First Successful Lung Transplantation for Sickle Cell Disease with Severe Pulmonary Arterial Hypertension and Pulmonary Veno‐Occlusive Disease

George, M. Patricia; Novelli, Enrico M.; Shigemura, Norihisa; Simon, Marc A.; Feingold, Brian; Krishnamurti, Lakshmanan; Morrell, Matthew R.; Gries, Cynthia G.; Haider, Sajjad; Johnson, Bruce A.; Crespo, Maria; Bhama, Jay K.; Bermúdez, C.; Yousem, Samuel A.; Toyoda, Yoshiya; Champion, Hunter C.; Pilewski, Joseph M.; Gladwin, Mark T.

doi:10.1086/674749

Cited by 11 publications

(8 citation statements)

References 33 publications

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“…The explanted lung of a SCD patient with precapillary pulmonary hypertension was reported to show histopathologic features of pulmonary arterial hypertension, CTEPH, and pulmonary venous obstructive disease. 22 …”

Section: Pulmonary Hypertension-its Classification and Pathologymentioning

confidence: 99%

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Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Gordeuk

Castro

Machado

2016

Blood

121

117

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Pulmonary hypertension affects ∼10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments improve SCD-related pulmonary hypertension.

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Section: Pulmonary Hypertension-its Classification and Pathologymentioning

confidence: 99%

“…The patient was maintained with a hemoglobin S percent ,10% after transplant through exchange blood transfusion. 22 BLOOD, 18 FEBRUARY 2016 x VOLUME 127, NUMBER 7 PULMONARY HYPERTENSION IN SCD 825…”

Section: Postcapillary Pulmonary Hypertension and Left Ventricular Dymentioning

confidence: 99%

Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Gordeuk

Castro

Machado

2016

Blood

121

117

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“…(8,19,79) Indeed, new studies have found that TSP1, via CD47, limited nitric oxide-mediated vasodilation of distal pulmonary arteries from healthy and end-stage PH lungs. (66) The finding that lungs explanted from patients with PH, (8) including a patient with SCD-associated PH, (23,68) had upregulated TSP1 and CD47 in pulmonary artery smooth muscle cells vessels and parenchyma, also supports the notion that TSP1 may play a pathogenic role in SCD-associated PH. (64) CD47 is also expressed in human and murine RBC, potentially contributing to RBC adhesion to the vascular wall.…”

Section: Introductionmentioning

confidence: 65%

Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice

Novelli

Little-Ihrig

Knupp

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a leading cause of death in sickle cell disease (SCD) patients. Hemolysis and oxidative stress contribute to SCD-associated PH. We have reported that the protein thrombospondin-1 (TSP1) is elevated in the plasma of patients with SCD and, by interacting with its receptor CD47, limits vasodilation of distal pulmonary arteries ex vivo. We hypothesized that the TSP1-CD47 interaction may promote PH in SCD. We found that TSP1 and CD47 are upregulated in the lungs of Berkeley (BERK) sickling (Sickle) mice and patients with SCD-associated PH. We then generated chimeric animals by transplanting BERK bone marrow into C57BL/6J ( n = 24) and CD47 knockout (CD47KO, n = 27) mice. Right ventricular (RV) pressure was lower in fully engrafted Sickle-to-CD47KO than Sickle-to-C57BL/6J chimeras, as shown by the reduced maximum RV pressure ( P = 0.013) and mean pulmonary artery pressure ( P = 0.020). The afterload of the sickle-to-CD47KO chimeras was also lower, as shown by the diminished pulmonary vascular resistance ( P = 0.024) and RV effective arterial elastance ( P = 0.052). On myography, aortic segments from Sickle-to-CD47KO chimeras showed improved relaxation to acetylcholine. We hypothesized that, in SCD, TSP1-CD47 signaling promotes PH, in part, by increasing reactive oxygen species (ROS) generation. In human pulmonary artery endothelial cells, treatment with TSP1 stimulated ROS generation, which was abrogated by CD47 blockade. Explanted lungs of CD47KO chimeras had less vascular congestion and a smaller oxidative footprint. Our results show that genetic absence of CD47 ameliorates SCD-associated PH, which may be due to decreased ROS levels. Modulation of TSP1-CD47 may provide a new molecular approach to the treatment of SCD-associated PH.

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“…PCH is a vascular proliferation of the septal capillaries, described in association with pulmonary veno‐occlusive disease as a rare cause of PH (Montani et al , ). George et al () described the lungs of a single transplanted patient with SCD, describing pulmonary veno‐occlusive disease but no PCH. Focal PCH‐like lesions have been described in several conditions other than in association with pulmonary veno‐occlusive disease.…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of pulmonary vasculature involvement in sickle cell disease

Carstens¹,

Paulino²,

Katayama³

et al. 2019

Br J Haematol

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Summary Pulmonary complications are frequent in patients with sickle cell disease (SCD), but few studies have described lung pathology in SCD. We studied the lung tissue of 30 deceased SCD patients (1994–2012). Demographics, genotype, clinical characteristics, cause of death and associated conditions are presented. We quantified the presence of pulmonary arterial changes, thrombosis and venous thickening. Alveolar capillary abnormalities were demonstrated using CD34 expression and confocal microscopy. Autopsy and echocardiography reports were reviewed to classify heart abnormalities. Tissue expression of markers of endothelial activation (vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and vascular endothelial growth factor) was quantified in pulmonary vessels. Median age was 33 years; genotype was SS in 19, SC in 7 and Sβ in 4, and there were 18 males. Hypertensive arterial changes were present in 76% of the patients, recent thrombosis in 80% and old thrombosis in 43%. Venous thickening was present in 23% and pulmonary capillary haemangiomatosis foci in 87%. Ten percent of the patients presented right ventricular hypertrophy. There was no increased expression of endothelial activation markers when compared to controls. SCD affects the whole pulmonary vascular tree and reflects the multiple burden on lung vasculature imposed by the disease upon time.

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First Successful Lung Transplantation for Sickle Cell Disease with Severe Pulmonary Arterial Hypertension and Pulmonary Veno‐Occlusive Disease

Cited by 11 publications

References 33 publications

Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice

Clinical relevance of pulmonary vasculature involvement in sickle cell disease

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