Pulmonary hypertension in sickle cell disease: Mechanisms, diagnosis, and management

In the last decade, pulmonary arterial hypertension (PAH) has emerged as one of the most frequent and serious complications in patients with sickle cell disease (SCD) [1-5]. The Sickle-Cell Pulmonary Hypertension Screening Study documented prospectively a 32% frequency of PAH in adult patients and its association with high mortality [4]. This and other prospective series (6,7] validated retrospective reports of the high frequency and Mortality of PAH in SCD [1,2]. It is not known why early reviews of die complications of SCD did not emphasize PAH, even though chromic lung disease and cor pulmonale were documented [8,9]. Although it is possible that the diagnosis was not recognized, it seems more likely that the high frequency of PAH in the current population of older SCD patients reflects the success in preventing the high mortality of severely affected children and young adults. The pathophysiology of PAH in SCD is unknown and probably multifactorial. All of the clinical manifestations of SCD ultimately derive from the tendency of deoxygenated HbS to polymerize and aggregate. Intracellular HbS polymerization increases the mechanic fragility of red blood cells, resulting in their premature mechanical destruction, that is, hemolytic anemia. In addition to mechanical stress on the erythrocyte membrane and cytoskeleton, inflammation and oxidant stress impair erythrocytic reductive potential and deplete ATP, contributing to energetic failure and increased surface phosphatidyl serine exposure [10], and marking die red cell for premature clearance. Polymerization also markedly reduces red blood cell deformability. That effect along with the increased tendency for sickle red blood cells to adhere to endothelium predisposes to episodes of vascular occlusion and ischemic damage to vital organs. All basic and clinical evidence obtained thus far indicates that intravascular hemolysis, which occurs in SCD [11,12], is an Important contributing factor to the development of PAH. Intravascular hemolysis interferes with the nitric oxide (NO) vasodilating system in two ways. It releases red blood cell arginase into the plasma, lowering the synthesis of NO [13]. At die same time, hemolysis increases the level of free plasma hemoglobin, which directly scavenges endodielial-derived NO [14,15]. This effect produces a state of endothelial dysfunction characterized by a resistance to NO, vasoconstriction, and secondary increases in the vasoconstrictor and mitogen endothelin 1. Hemolysis also activates the thrombotic system via direct effects on platelet activation through release of red cell ADP and indirectly by plasma hemoglobin-mediated NO scavenging and increased phosphatidyl serine exposure, which activate platelets and tissue factor [16]. The NO scavenging and prothrombotic effects of the damaged erythrocyte membrane, plasma red cell microvesicles, and plasma hemolysate likely produce progressive vascular pathologic remodeling, including intimal and smooth muscle proliferation and in situ thrombosis of the pulmonary arteries. PAH must be added to the classically recognized complications of hemolysis in SCD-anemia, cholelithiasis, and leg ulcers. It is unknown to what extent the endothelial dysfunction and NO resistance may contribute to the common vaso-occlusive manifestations of SCD (acute chest syndrome, painful events, priapism) and, in particular, to the proliferative cerebral vasculopathy that develops during childhood. This SCD vasculopathy bears similarities to PAH in its risk factors (low hemoglobin, high systolic blood pressure [17]) and pathologic features (large and medium sized vessel intimal and smooth muscle proliferation [18,19]). Nolan and colleagues showed in the journal, Blood June 28, 2005, Epub ahead of print), that markers of hemolysis (anemia, LDH, bilirubin, reticulocyte count) are significant risk factors for sickle cell-priapism. This provides additional support for the role of hemolysis and the NO system in SCD complications. In view of the mechanistic role of hemolysis in SCD-related pulmonary hypertension, it is not surprising that pulmonary hypertension also complicates thalassemia intermedia [20,21], hereditary spherocytosis [22], and other chronic hemolytic anemias [23-27]. The concept that the anemia, per se, is not involved in the genesis of PAH is supported by the absence of PAH reports in hypoproliferative nonhemolytic anemias such as iron deficiency, end-stage renal disease, and Fanconi anemia (Table 1). PAH is prevented in well-transfused patients with thalassemia major, in whom the anemia, ineffective erythropoiesis, and intramedullary hemolysis are largely suppressed [28].