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.

Increased platelet activation is recognized in patients with sickle cell disease (SCD), but its pathogenesis and clinical relevance remain uncertain. Pulmonary arterial hypertension (PAH), an important complication of SCD, is characterized by a proliferative pulmonary vasculopathy, in situ thrombosis, and vascular dysfunction related to scavenging of nitric oxide (NO) by hemoglobin released into blood plasma during intravascular hemolysis. We investigated links between platelet activation, PAH and NO scavenging in patients with SCD. Platelet activation marked by activated fibrinogen receptor correlated to the severity of PAH (r ‫؍‬ 0.58, P < .001) and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r ‫؍‬ 0.44, P ‫؍‬ .02). In vitro exposure of platelets to pathologically relevant concentrations of cell-free hemoglobin promoted basal-and agonist-stimulated activation and blocked the inhibitory effects on platelet activation by an NO donor. In patients with SCD, administration of sildenafil, a phosphodiesterase-5 inhibitor that potentiates NO-dependent signaling, reduced platelet activation (P ‫؍‬ .01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability, and pathologic platelet activation that might contribute to thrombosis and pulmonary hypertension in SCD, and potentially other disorders of intravascular hemolysis. This supports a role for NO-based therapeutics for SCD vasculopathy. This trial was registered at www.clinicaltrials.gov as no. IntroductionA chronic state of hemostatic activation in sickle cell disease (SCD) has been well documented by several investigators. Some have highlighted the role of the sickle red cell 1,2 ; others have highlighted the contribution of abnormal tissue factor and secondary thrombin generation by a dysfunctional endothelium, 3 the depletion of endogenous anticoagulants, 4 or the activation of white blood cells. 5 It is likely that the increased expression of adhesion molecules, tissue factor, and thrombin generation, the result of chronic endothelial dysfunction or acute injury, are all important contributors to the coagulopathy of SCD. 6 Increased platelet activation is another known component of hemostatic activation in patients with SCD 1,7-9 Increased percentages of platelets are activated during steady state in patients with SCD, and this accelerates during vaso-occlusive crisis (VOC). [7][8][9] The exact inciting mechanism and clinical consequences of this process remain unknown, but platelet activation hypothetically might play a role in the development of chronic vascular complications, such as pulmonary arterial hypertension, by secreting mitogenic and vasoactive substances that promote intimal hyperplasia. In patients without SCD, platelet-derived growth factor plays a fundamental role in the pathogenesis of plexogenic pulmonary hypertension, and pathologic platelet activation likely contributes to the in situ thrombosis in pulmonary hypertension, which has recently been reviewed. 10 Pulmonary a...

Rationale: Although pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) associated with high mortality, there exist few data characterizing hemodynamics and cardiopulmonary function in this population. Objectives: To characterize hemodynamics and cardiopulmonary function in patients with SCD with and without PH. Methods: Patients with SCD with PH (n ϭ 26) were compared with control subjects with SCD but without PH (n ϭ 17), matched for age, hemoglobin levels, and fetal hemoglobin levels. Measurements and Main Results: Upon catheterization, 54% of the patients with PH had pulmonary arterial hypertension, and 46% had pulmonary venous hypertension. When compared with control subjects, patients with PH exhibited lower six-minute-walk distance (435 Ϯ 31 vs. 320 Ϯ 20 m, p ϭ 0.002) and oxygen consumption (50 Ϯ 3% vs. 41 Ϯ 2% of predicted, p ϭ 0.02), and also had mild restrictive lung disease and more perfusion abnormalities on radionuclide lung scans. The six-minute-walk distance in this population inversely correlated with tricuspid regurgitant jet velocity (r ϭ Ϫ0.55, p Ͻ 0.001), and mean pulmonary artery pressure (r ϭ Ϫ0.57, p Ͻ 0.001), and directly correlated with maximal oxygen consumption (r ϭ 0.49, p ϭ 0.004), even after adjustment for hemoglobin, supporting an independent contribution of increasing pulmonary artery pressures to loss of exercise capacity. Conclusions: Patients with SCD-associated PH have both pulmonary arterial and venous PH associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia. These data support the use of the six-minute-walk distance as an index of PH and cardiopulmonary function in patients with SCD.Keywords: sickle cell disease; pulmonary hypertension; six-minute walk; hemodynamics; echocardiogram Pulmonary arterial hypertension is an increasingly recognized complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease (SCD), thalassemia intermedia and major, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis and stomatocytosis, microangiopathic hemolytic anemias, pyruvate kinase deficiency, alloimmune hemolytic anemia, and possibly malaria (1, 2). In addition, certain conditions AT A GLANCE COMMENTARY Scientific Knowledge on the SubjectPulmonary hypertension is an emerging complication of sickle cell disease with high mortality. There are few data characterizing hemodynamics and cardiopulmonary function in this population. What This Study Adds to the FieldPatients with sickle cell disease-associated pulmonary hypertension have both pulmonary arterial and venous pulmonary hypertension associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia.are associated with intravascular hemolysis, and consequently there is the potential risk for the development of pulmonary hypertension, such as schistosomiasis (3, 4), and iatrogenic hemolysis from mechanical heart valves (5, 6), left ventricula...

Pulmonary hypertension, as indicated by an NT-proBNP level of 160 pg/mL or greater, was very common in patients in the NIH study and in the MSH cohort. The MSH analysis suggests that rates of vaso-occlusive pain episodes in these patients were unrelated to risk of death; this risk was largely determined by occult hemolytic anemia-associated pulmonary hypertension.

SummaryEndothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.