table 2). There was a slight decrease in the ejection fraction at the highest levels of jet velocity (P=0.10). There was no association between jet velocity and stroke volume, and cardiac output increased slightly but not significantly with increasing jet velocity (P=0.24). There was qualitative evidence of left ventricular systolic dysfunction (an ejection fraction of 0.5 or less) in only 5 of the 195 patients.

Measurements of the left ventricular diastolic function are shown in Table 2. Only the deceleration time was weakly associated with tricuspid regurgitant jet velocity (r=0.17, P=0.01), but the mean values remained in the normal range for all categories of tricuspid regurgitant jet velocity. Variables indicative of diastolic dysfunction did not contribute significantly to the logistic-regression model (Table 3) or affect the risk of death, suggesting that pulmonary hypertension is largely independent of diastolic dysfunction.

View this table: [in this window] [in a new window]   Table 3. Logistic-Regression Analysis of a Tricuspid Regurgitant Jet Velocity Dichotomized as Less Than 2.5 m per Second or 2.5 m per Second or More.

 
Evaluation of Risk Factors and Effects of Hydroxyurea Therapy

Logistic-regression analysis of clinical and laboratory values identified a number of factors associated with high tricuspid regurgitant jet velocity; these factors, which accounted for approximately 35 percent of the variability in tricuspid regurgitant jet velocity (Table 3), include a self-reported history of renal or cardiovascular problems; elevated systolic blood pressure, plasma lactate dehydrogenase levels, and alkaline phosphatase levels; and decreased plasma transferrin levels. In a model that included only men, priapism was an additional important variable (odds ratio for a jet velocity of at least 2.5 m per second, as compared with a value of less than 2.5 m per second, 5.0; 95 percent confidence interval, 1.5 to 17.0). Factors reflecting the presence of hemolysis, chronic anemia, and the need for frequent blood transfusions, including low hemoglobin and hematocrit values, high lactate dehydrogenase and aspartate aminotransferase levels (but not high alanine aminotransferase levels, which are specific to liver dysfunction), high direct bilirubin levels, high iron and ferritin levels, low transferrin levels, and the receipt of a total of more than 10 transfusions, were all significant univariate predictors of a high tricuspid regurgitant jet velocity (Table 2).

Increasing age, oxyhemoglobin desaturation as measured by pulse oximetry, and increasing levels of blood urea nitrogen, creatinine, and direct bilirubin were significant univariate — but not multivariate — predictors of high tricuspid regurgitant jet velocity. The plasma arginine:ornithine ratio, probably reflecting arginase activity, was low in patients with sickle cell disease, and this ratio decreased significantly as tricuspid regurgitant jet velocity increased. The fetal hemoglobin level, the hemoglobin S–thalassemia phenotype (⁰ or ⁺), hydroxyurea therapy, the white-cell count, and the platelet count were not significantly associated with tricuspid regurgitant jet velocity, whereas the hemoglobin SC genotype was associated with a significantly reduced tricuspid regurgitant jet velocity (P=0.02 as calculated with the use of a t-test in which tricuspid regurgitant jet velocity was considered to be a continuous variable). Analysis of the patients who did not receive hydroxyurea or have hemoglobin C, as well as of all patients, showed no evidence of an association between the fetal hemoglobin level and tricuspid regurgitant jet velocity.

The number of episodes of the acute chest syndrome and the number of visits to the emergency room per year were not associated with tricuspid regurgitant jet velocity (P=0.92 and P=0.68, respectively). The fact that there were significantly more patients with a self-reported history of cardiovascular problems who had pulmonary hypertension suggests that pulmonary hypertension and its complications, such as cor pulmonale, may be misdiagnosed as congestive heart failure.

Right Heart Catheterization

Among the 18 patients who underwent right heart catheterization, the mean (±SE) values for pulmonary-artery systolic pressure (51.9±4.1 mm Hg), diastolic pressure (26.1±2.16 mm Hg), mean pulmonary-artery pressure (34.5±2.7 mm Hg), pulmonary-artery wedge pressure (17.2±1.2 mm Hg), cardiac output (10.2±0.7 liters per minute as measured by thermodilution and 9.6±0.4 liters per minute as calculated with the Fick equation), and pulmonary vascular resistance (148.5±26.2 dyn · sec · cm^–5) were similar to previously reported values in patients with sickle cell disease who had secondary pulmonary hypertension.^6,8

Survival

Among the 195 patients, 5 were lost to follow-up: all had a tricuspid regurgitant jet velocity of less than 2.5 m per second. Death certificates were used to confirm the death of any patient. No death certificates were found for these five patients who were lost to follow-up, suggesting that they are still living. The median follow-up was 18.3 months for the 128 patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second and 17.3 months for the 62 patients with a tricuspid regurgitant jet velocity of at least 2.5 m per second.

