SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-03-0948. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-03-0948v1 101/4/1257    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Castro, O. Articles by Brown, B. D. Search for Related Content PubMed PubMed Citation Articles by Castro, O. Articles by Brown, B. D. Related Collections Red Cells Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1257-1261 CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival Oswaldo Castro, Mohammed Hoque, and Bernice D. Brown From the Center for Sickle Cell Disease and Division of Cardiology, Department of Medicine, Howard University College of Medicine, Washington, DC.     Abstract Top Abstract Introduction Patients and methods Results Discussion References Few results on cardiac catheterization have been published for patients with sickle cell disease (SCD) with pulmonary hypertension (PHTN). Their survival once this complication develops is unknown. We analyzed hemodynamic data in 34 adult patients with SCD at right-sided cardiac catheterization and determined the relationship of PHTN to patient survival. In 20 patients with PHTN the average systolic, diastolic, and mean pulmonary artery pressures were 54.3, 25.2, and 36.0 mm Hg, respectively. For 14 patients with SCD without PHTN these values were 30.3, 11.7, and 17.8 mm Hg, respectively. The mean pulmonary capillary wedge pressure in patients with PHTN was higher than that in patients without PHTN (16.0 versus 10.6 mm Hg; P = .0091) even though echocardiography showed normal left ventricular systolic function. Cardiac output was high (8.6 L/min) for both groups of patients. The median postcatheterization follow-up was 23 months for patients with PHTN and 45 months for those without PHTN. Eleven patients (55%) with PHTN died compared to 3 (21%) patients without PHTN (2 = 3.83; P = .0503). The mean pulmonary artery pressure had a significant inverse relationship with survival (Cox proportional hazards modeling). Each increase of 10 mm Hg in mean pulmonary artery pressure was associated with a 1.7-fold increase in the rate (hazards ratio) of death (95% CI = 1.1-2.7; P = .028). The median survival for patients with PHTN was 25.6 months, whereas for patients without PHTN the survival was still over 70% at the end of the 119-month observation period (P = .044, Breslow-Gehan log-rank test). Our findings suggest that PHTN in patients with SCD shortened their survival. (Blood. 2003;101:1257-1261) © 2003 by The American Society of Hematology.     Introduction Top Abstract Introduction Patients and methods Results Discussion References Pulmonary hypertension (PHTN) is a relatively common complication in adult patients with sickle cell disease (SCD).1,2 Its precise prevalence is unknown but estimates range from 5% to 30% of adult patients.1-3 There are few reports on the pulmonary pressures in patients with SCD with PHTN.4-8 Furthermore, their prognosis, once the diagnosis of PHTN has been established by cardiac catheterization, has not been determined. The median survival of untreated primary PHTN, that is, without SCD, is 2.8 years.9 In patients with SCD, PHTN could add to their sickling-related pulmonary pathology, which includes recurrent vascular occlusion (chest syndrome) and pulmonary fibrosis.10 Perhaps for this reason anecdotal reports suggest shorter survival times in these patients.1,2 In this report, we review the results of right-sided cardiac catheterization in 34 adults with SCD, 20 patients with and 14 patients without PHTN. The catheterization procedures were not carried out in the context of a study but were performed for clinical indications. We also compare the survival of patients with SCD with PHTN to that from patients with normal pulmonary pressures.     Patients and methods Top Abstract Introduction Patients and methods Results Discussion References Patient population All 34 patients were adults, aged 18 years or older, with SCD followed at the Howard University Center for Sickle Cell Disease. Their hemoglobinopathy type was determined by hemoglobin electrophoresis and their demographic and some of their clinical characteristics, including age at cardiac catheterization, are shown in Table 1. All catheterizations were carried out between 1991 and 2001. At the time of the procedure all patients were hospitalized, mostly in the resolution phase of a painful sickle cell episode (crisis). Patients whose anemia was worse than that characteristic of their steady state generally received a transfusion before the procedure. Fourteen patients had undergone transfusions within a 3-month period before the cardiac catheterization, 7 (35%) in the PHTN group and 7 (50%) in the group without this abnormality. The indication for cardiac catheterization in most cases was the suspicion of PHTN by criteria such as increased intensity of the second heart sound at the pulmonary area, right-sided cardiac chamber enlargement by chest radiography or electrocardiogram, or an abnormal echocardiogram suggesting this diagnosis. In 6 patients (nos. 10, 15, 16, 19, 25, and 30), the indication for catheterization was evaluation of left ventricular function or suspicion of coronary artery disease (or both), in which case they had both right and left cardiac catheterization. All patients had at least one right-sided cardiac catheterization and all gave their written informed consent in accordance with our hospital's policy for clinically indicated procedures. The diagnosis of PHTN was defined as a mean pulmonary artery pressure (MPAP) of more than 25 mm Hg at cardiac catheterization.11 Five patients had one or more additional procedures as follow-up and in these cases we report the results from only the first cardiac catheterization. One of the patients who had normal pressures initially had PHTN at a repeat cardiac catheterization. Only the data from the second catheterization are reported for this patient (no. 18), and she was assigned to the PHTN group. Another patient (no. 9), who initially had increased pulmonary pressures, had normal values at a repeat cardiac catheterization 4.5 years later. Only the initial catheterization data are reported and she was assigned to the PHTN group. We used only the abnormal results in these 2 instances so that our mortality analyses would be based on as large a number of patients with PHTN as this retrospective study would allow. In patient no. 9, use of the abnormal results also allowed reporting of the hemodynamic response to prostacyclin.                                View this table: [in this window] [in a new window]   Table 1. Clinical data on patients with SCD at cardiac catheterization Cardiac catheterization All but one of the patients (no. 19) had their cardiac catheterizations performed at the Catheterization Laboratory in the Cardiology Division of Howard University Hospital. The patient's right groin was prepped and draped in a sterile fashion with the right groin exposed. Under local anesthesia and using the Seldinger technique, a no. 8 French sheath was inserted into the right femoral vein. Hemodynamic and electrocardiographic monitoring was continuous. A no. 7 French Swan-Ganz catheter was advanced to the right atrium, right ventricle, pulmonary artery, and pulmonary capillary wedge position, with pressures obtained at each position. Cardiac output was determined by the thermodilution technique. In some patients with PHTN, a vasodilator, prostacyclin, was administered via the Swan-Ganz catheter to assess the reversibility of the PHTN. Incremental dosing was used until a significant reduction in pulmonary artery pressure and pulmonary vascular resistance (20%) occurred, symptoms developed, or systemic blood pressure decreased more than 30%, or heart rate increased more than 50%. Each dose was infused for 15 minutes and pulmonary artery pressure, MPAP, pulmonary capillary wedge pressure (PCWP), and cardiac output were obtained at each dose. At the end of the procedure the sheath was removed and hemostasis was achieved with direct pressure. Statistical analysis Categorical variables were compared with the 2 test. Continuous variables were compared with the Student t test if they followed a normal distribution or with the Wilcoxon rank test if they followed a skewed distribution. The relationship of survival with MPAP, age, sex, hemoglobin type, and PCWP was examined with Cox proportional hazards modeling. Kaplan-Meier analysis was used to compare survival between patients with SCD with and without PHTN. For each patient the length of follow-up was calculated from the date of initial cardiac catheterization to either date of death, the date last seen (for patients lost to follow-up), or June 30, 2001. The Systat (SPSS, Chicago, IL) and the GB-STAT (Dynamic Microsystems, Silver Spring, MD) statistical software programs were used for the analyses.     