The pathophysiology of PAH in hemoglobinopathies is undoubtedly multifactorial, but epidemiological and biochemical data support a prominent role for intravascular hemolysis inducing a state of vascular dysfunction. Clinical variables independently associated with PAH in adults with SCD include the following: low hemoglobin levels, suggestive of more severe hemolytic anemia; high steady-state serum lactate dehydrogenase (LDH) levels, largely reflecting intravascular hemolysis [25]; high serum creatinine levels, indicative of renal insufficiency; high serum direct bilirubin and alkaline phosphatase levels, suggesting cholestatic hepatic dysfunction; low serum transferrin or high serum ferritin levels, indicative of iron overload (Table 1) [8]. In addition, the prevalence of an elevated TRV appears to rise with age during adulthood, exceeding 65% after 50 years of age [8, 9] One study has conflicting findings regarding the relationship of high TRV to systolic blood pressure [9]. Another has found an additional correlation of high TRV to proteinuria [10]. Overall, there is a relationship of elevated TRV to the degree of intravascular hemolysis, and the degrees of renal and hepatic dysfunction, and to iron overload. Except for the contribution of hemolysis, there are no studies to indicate whether the other factors contribute to the development of PAH, or whether they reflect other organs concurrently affected by vasculopathy.

Our group has accumulated additional biochemical and physiological evidence implicating intravascular hemolysis in the development of impaired nitric oxide bioavailability and chronic vascular dysfunction [26, 27]. Nitric oxide (NO) is a master regulator of vascular health, producing vasodilation and increased blood flow, in part by promoting vasodilation, and by inhibiting endothelial adhesion molecule expression, vascular smooth muscle proliferation, platelet aggregation and blood coagulation [28]. Pathological processes in SCD accelerate the destruction of NO, and limit the compensatory increase in NO production. Hemoglobin decompartmentalized from the red cell into blood plasma by intravascular hemolysis reaches steady-state levels of 5–10 μM, and at times exceeding 50 μM [29–31]. This hemoglobin reacts with NO in a rapid, nearly diffusion-limited reaction to produce methemoglobin and inert nitrate [29]. This plasma hemoglobin is associated with a relative resistance of vasodilation to NO donors in patients with SCD [32]. It is also clear that from canine hemolysis studies that plasma hemoglobin scavenges NO and produces pulmonary vasoconstriction, hypertension, and renal dysfunction, all partly reversible by inhaled NO [27]. In addition, NO is also consumed by reaction with reactive oxygen species produced as a by-product of the highly expressed enzymatic activities of xanthine oxidase and NADPH oxidase (Table 2) [33, 34]. Lastly, more recent studies suggest that hemolysis leads to uncoupling of endothelial NO synthase activity, likely secondary to heme-mediated oxidative damage to the enzyme, also producing reactive oxygen species [35]. These mechanisms may combine additively to markedly accelerate NO destruction.

As might be expected, in mild PAH, the patients may report no symptoms, but screening echocardiography reveals a TRV of 2.5–2.9 m/s. The same laboratory abnormalities as above may be seen, but typically to a milder degree than in patients with more severe PAH. This mild degree of elevation in the TRV frequently goes unreported on echocardiography reports, with the inappropriate interpretation that it is too small to have clinical consequences. However, adults with SCD have severe anemia with very high cardiac output, less cardiopulmonary reserve, and frequent co-morbid organ dysfunction, and even this small degree of TRV elevation epidemiologically is associated with early mortality.

Adults with SCD during vaso-occlusive pain crisis (VOC) may sometimes develop peripheral or periorbital edema. Although this may be related to overly vigorous hydration, many of these patients have acutely elevated TRV during VOC, with the edema and TRV both returning to normal afterward [44]. These findings suggest that NO bioavailability falls further during hyperhemolysis associated with VOC [30, 31, 45], leading to acute worsening of pulmonary vasoconstriction and consequent right ventricular failure [44]. This may contribute to deaths observed during VOC [12, 44, 46].

We propose that a similar sequence of events may occur in patients with SCD (Figure 1). In this model, hemolysis-associated impairment of NO bioavailability over decades causes chronic vasoconstriction and mild pulmonary hypertension. At this point, decreasing hemolysis by chronic transfusion might ameliorate the NO consumption and deficiency, and thereby reverse the pulmonary vasoconstriction and pulmonary hypertension. There are some data available to support this model. Lezcano et al. have reported that chronic transfusion lowers plasma hemoglobin in children with sickle cell disease [56]. Furthermore, one group has indicated that children with SCD on chronic transfusion have lower average TRV and estimated RV pressure than those not chronically transfused [57]. In an informative case, a 5-year old child with a TRV of 3.1 m/s was treated with chronic transfusion therapy, on which the TRV declined to 0.7 m/s after 19 months, supporting a potential for reversal of high TRV in young children (personal communication, Margaret T. Lee).

By age 20–50 years, we suggest that more extensive vascular smooth muscle hyperplasia will have occurred, with luminal narrowing that may not respond to therapeutic maneuvers to reduce hemolysis (Figure 1, bottom two stages). In even more advanced cases, irregular, chronically activated endothelium may have accrued in situ thrombosis and plexogenic changes that dramatically increase pulmonary vascular resistance. In such advanced stages, reduction of hemolysis by transfusion may be ineffective, and only pharmacological treatment with pulmonary vasodilator drugs may produce improvement. These drugs are expected to improve pulmonary pressures and cardiopulmonary performance, but gradual progression of the disease is still likely, as in other forms of PAH.