Proportional-hazards regression analysis showed that patients with a tricuspid regurgitant jet velocity of at least 2.5 m per second had a significantly higher mortality rate than those with a jet velocity of less than 2.5 m per second (P<0.001) (Figure 2); the rate ratio for death was 10.1 (95 percent confidence interval, 2.2 to 47.0). Analyses were also performed separately for age, cardiac output, stroke volume, the ratio for the E wave to the A wave, deceleration time, isovolumic relaxation time, hemoglobin level, fetal hemoglobin level, lactate dehydrogenase level, white-cell count, and creatinine level. Besides the tricuspid regurgitant jet velocity, the only significant univariate correlate of the risk of death was the creatinine level (P=0.007). After adjustment for the tricuspid regurgitant jet velocity, the creatinine level was not significantly related to the risk of death (P=0.08), whereas the jet velocity remained a significant independent correlate (P=0.004).

View larger version (8K): [in this window] [in a new window]   Figure 2. Kaplan–Meier Survival Curves According to the Tricuspid Regurgitant Jet Velocity. The survival rate was significantly higher among patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second (indicating normal pulmonary-artery pressure) than among those with a tricuspid regurgitant jet velocity of at least 2.5 m per second (P<0.001). Because patients were enrolled over a 20-month period, the first patients enrolled were followed for the entire time. Thus, the number of patients at risk at the time of each death is shown for both groups.

 
Because we were concerned that pulmonary hypertension conferred a substantial risk of death, the study was not designed as a natural-history study. Patients and referring physicians were made aware of the results of echocardiography, and the patients who were identified as having severe pulmonary hypertension (on the basis of a tricuspid regurgitant jet velocity of at least 3.0 m per second) were offered treatments such as exchange transfusion, oxygen, and selective pulmonary vasodilator therapy according to a National Heart, Lung, and Blood Institute protocol. Eleven of the 17 patients with a tricuspid regurgitant jet velocity of at least 3.0 m per second began either an aggressive exchange-transfusion program or inhaled nitric oxide therapy after pulmonary hypertension was diagnosed, and 10 of these patients are still alive.

Discussion

We found that the prevalence of pulmonary hypertension among patients with sickle cell disease was 32 percent, which is consistent with previously published retrospective studies. Despite having lower pulmonary-artery pressures and higher cardiac outputs than patients with primary pulmonary hypertension, patients with sickle cell disease and pulmonary hypertension had a significantly higher mortality rate than did patients with sickle cell disease who did not have pulmonary hypertension, a finding that is consistent with the results of previous retrospective studies.^6,10,11,13 Our findings suggest that the noninvasive measurement of tricuspid regurgitant jet velocity by echocardiography can be used to identify patients at high risk for death and may thus be viewed as a prognostic tool analogous to transcranial carotid Doppler flow-velocity assessment, which is used to predict the risk of stroke in children with sickle cell disease.²⁴

The observation that markers of hemolysis are associated with pulmonary hypertension provides a link between sickle cell disease and other chronic hemolytic disorders and suggests that there is a distinct syndrome of hemolysis-associated pulmonary hypertension. Thalassemia, for example, is another chronic hemolytic disease that is associated with secondary pulmonary hypertension; the prevalence of pulmonary hypertension among patients with thalassemia ranges from 10 percent to 93 percent, depending on the patient population studied.^{2,25,26,27,28} Patients with sickle cell disease and patients with thalassemia both have chronic hemolysis, which results in the release of hemoglobin into plasma. Plasma hemoglobin can scavenge nitric oxide as well as catalyze the formation of reactive oxygen and nitrogen species, processes that can lead to acute and chronic pulmonary vasoconstriction.²⁹ Hemolysis could also release erythrocyte arginase, as suggested by recent reports that arginase activity may be increased (a possibility that is consistent with our finding that arginine:ornithine ratios were significantly lower in patients than in control subjects) and that the bioavailability of arginine and nitric oxide is reduced in patients with sickle cell disease.^{29,30,31,32,33} Hemoglobin-induced scavenging of nitric oxide results in transcriptional up-regulation of adhesion molecules such as vascular-cell adhesion molecule 1 and E-selectin and induces the expression of endothelin-1, a potent vasoconstrictor.^33,34,35 Indeed, endothelin-1 levels are elevated in the plasma of patients with primary pulmonary hypertension and patients with sickle cell disease.^36,37 The statistical linkage among pulmonary hypertension, systolic systemic hypertension, and the hemolytic rate (associated with nitric oxide scavenging²⁹) is consistent with previous clinical observations that systemic hypertension is a risk factor for stroke and early death in patients with sickle cell disease.^38,39,40

Additional insults common to sickle cell disease and thalassemia that might lead to end-organ dysfunction and pulmonary hypertension include iron deposition, cirrhosis, anemia with a high cardiac-output state, and asplenism. Although cirrhosis can result in secondary pulmonary hypertension, cirrhosis and hepatic synthetic dysfunction were not common in our patients with pulmonary hypertension. It is unclear whether the significant increases in alkaline phosphatase and direct bilirubin in patients with pulmonary hypertension were due to more subtle liver dysfunction or to a secondary effect of pulmonary hypertension and increased passive liver congestion. The absence of an association between cardiac output and tricuspid regurgitant jet velocity in our study argues against a role for chronic anemia and a high cardiac-output state, leading to vascular remodeling and arteriopathy. If anemia itself were responsible, one would expect to find reports of pulmonary hypertension associated with iron-deficiency anemia, the most common cause of anemia in the world.