Results Top Abstract Introduction Patients and methods Results Discussion References Characteristics of patients with PHTN Patients with PHTN were older (mean age, 37.2 ± 11.0 years; range, 21-59 years) than those without this complication (mean age, 30.7 ± 9.45 years; range, 20-48 years; Table 1). The difference, however, was not statistically significant (P = .1). Seventy percent of the patients with PHTN were women and this proportion was significantly greater than that (29%) in patients with normal pulmonary pressures (2 = 5.67; P = .017). The distribution of SS (homozygosity for SCD) and non-SS patients was similar for both groups. Eight of the 20 patients with PHTN and 6 of the 14 patients without PHTN had additional complications such as renal disease, liver disease, or stroke. However, all 3 patients with end-stage renal disease (ESRD) were in the PHTN group. Results of cardiac catheterization Table 2 shows pulmonary hemodynamic data for 20 SCD patients with PHTN and for 14 patients without this complication. PHTN was defined by a MPAP of more than 25 mm Hg.11 The PA pressures for patients with PHTN were 54.3 mm Hg, 25.2 mm Hg, and 36.0 mm Hg for systolic, diastolic, and mean pressures, respectively.                                View this table: [in this window] [in a new window]   Table 2. Cardiac catheterization results in patients with SCD with and without PHTN Probably as a result of their anemia, all patients with SCD had a high cardiac output. For patients with PHTN the mean cardiac output was 8.60 L/min, essentially the same as in SCD patients without PHTN (8.62 L/min). SCD patients with PHTN also had higher than normal PCWPs (mean, 16.01 mm Hg; range, 7-28 mm Hg). This was unexpected because all patients had normal left ventricular systolic function on echocardiography. In 8 of 13 (62%) patients with high PCWP (> 13 mm Hg) the PHTN was not merely passive because the difference between their pulmonary artery diastolic pressure and wedge pressure exceeded 5 mm Hg. Reversibility of PHTN Eight of the patients were given prostacyclin infusions at cardiac catheterization to test the reversibility of their PHTN (Table 3). All 8 had their cardiac catheterizations performed in 1998 or thereafter. Since 1998, prostacyclin administration is a routine procedure for all patients with PHTN diagnosed at our catheterization laboratory. In 2 patients (nos. 11 and 12) prostacyclin did not substantially lower the pulmonary vascular resistance. In the remaining 6 patients pulmonary vascular resistance decreased by at least 20% so that for the 8 patients as a group prostacyclin infusions lowered pulmonary pressures by a mean of 34%. In an additional patient (no. 18, data not shown), prostacyclin lowered the pulmonary pressures, but it also decreased the systemic blood pressure so she was unable to tolerate the vasodilator infusion.                                View this table: [in this window] [in a new window]   Table 3. Effect of prostacyclin infusion on PHTN in 8 patients with SCD at cardiac or Swan-Ganz catheterization PHTN and survival of patients with SCD The median postcatheterization follow-up was 23 months for patients with PHTN and 45 months for those without PHTN. During follow-up 11 of 20 patients (55%) with PHTN died, compared to 3 of the 14 (21%) patients without this abnormality (2 = 3.83; P = .0503). In Cox proportional hazards modeling involving the results from all subjects, MPAP had a significant inverse relationship with survival. Each increase of 10 mm Hg in MPAP was associated with a 1.7-fold increase in the rate (hazards ratio) of death (95% CI = 1.1-2.7; P = .028). In this modeling, age, sex, hemoglobin type, and PCWP did not have a significant influence on survival. Kaplan-Meier survival curves of SCD patients with and without PHTN are shown in Figure 1. The estimated median survival for patients with PHTN was 25.6 months from the date of cardiac catheterization. By comparison, the estimated median survival of SCD patients with normal pulmonary pressures had not been reached at the end of the follow-up period and the estimated survival was still more than 70% at the end of the 119 months of observation (P = .044, Breslow-Gehan log-rank test). Whether the reversibility of PHTN by test doses of prostacyclin affected survival could not be determined because only few of our patients were so tested. View larger version (28K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival of patients with SCD with and without PHTN. The upper (red) line is the survival estimate for SCD patients without PHTN, that is, with normal MPAP. The lower (blue) line is the survival estimate for SCD patients with PHTN, that is, with MPAP more than 25 mm Hg. The x-axis measures months of follow-up after cardiac catheterization. The causes of death of patients with and without PHTN are shown in Table 4. Eight of the 11 patients with PHTN who died during follow-up probably died of complications usually associated with PHTN, such as cor pulmonale, sudden death, and respiratory failure. However, 1 of the 3 patients without PHTN also died suddenly; he was known to have recurrent cardiac arrhythmias.                                View this table: [in this window] [in a new window]   Table 4. Causes of death in patients with SCD with and without PHTN     Discussion Top Abstract Introduction Patients and methods Results Discussion References The normal blood pressure in the pulmonary artery is 25/9 mm Hg (systolic range, 17-32 mm Hg; diastolic range, 2-13 mm Hg) and the MPAP is 15 mm Hg.12 Hemodynamically, PHTN is defined as a MPAP above 25 mm Hg at rest and can be secondary to a large variety of abnormalities.11 Common causes of secondary PHTN include left ventricular failure, a left-to-right intracardiac shunt, pulmonary vascular abnormalities in disorders such as collagen vascular disease, thromboembolism and other lung disorders, chronic hypoxia, and portal hypertension.13 Patients with increased pulmonary arterial pressure in whom all of these disorders are excluded are diagnosed as having primary PHTN.11 These patients have a progressively increasing pulmonary pressure leading to cor pulmonale and death. We reviewed the clinical characteristics, cardiac catheterization data, and the outcomes of 20 adult patients with SCD who also had PHTN. Their mean age was 37.2 years, not significantly different from that of 14 SCD patients with normal pulmonary pressures (30.7 years). The age range included 2 patients younger than 25 years, suggesting that in some SCD patients, PHTN may start developing even during the teenage years. In our series, 70% of subjects with PHTN were women, and this value was significantly higher than the proportion of women (29%) in the group of patients with normal pressures. A reasonable explanation for this difference could be that our small sample of patients without PHTN was not representative of the total adult population in our clinic, which in the years 1986-1995, for example, included 54.2% women.14 In fact, when we compared the proportion of women in the PHTN group with that of the total SCD patient population at our institution, the higher proportion of women with increased pulmonary pressure was no longer statistically significant (2 = 1.96; P = .16). Most of the patients had homozygous sickle cell disease (Hb SS) and the frequency of non-SS patients was similar for patients with and without PHTN. In contrast to patients with primary PHTN, who by definition have normal left ventricular function, our group of patients included also 13 in whom PCWP was elevated (> 13 mm Hg). Only 3 of the patients with normal pulmonary artery pressures had high PCWPs. None of the patients had evidence of left ventricular systolic dysfunction (low ejection fraction) on echocardiography. It is thus possible that despite normal systolic function, the high wedge pressures were indicative of impaired left ventricular diastolic function. This has been previously reported in patients with SCD from our institution15 and from other centers.16,17 Additionally, a reverse Bernheim effect in which paradoxical ventricular septal motion inhibits left ventricular filling,18 may explain the high wedge pressures. The pulmonary artery pressures in SCD patients with PHTN (systolic, 54.3 ± 12.26 mm Hg; diastolic, 25.2 ± 7.72 mm Hg; and mean, 36 ± 7.78 mm Hg) though elevated, were not as high as those reported in the literature for patients with primary PHTN whose average values are 90, 45, and 61 mm Hg, respectively in men, and 92, 43, and 60 mm Hg, respectively in women.11 Also, the cardiac output was higher in SCD at 8.6 ± 1.76 L/min (regardless of PHTN) than that reported for primary PHTN (3.0 L/min).19 Despite these more favorable hemodynamic findings, patients with SCD did not appear to tolerate even milder elevations of pulmonary pressures because their median survival was 25.6 months compared with 33.6 months in patients with (untreated) primary PHTN.9 In 8 of our patients PHTN improved with short-term prostacyclin infusion. Two of our patients were tried on long-term intravenous prostacyclin (epoprostenol) infusion. One of them (no. 13) could not tolerate the drug because of jaw pain. The other patient (no. 2) has been on home treatment with intravenous prostacyclin for 1.5 years. Her pulmonary vascular resistance decreased from a baseline of 366 dynes/s/cm5 to 185 dynes/s/cm5 after home prostacyclin infusion. Before this treatment she had syncopal episodes that have now ceased. She also developed jaw pain during the early phase of intravenous prostacyclin treatment. In both of these patients, the jaw pain was exacerbated while eating and they both had increased serum amylase and lipase levels, which suggested parotitis as a mechanism of their jaw pain. In our patients, increased pulmonary pressures were associated with short survival. These