We were surprised that hydroxyurea therapy was not associated with lower tricuspid regurgitant jet velocity and that there was no significant association between the fetal hemoglobin level or the white-cell count and tricuspid regurgitant jet velocity; both are independent markers of disease severity and predictors of the outcome in sickle cell disease.⁴¹ Although neither prospective nor randomized, our study suggests that hydroxyurea and other drugs that increase the expression of fetal hemoglobin may not prevent pulmonary hypertension. We speculate that this may be explained by the relatively limited induction of fetal hemoglobin associated with such therapy, the lack of full fetal-cell penetrance, and the presence of persistent hemolysis in most of our patients. Analysis of polymerization tendencies suggests that fetal hemoglobin levels of more than 25 percent in a pancellular distribution would be required to eliminate intracellular polymerization and hemolysis.^42,43 This possibility is supported by the observation that hemoglobin C, which is present in all erythrocytes and reduces the rate of hemolysis, was associated with a reduced tricuspid regurgitant jet velocity.

In conclusion, pulmonary hypertension is common in adults with sickle cell disease and is associated with an ominous outcome. Our results support the use of Doppler echocardiographic screening in all adults with sickle cell disease to identify a high-risk group that may benefit from intervention. Therapeutic trials of oxygen, warfarin, transfusion, and pulmonary vasodilator and remodeling medications are urgently required to evaluate their potential to decrease the substantial morbidity and mortality associated with pulmonary hypertension in this population.

Supported by intramural funds from the Clinical Center, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung, and Blood Institute; the Center for Research on Minority Health and Health Disparities; and a Collaborative Research and Development Agreement with INO Therapeutics, (Clinton, N.J.).

We are indebted to the respiratory therapy, nursing, and physician staffs of the Critical Care Medicine Department and 7 East Unit of the Clinical Center, National Institutes of Health, and to Mary K. Hall for assistance with the protocol.

Source Information

From the Critical Care Medicine Department, Clinical Center (M.T.G., M.L.J., K.M., W.A.C., J.S.N., I.E., L.A.H., W.C.B., F.P.O.), the Cardiovascular Branch, National Heart, Lung, and Blood Institute (M.T.G., V.S., Y.S., J.F.P., I.E.), and the Laboratory of Chemical Biology (M.T.G., A.N.S.) and the Molecular and Clinical Hematology Branch (G.P.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.; and the Cardiology Division, Department of Medicine (B.B.), and the Center for Sickle Cell Disease (O.C.), Howard University College of Medicine, Washington, D.C.

Address reprint requests to Dr. Gladwin at the National Institutes of Health, Bldg. 10, Rm. 7D-43, 10 Center Dr., Bethesda, MD 20892-1662, or at mgladwin{at}nih.gov.

References

1. Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med 1982;73:814-821.
2. Aessopos A, Farmakis D, Karagiorga M, et al. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood 2001;97:3411-3416.
3. Hayag-Barin JE, Smith RE, Tucker FC Jr. Hereditary spherocytosis, thrombocytosis, and chronic pulmonary emboli: a case report and review of the literature. Am J Hematol 1998;57:82-84.
4. Heller PG, Grinberg AR, Lencioni M, Molina MM, Roncoroni AJ. Pulmonary hypertension in paroxysmal nocturnal hemoglobinuria. Chest 1992;102:642-643.
5. Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002;33:1037-1043.
6. Castro OL, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2002;101:1257-1261.
7. Adedeji MO, Cespedes J, Allen K, Subramony C, Hughson MD. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med 2001;125:1436-1441.
8. Norris SL, Johnson C, Haywood LJ. Left ventricular filling pressure in sickle cell anemia. J Assoc Acad Minor Phys 1992;3:20-23.
9. Simmons BE, Santhanam V, Castaner A, Rao KR, Sachdev N, Cooper R. Sickle cell heart disease: two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med 1988;148:1526-1528.
10. Van Enk A, Visschers G, Jansen W, Statius van Eps LW. Maternal death due to sickle cell chronic lung disease. Br J Obstet Gynaecol 1992;99:162-163.
11. Sutton LL, Castro O, Cross DJ, Spencer JE, Lewis JF. Pulmonary hypertension in sickle cell disease. Am J Cardiol 1994;74:626-628.
12. Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am 1996;10:1289-1303.
13. Powars D, Weidman JA, Odom-Maryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 1988;67:66-76.
14. Escoffery CT, Shirley SE. Causes of sudden natural death in Jamaica: a medicolegal (coroner's) autopsy study from the University Hospital of the West Indies. Forensic Sci Int 2002;129:116-121.
15. Liesner RJ, Vandenberghe EA. Sudden death in sickle cell disease. J R Soc Med 1993;86:484-485.
16. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358-367.
17. Appleton CP, Jensen JL, Hatle LK, Oh JK. Doppler evaluation of left and right ventricular diastolic function: a technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997;10:271-292.
18. Chopra HK, Nanda NC, Fan P, et al. Can two-dimensional echocardiography and Doppler color flow mapping identify the need for tricuspid valve repair? J Am Coll Cardiol 1989;14:1266-1274.
19. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984;70:425-431.
20. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167-184.
21. Berger M, Haimowitz A, Van Tosh A, Berdoff RL, Goldberg E. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 1985;6:359-365.
22. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493-496.
23. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.
24. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11.
25. Du ZD, Roguin N, Milgram E, Saab K, Koren A. Pulmonary hypertension in patients with thalassemia major. Am Heart J 1997;134:532-537.
26. Hahalis G, Manolis AS, Apostolopoulos D, Alexopoulos D, Vagenakis AG, Zoumbos NC. Right ventricular cardiomyopathy in beta-thalassaemia major. Eur Heart J 2002;23:147-156.
27. Derchi G, Fonti A, Forni GL, et al. Pulmonary hypertension in patients with thalassemia major. Am Heart J 1999;138:384-384.
28. Grisaru D, Rachmilewitz EA, Mosseri M, et al. Cardiopulmonary assessment in beta-thalassemia major. Chest 1990;98:1138-1142.
29. Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8:1383-1389.
30. Morris CR, Kuypers FA, Larkin S, Vichinsky EP, Styles LA. Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome. J Pediatr Hematol Oncol 2000;22:515-520.
31. Morris CR, Morris SM Jr, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63-69.
32. Aslan M, Ryan TM, Adler B, et al. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci U S A 2001;98:15215-15220.
33. Gladwin MT, Schechter AN, Ognibene FP, et al. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 2003;107:271-278.
34. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60-68.
35. Lin G, Macdonald RL, Marton LS, Kowalczuk A, Solenski NJ, Weir BK. Hemoglobin increases endothelin-1 in endothelial cells by decreasing nitric oxide. Biochem Biophys Res Commun 2001;280:824-830.
36. Hammerman SI, Kourembanas S, Conca TJ, Tucci M, Brauer M, Farber HW. Endothelin-1 production during the acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 1997;156:280-285.
37. Rybicki AC, Benjamin LJ. Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood 1998;92:2594-2596.
38. Rodgers GP, Walker EC, Podgor MJ. Is "relative" hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am J Med Sci 1993;305:150-156.
39. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997;102:171-177.
40. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288-294.
41. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-1644.
42. Atweh GF, Schechter AN. Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease. Curr Opin Hematol 2001;8:123-130.
43. Noguchi CT, Rodgers GP, Serjeant G, Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med 1988;318:96-99.

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Vichinsky, E. P. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

Related Letters:

Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease
Klings E. S., Farber H. W., Hassoun P. M., Krishnan J. A., Gladwin M. T., Sachdev V., Ognibene F. P.
Extract | Full Text | PDF  
N Engl J Med 2004; 350:2521-2522, Jun 10, 2004. Correspondence

This article has been cited by other articles:

• Landburg, P. P., Teerlink, T., van Beers, E. J., Muskiet, F. A.J., Kappers-Klunne, M. C., van Esser, J. W.J., Mac Gillavry, M. R., Biemond, B. J., Brandjes, D. P.M., Duits, A. J., Schnog, J.-J., on behalf of the CURAMA study group, (2008). Association of asymmetric dimethylarginine with sickle cell disease-related pulmonary hypertension. haematol 93: 1410-1412 [Full Text]  
• Minneci, P. C., Deans, K. J., Shiva, S., Zhi, H., Banks, S. M., Kern, S., Natanson, C., Solomon, S. B., Gladwin, M. T. (2008). Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis. Am. J. Physiol. Heart Circ. Physiol. 295: H743-H754 [Abstract] [Full Text]  
• Patel, N., Gonsalves, C. S., Malik, P., Kalra, V. K. (2008). Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1{alpha}. Blood 112: 856-865 [Abstract] [Full Text]  
• Steinberg, M. H. (2008). SNPing away at sickle cell pathophysiology. Blood 111: 5420-5421 [Full Text]  
• Ashley-Koch, A. E., Elliott, L., Kail, M. E., De Castro, L. M., Jonassaint, J., Jackson, T. L., Price, J., Ataga, K. I., Levesque, M. C., Weinberg, J. B., Orringer, E. P., Collins, A., Vance, J. M., Telen, M. J. (2008). Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease. Blood 111: 5721-5726 [Abstract] [Full Text]  
• De Franceschi, L., Platt, O. S., Malpeli, G., Janin, A., Scarpa, A., Leboeuf, C., Beuzard, Y., Payen, E., Brugnara, C. (2008). Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice. FASEB J. 22: 1849-1860 [Abstract] [Full Text]  
• Rees, D. C., Dick, M. C., Height, S. E., O'Driscoll, S., Pohl, K. R.E., Goss, D. E., Deane, C. R. (2008). A Simple Index Using Age, Hemoglobin, and Aspartate Transaminase Predicts Increased Intracerebral Blood Velocity as Measured by Transcranial Doppler Scanning in Children With Sickle Cell Anemia. Pediatrics 121: e1628-e1632 [Abstract] [Full Text]  
• Machado, R. F., Hsue, P. Y., Barnett, C. F. (2008). Normal Range for Pulmonary Artery Systolic Pressure--Reply. JAMA 299: 2022-2023 [Full Text]  
• van Beers, E.J., Spronk, H.M.H., ten Cate, H., Duits, A.J., Brandjes, D.P.M., van Esser, J.W.J., Biemond, B.J., Schnog, J.B., on behalf of the CURAMA study Group, (2008). No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension. haematol 93: e42-e44 [Full Text]  
• van Beers, E. J., van Tuijn, C. F.J., Mac Gillavry, M. R., van der Giessen, A., Schnog, J.-J. B., Biemond, B. J., on behalf of the CURAMA study group, (2008). Sickle cell disease-related organ damage occurs irrespective of pain rate: implications for clinical practice. haematol 93: 757-760 [Abstract] [Full Text]  
• Ataga, K. I., Smith, W. R., De Castro, L. M., Swerdlow, P., Saunthararajah, Y., Castro, O., Vichinsky, E., Kutlar, A., Orringer, E. P., Rigdon, G. C., Stocker, J. W., for the ICA-17043-05 Investigators, (2008). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 111: 3991-3997 [Abstract] [Full Text]  
• Yu, B., Raher, M. J., Volpato, G. P., Bloch, K. D., Ichinose, F., Zapol, W. M. (2008). Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension. Circulation 117: 1982-1990 [Abstract] [Full Text]  
• Pashankar, F. D., Carbonella, J., Bazzy-Asaad, A., Friedman, A. (2008). Prevalence and Risk Factors of Elevated Pulmonary Artery Pressures in Children With Sickle Cell Disease. Pediatrics 121: 777-782 [Abstract] [Full Text]  
• Platt, O. S. (2008). Hydroxyurea for the Treatment of Sickle Cell Anemia. NEJM 358: 1362-1369 [Full Text]  
• Humbert, M. (2008). Update in Pulmonary Arterial Hypertension 2007. Am. J. Respir. Crit. Care Med. 177: 574-579 [Full Text]  
• Mekontso Dessap, A., Leon, R., Habibi, A., Nzouakou, R., Roudot-Thoraval, F., Adnot, S., Godeau, B., Galacteros, F., Brun-Buisson, C., Brochard, L., Maitre, B. (2008). Pulmonary Hypertension and Cor Pulmonale during Severe Acute Chest Syndrome in Sickle Cell Disease. Am. J. Respir. Crit. Care Med. 177: 646-653 [Abstract] [Full Text]  
• van Beers, E. J., van Eck-Smit, B. L. F., Mac Gillavry, M. R., van Tuijn, C. F. J., van Esser, J. W. J., Brandjes, D. P. M., Kappers-Klunne, M. C., Duits, A. J., Biemond, B. J., Schnog, J.-J. B., on Behalf of the CURAMA Study Group, (2008). Large and Medium-Sized Pulmonary Artery Obstruction Does Not Play a Role of Primary Importance in the Etiology of Sickle-Cell Disease-Associated Pulmonary Hypertension. Chest 133: 646-652 [Abstract] [Full Text]  