early deaths may have been due to progressive PHTN. However, our data do not allow demonstration of a cause-and-effect relationship. PHTN may have been associated with short survival because it was a manifestation of severe SCD in these patients, who may have had sickling-related vasculopathy involving other vital organs. In any case, it seems reasonable to conclude that the SCD patients in our series tolerated poorly their PHTN. For this reason carefully conducted prospective treatment trials with prostacyclin via the intravenous,20,21 subcutaneous,22 or inhalation23 route in patients such as ours are indicated. Other interventions, including treatment with the endothelin antagonist bosentan,24 long-term transfusion programs,25 nitric oxide (NO) inhalation,26 or administration of the NO precursor, arginine,27,28 could also be explored.     Acknowledgments We thank Dr Victor R. Gordeuk (Howard University College of Medicine, Washington, DC) for assistance in statistical analysis, Dr Anantha K. Rao (Washington Hospital Center, Washington, DC) for the catheterization results from patient no. 19, and Dr Mark Gladwin (Critical Care Section, Clinical Center, National Institutes of Health, Bethesda, MD) for helpful comments on the manuscript.     Footnotes Submitted March 28, 2002; accepted September 20, 2002. Prepublished online as Blood First Edition Paper, October 3, 2002; DOI 10.1182/blood-2002-03-0948. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Oswaldo Castro, Center for Sickle Cell Disease, Howard University College of Medicine, 2121 Georgia Ave NW, Washington, DC 20059; e-mail: olcastro{at}aol.com.     References Top Abstract Introduction Patients and methods Results Discussion References 1. Sutton LL, Castro O, Cross DJ, et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74:626-628[CrossRef][Medline] [Order article via Infotrieve]. 2. Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am. 1996;10:1289-1303[CrossRef][Medline] [Order article via Infotrieve]. 3. Al-Sukhun S, Aboubakr SE, Girgis RE, Swerdlow PS. Pulmonary hypertension is present in 10-30% of adult patients with sickle cell disease [abstract]. Blood 2000;96(suppl 1):9a. 4. Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med. 1982;73:814-821[CrossRef][Medline] [Order article via Infotrieve]. 5. Case records of the Massachusetts General Hospital (case 52-1983). N Engl J Med. 1983;309:1627-1636[Medline] [Order article via Infotrieve]. 6. Hammond TG, Mosesson MW. Fatal small-bowel necrosis and pulmonary hypertension in sickle cell disease. Arch Intern Med. 1989;149:447-448[Abstract]. 7. Durant JR, Cortes FM. Occlusive pulmonary vascular disease associated with hemoglobin SC disease. Am Heart J. 1966;71:100-106[CrossRef][Medline] [Order article via Infotrieve]. 8. Yung GL, Channick RN, Fedullo PF, et al. Successful pulmonary thromboendarterectomy in two patients with sickle cell disease. Am J Respir Crit Care Med. 1998;157:1690-1693[Abstract/Free Full Text]. 9. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results form a national prospective registry. Ann Intern Med. 1991;115:343-349[Medline] [Order article via Infotrieve]. 10. 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. 1988;67:66-76[Medline] [Order article via Infotrieve]. 11. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216-223[CrossRef][Medline] [Order article via Infotrieve]. 12. Fyke FA III, Mair DD, Smith HC. Cardiac catheterization and angiography. A. Techniques and structures. In: Brandenburg RO,Fuster V,Giuliani ER,McGoon DC, eds. Cardiology: Fundamentals and Practice. Chicago, IL: Year Book Medical Publishers; 1987:415-450. 13. Krowka MJ. Pulmonary hypertension: diagnostics and therapeutics. Mayo Clin Proc. 2000;75:625-630[Medline] [Order article via Infotrieve]. 14. Dawkins FW, Kim KS, Squires RS, et al. Cancer incidence and mortality rate in sickle cell disease patients at Howard University Hospital: 1986-1995. Am J Hematol. 1997;55:188-192[CrossRef][Medline] [Order article via Infotrieve]. 15. Lewis JF, Maron BJ, Castro O, Moosa YA. Left ventricular diastolic filling abnormalities identified by Doppler echocardiography in asymptomatic patients with sickle cell anemia. J Am Coll Cardiol. 1991;17:1473-1478[Abstract]. 16. Norris SL, Johnson C, Haywood LJ. Left ventricular filling pressure in sickle cell anemia. J Assoc Acad Minor Phys. 1992;3:20-23[Medline] [Order article via Infotrieve]. 17. Braden DS, Covitz W, Milner PF. Cardiovascular function during rest and exercise in patients with sickle-cell anemia and coexisting alpha thalassemia-2. Am J Hematol. 1996;52:96-102[CrossRef][Medline] [Order article via Infotrieve]. 