• National Pulmonary Hypertension Centres of the UK, (2008). Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart 94: i1-i41 [Full Text]  
• National Pulmonary Hypertension Centres of the UK, (2008). Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax 63: ii1-ii41 [Full Text]  
• Barnett, C. F., Hsue, P. Y., Machado, R. F. (2008). Pulmonary Hypertension: An Increasingly Recognized Complication of Hereditary Hemolytic Anemias and HIV Infection. JAMA 299: 324-331 [Abstract] [Full Text]  
• Ataga, K. I., Moore, C. G., Hillery, C. A., Jones, S., Whinna, H. C., Strayhorn, D., Sohier, C., Hinderliter, A., Parise, L. V., Orringer, E. P. (2008). Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. haematol 93: 20-26 [Abstract] [Full Text]  
• Liem, R. I., Young, L. T., Thompson, A. A. (2007). Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension. haematol 92: 1549-1552 [Abstract] [Full Text]  
• Taveira-DaSilva, A. M., Hathaway, O. M., Sachdev, V., Shizukuda, Y., Birdsall, C. W., Moss, J. (2007). Pulmonary Artery Pressure in Lymphangioleiomyomatosis: An Echocardiographic Study. Chest 132: 1573-1578 [Abstract] [Full Text]  
• Sebastiani, P., Nolan, V. G., Baldwin, C. T., Abad-Grau, M. M., Wang, L., Adewoye, A. H., McMahon, L. C., Farrer, L. A., Taylor, J. G. IV, Kato, G. J., Gladwin, M. T., Steinberg, M. H. (2007). A network model to predict the risk of death in sickle cell disease. Blood 110: 2727-2735 [Abstract] [Full Text]  
• Bernaudin, F., Socie, G., Kuentz, M., Chevret, S., Duval, M., Bertrand, Y., Vannier, J.-P., Yakouben, K., Thuret, I., Bordigoni, P., Fischer, A., Lutz, P., Stephan, J.-L., Dhedin, N., Plouvier, E., Margueritte, G., Bories, D., Verlhac, S., Esperou, H., Coic, L., Vernant, J.-P., Gluckman, E., for the Societe Francaise de Greffe de Moelle et d, (2007). Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 110: 2749-2756 [Abstract] [Full Text]  
• Villagra, J., Shiva, S., Hunter, L. A., Machado, R. F., Gladwin, M. T., Kato, G. J. (2007). Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 110: 2166-2172 [Abstract] [Full Text]  
• Humbert, M., Khaltaev, N., Bousquet, J., Souza, R. (2007). Pulmonary Hypertension: From an Orphan Disease to a Public Health Problem. Chest 132: 365-367 [Full Text]  
• Boyd, J. H., Macklin, E. A., Strunk, R. C., DeBaun, M. R. (2007). Asthma is associated with Increased mortality in individuals with sickle cell anemia. haematol 92: 1115-1118 [Abstract] [Full Text]  
• Sachdev, V., Machado, R. F., Blackwelder, W. C., Kato, G. J., Gladwin, M. T. (2007). Reply. J Am Coll Cardiol 50: 378-379 [Full Text]  
• Humbert, M. (2007). The burden of pulmonary hypertension. Eur Respir J 30: 1-2 [Full Text]  
• Schaer, C. A., Vallelian, F., Imhof, A., Schoedon, G., Schaer, D. J. (2007). CD163-expressing monocytes constitute an endotoxin-sensitive Hb clearance compartment within the vascular system. J. Leukoc. Biol. 82: 106-110 [Abstract] [Full Text]  
• Driscoll, M. C. (2007). Sickle Cell Disease. Pediatr. Rev. 28: 259-268 [Full Text]  
• McLaughlin, V. V., Channick, R. (2007). Sickle Cell Disease-associated Pulmonary Hypertension: A Coat of Many Colors. Am. J. Respir. Crit. Care Med. 175: 1218-1219 [Full Text]  
• Anthi, A., Machado, R. F., Jison, M. L., Taveira-DaSilva, A. M., Rubin, L. J., Hunter, L., Hunter, C. J., Coles, W., Nichols, J., Avila, N. A., Sachdev, V., Chen, C. C., Gladwin, M. T. (2007). Hemodynamic and Functional Assessment of Patients with Sickle Cell Disease and Pulmonary Hypertension. Am. J. Respir. Crit. Care Med. 175: 1272-1279 [Abstract] [Full Text]  
• Voskaridou, E., Tsetsos, G., Tsoutsias, A., Spyropoulou, E., Christoulas, D., Terpos, E. (2007). Pulmonary hypertension in patients with sickle cell/{beta} thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations. haematol 92: 738-743 [Abstract] [Full Text]  
• Sonveaux, P., Lobysheva, I. I., Feron, O., McMahon, T. J. (2007). Transport and Peripheral Bioactivities of Nitrogen Oxides Carried by Red Blood Cell Hemoglobin: Role in Oxygen Delivery. Physiology 22: 97-112 [Abstract] [Full Text]  
• Vercellotti, G. M. (2007). The "NO" tipping point. Blood 109: 2675-2675 [Full Text]  
• Hsu, L. L., Champion, H. C., Campbell-Lee, S. A., Bivalacqua, T. J., Manci, E. A., Diwan, B. A., Schimel, D. M., Cochard, A. E., Wang, X., Schechter, A. N., Noguchi, C. T., Gladwin, M. T. (2007). Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 109: 3088-3098 [Abstract] [Full Text]  
• Raghavachari, N., Xu, X., Harris, A., Villagra, J., Logun, C., Barb, J., Solomon, M. A., Suffredini, A. F., Danner, R. L., Kato, G., Munson, P. J., Morris, S. M. Jr, Gladwin, M. T. (2007). Amplified Expression Profiling of Platelet Transcriptome Reveals Changes in Arginine Metabolic Pathways in Patients With Sickle Cell Disease. Circulation 115: 1551-1562 [Abstract] [Full Text]  
• Sachdev, V., Machado, R. F., Shizukuda, Y., Rao, Y. N., Sidenko, S., Ernst, I., St. Peter, M., Coles, W. A., Rosing, D. R., Blackwelder, W. C., Castro, O., Kato, G. J., Gladwin, M. T. (2007). Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients With Sickle Cell Disease. J Am Coll Cardiol 49: 472-479 [Abstract] [Full Text]  
• Ristow, B., Ali, S., Ren, X., Whooley, M. A., Schiller, N. B. (2007). Elevated Pulmonary Artery Pressure by Doppler Echocardiography Predicts Hospitalization for Heart Failure and Mortality in Ambulatory Stable Coronary Artery Disease: The Heart and Soul Study. J Am Coll Cardiol 49: 43-49 [Abstract] [Full Text]  
• Buchanan, G. R., Kahn, M. J. (2007). Hemolytic anemias. ASH-SAP 2007: 102-142 [Full Text]  
• Quinn, C. T., Shull, E. P., Ahmad, N., Lee, N. J., Rogers, Z. R., Buchanan, G. R. (2007). Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia. Blood 109: 40-45 [Abstract] [Full Text]  
• Machado, R. F., Anthi, A., Steinberg, M. H., Bonds, D., Sachdev, V., Kato, G. J., Taveira-DaSilva, A. M., Ballas, S. K., Blackwelder, W., Xu, X., Hunter, L., Barton, B., Waclawiw, M., Castro, O., Gladwin, M. T., for the MSH Investigators, (2006). N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease.. JAMA 296: 310-318 [Abstract] [Full Text]  
• Humbert, M., Simonneau, G., on behalf of the French Network on Pulmonary Arter, (2006). The Need for National Registries in Rare Diseases. Am. J. Respir. Crit. Care Med. 174: 228a-229 [Full Text]  
• Kim-Shapiro, D. B., Schechter, A. N., Gladwin, M. T. (2006). Unraveling the Reactions of Nitric Oxide, Nitrite, and Hemoglobin in Physiology and Therapeutics. Arterioscler. Thromb. Vasc. Bio. 26: 697-705 [Abstract] [Full Text]  
• Kato, G. J., McGowan, V., Machado, R. F., Little, J. A., Taylor, J. VI, Morris, C. R., Nichols, J. S., Wang, X., Poljakovic, M., Morris, S. M. Jr, Gladwin, M. T. (2006). Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107: 2279-2285 [Abstract] [Full Text]  
• Elliot, C A, Kiely, D G (2006). Pulmonary hypertension. Contin Educ Anaesth Crit Care Pain 6: 17-22 [Full Text]  
• Thistlethwaite, P. A., Kemp, A., Du, L., Madani, M. M., Jamieson, S. W. (2006). Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J. Thorac. Cardiovasc. Surg. 131: 307-313 [Abstract] [Full Text]  
• Castro, O., Kato, G., Sachdev, V., Machado, R., Ernst, I., Coles, W. A., Nichols, J. S., Hunter, L. A., Gladwin, M. T. (2005). The Sickle Cell-Pulmonary Hypertension Screening Study: ECHO Findings at Two-Years of Follow Up.. ASH ANNUAL MEETING ABSTRACTS 106: 314-314 [Abstract]  
• Gordeuk, V. R., Gladwin, M. T., Kato, G., Castro, O. (2005). Prevalence of Pulmonary Hypertension and Renal Dysfunction by Systemic Blood Pressure Categories in Sickle Cell Disease.. ASH ANNUAL MEETING ABSTRACTS 106: 3169-3169 [Abstract]  
• Morris, C. R., Vichinsky, E. P., Kato, G. J., Gladwin, M. T., Hazen, S., Morris, S. M. Jr (2005). Arginine Metabolism, Pulmonary Hypertension, and Sickle Cell Disease--Reply. JAMA 294: 2433-2434 [Full Text]  
• Delclaux, C., Zerah-Lancner, F., Bachir, D., Habibi, A., Monin, J.-L., Godeau, B., Galacteros, F. (2005). Factors Associated With Dyspnea in Adult Patients With Sickle Cell Disease. Chest 128: 3336-3344 [Abstract] [Full Text]  