18. Clyne CA, Alpert JS, Benotti JR. Interdependence of the left and right ventricles in health and disease. Am Heart J. 1989;117:1366-1373[CrossRef][Medline] [Order article via Infotrieve]. 19. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214-221[Abstract/Free Full Text]. 20. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296-302[Abstract/Free Full Text]. 21. McLaughlin V, Genthner DE, Panella MM, Hess DM, Rich S. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130:740-743[Abstract/Free Full Text] 22. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:800-804[Abstract/Free Full Text]. 23. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-329[Abstract/Free Full Text]. 24. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;359:1119-1123. 25. Claster S, Hammer M, Hagar W, Ataga K, Orringer E, Vichinsky E. Treatment of pulmonary hypertension in sickle cell disease with transfusion [abstract]. Blood. 1999;94(suppl 1):420a. 26. Perez-Penate G, Julia-Serda G, Pulido-Duque JM, Gorriz-Gomez E, Cabrera-Navarro P. One-year continuous inhaled nitric oxide for primary pulmonary hypertension. Chest. 2001;119:970-973[Abstract/Free Full Text]. 27. Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med. 2001;163:887-891[Abstract/Free Full Text]. 28. Morris CR, Hagar W, van Warmerdam J, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease [abstract]. Blood 2000;96(suppl 1):485a. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. E. Ashley-Koch, L. Elliott, M. E. Kail, L. M. De Castro, J. Jonassaint, T. L. Jackson, J. Price, K. I. Ataga, M. C. Levesque, J. B. Weinberg, et al. Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease Blood, June 15, 2008; 111(12): 5721 - 5726. [Abstract] [Full Text] [PDF] L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF] F. D. Pashankar, J. Carbonella, A. Bazzy-Asaad, and A. Friedman Prevalence and Risk Factors of Elevated Pulmonary Artery Pressures in Children With Sickle Cell Disease Pediatrics, April 1, 2008; 121(4): 777 - 782. [Abstract] [Full Text] [PDF] K. I. Ataga, C. G. Moore, C. A. Hillery, S. Jones, H. C. Whinna, D. Strayhorn, C. Sohier, A. Hinderliter, L. V. Parise, and E. P. Orringer Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension Haematologica, January 1, 2008; 93(1): 20 - 26. [Abstract] [Full Text] [PDF] J. Villagra, S. Shiva, L. A. Hunter, R. F. Machado, M. T. Gladwin, and G. J. Kato Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin Blood, September 15, 2007; 110(6): 2166 - 2172. [Abstract] [Full Text] [PDF] V. V. McLaughlin and R. Channick Sickle Cell Disease-associated Pulmonary Hypertension: A Coat of Many Colors Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1218 - 1219. [Full Text] [PDF] A. Anthi, R. F. Machado, M. L. Jison, A. M. Taveira-DaSilva, L. J. Rubin, L. Hunter, C. J. Hunter, W. Coles, J. Nichols, N. A. Avila, et al. Hemodynamic and Functional Assessment of Patients with Sickle Cell Disease and Pulmonary Hypertension Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1272 - 1279. [Abstract] [Full Text] [PDF] E. Voskaridou, G. Tsetsos, A. Tsoutsias, E. Spyropoulou, D. Christoulas, and E. Terpos Pulmonary hypertension in patients with sickle cell/{beta} thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations Haematologica, June 1, 2007; 92(6): 738 - 743. [Abstract] [Full Text] [PDF] L. L. Hsu, H. C. Champion, S. A. Campbell-Lee, T. J. Bivalacqua, E. A. Manci, B. A. Diwan, D. M. Schimel, A. E. Cochard, X. Wang, A. N. Schechter, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability Blood, April 1, 2007; 109(7): 3088 - 3098. [Abstract] [Full Text] [PDF] N. Raghavachari, X. Xu, A. Harris, J. Villagra, C. Logun, J. Barb, M. A. Solomon, A. F. Suffredini, R. L. Danner, G. Kato, et al. Amplified Expression Profiling of Platelet Transcriptome Reveals Changes in Arginine Metabolic Pathways in Patients With Sickle Cell Disease Circulation, March 27, 2007; 115(12): 1551 - 1562. [Abstract] [Full Text] [PDF] V. Sachdev, R. F. Machado, Y. Shizukuda, Y. N. Rao, S. Sidenko, I. Ernst, M. St. Peter, W. A. Coles, D. R. Rosing, W. C. Blackwelder, et al. Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients With Sickle Cell Disease J. Am. Coll. Cardiol., January 30, 2007; 49(4): 472 - 479. [Abstract] [Full Text] [PDF] R. F. Machado, A. Anthi, M. H. Steinberg, D. Bonds, V. Sachdev, G. J. Kato, A. M. Taveira-DaSilva, S. K. Ballas, W. Blackwelder, X. Xu, et al. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA, July 19, 2006; 296(3): 310 - 318. [Abstract] [Full Text] [PDF] V. G. Nolan, D. F. Wyszynski, L. A. Farrer, and M. H. Steinberg Hemolysis-associated priapism in sickle cell disease Blood, November 1, 2005; 106(9): 3264 - 3267. [Abstract] [Full Text] [PDF]