• Gladwin, M. T. (2005). Unraveling the hemolytic subphenotype of sickle cell disease. Blood 106: 2925-2926 [Full Text]  
• Nolan, V. G., Wyszynski, D. F., Farrer, L. A., Steinberg, M. H. (2005). Hemolysis-associated priapism in sickle cell disease. Blood 106: 3264-3267 [Abstract] [Full Text]  
• Nadrous, H. F., Pellikka, P. A., Krowka, M. J., Swanson, K. L., Chaowalit, N., Decker, P. A., Ryu, J. H. (2005). Pulmonary Hypertension in Patients With Idiopathic Pulmonary Fibrosis. Chest 128: 2393-2399 [Abstract] [Full Text]  
• Firth, P. G. (2005). Anaesthesia for peculiar cells--a century of sickle cell disease. Br J Anaesth 95: 287-299 [Abstract] [Full Text]  
• Rubin, L. J., Badesch, D. B. (2005). Evaluation and Management of the Patient with Pulmonary Arterial Hypertension. ANN INTERN MED 143: 282-292 [Abstract] [Full Text]  
• Trow, T. K. (2005). Clinical Year in Review I: Lung Cancer, Interventional Pulmonology, Noninvasive Mask Ventilation, and Pulmonary Vascular Disease. Proc Am Thorac Soc 2: 102-104 [Full Text]  
• Nakhoul, F., Yigla, M., Gilman, R., Reisner, S. A., Abassi, Z. (2005). The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access. Nephrol Dial Transplant 20: 1686-1692 [Abstract] [Full Text]  
• Morris, C. R., Kato, G. J., Poljakovic, M., Wang, X., Blackwelder, W. C., Sachdev, V., Hazen, S. L., Vichinsky, E. P., Morris, S. M. Jr, Gladwin, M. T. (2005). Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension, and Mortality in Sickle Cell Disease. JAMA 294: 81-90 [Abstract] [Full Text]  
• Medoff, B. D., Shepard, J.-A. O., Smith, R. N., Kratz, A. (2005). Case 17-2005 - A 22-Year-Old Woman with Back and Leg Pain and Respiratory Failure. NEJM 352: 2425-2434 [Full Text]  
• Klings, E. S., Safaya, S., Adewoye, A. H., Odhiambo, A., Frampton, G., Lenburg, M., Gerry, N., Sebastiani, P., Steinberg, M. H., Farber, H. W. (2005). Differential gene expression in pulmonary artery endothelial cells exposed to sickle cell plasma. Physiol. Genomics 21: 293-298 [Abstract] [Full Text]  
• Aessopos, A., Farmakis, D., Deftereos, S., Tsironi, M., Tassiopoulos, S., Moyssakis, I., Karagiorga, M. (2005). Thalassemia Heart Disease: A Comparative Evaluation of Thalassemia Major and Thalassemia Intermedia. Chest 127: 1523-1530 [Abstract] [Full Text]  
• Rother, R. P., Bell, L., Hillmen, P., Gladwin, M. T. (2005). The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin: A Novel Mechanism of Human Disease. JAMA 293: 1653-1662 [Abstract] [Full Text]  
• Gladwin, M. T., Kato, G. J. (2005). Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia. ASH Education Book 2005: 51-57 [Abstract] [Full Text]  
• Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Polyakova, L. A., Okhotin, D. J., Castro, O. L., Prchal, J. T. (2004). Elevated Estimated Pulmonary Arterial Pressures in Patients with Chuvash Polycythemia.. ASH ANNUAL MEETING ABSTRACTS 104: 1634-1634 [Abstract]  
• Farber, H. W., Loscalzo, J. (2004). Pulmonary Arterial Hypertension. NEJM 351: 1655-1665 [Full Text]  
• Quirolo, Col. K. C. (2004). Resources aid in management of sickle cell disease. AAP News 25: 190-191 [Full Text]  
• Klings, E. S., Farber, H. W., Hassoun, P. M., Krishnan, J. A., Gladwin, M. T., Sachdev, V., Ognibene, F. P. (2004). Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. NEJM 350: 2521-2522 [Full Text]  
• Bratton, S. L. (2004). Death, Pulmonary Hypertension, and Sickle Cell Disease. AAP Grand Rounds 11: 63-64 [Full Text]  
• (2004). Pulmonary Hypertension in Sickle Cell Disease. Journal Watch Cardiology 2004: 3-3 [Full Text]  
• Gottlieb, S. (2004). People with sickle cell disease should be screened for pulmonary hypertension. BMJ 328: 543- [Full Text]  
• Cohen, A. R., Galanello, R., Pennell, D. J., Cunningham, M. J., Vichinsky, E. (2004). Thalassemia. ASH Education Book 2004: 14-34 [Abstract] [Full Text]  
• Buchanan, G. R., DeBaun, M. R., Quinn, C. T., Steinberg, M. H. (2004). Sickle Cell Disease. ASH Education Book 2004: 35-47 [Abstract] [Full Text]