The Myriad Presentations of Sickle Cell Disease-Related Pulmonary Hypertension

Epidemiology and Prevalence of SCD

Between 300 000 and 400 000 individuals are born annually with SCD worldwide,⁹ and around 100 000 individuals in the United States live with the disease.¹⁰ Individuals with one copy of HbS are protected against severe forms of Plasmodium falciparum malaria; therefore, the βs allele is found more frequently in sub-Saharan Africa, parts of the Mediterranean, the Middle East, and India.^9,11,12 Approximately 1 in 360 African American newborns has SCD.¹³ Despite nearly 100 years of research, the natural history of SCD remains poorly described. Mortality rates have improved over the past 60 years, but the median age at death remains unacceptably low: between 42 to 53 years for men and 48 to 58.5 years for women. ^5,14,15

Splenectomy in SCD

Many individuals with SCD have functional asplenia. In fact, splenectomy has been identified as an independent risk factor for the development of PH, particularly in patients with underlying hemolytic disorders.^35–38 Loss of splenic function may also trigger platelet activation, promoting pulmonary microthrombosis and red cell adhesion to the endothelium.³⁹ Furthermore, after splenectomy, the rate of intravascular hemolysis increases.²⁹

The Effect of Anemia on Cardiac Output

Hemolysis and anemia appear to have a synergistic effect on the heart and systemic and pulmonary vasculature. Anemia leads to decreased blood oxygen content, which causes a high cardiac output state; this is necessary to maintain oxygen delivery and is characterized by increased stroke volume, primarily from decreased blood viscosity. In this high-output state, patients with SCD are more sensitive to changes in hemoglobin concentration and less able to compensate to stressors from a cardiac output standpoint. Elevated cardiac output leads to the development of ventricular dilation, hypertrophy, and wall stress.^40–44 If anemia is corrected via transfusion, cardiac output returns to normal and systemic vascular resistance increases.⁴²

In individuals with severe anemia, particularly those with underlying cardiopulmonary disease, anemic hypoxia can occur because of the decreased ability of blood to transport oxygen and participate in gas exchange. There is a strong correlation between the severity of hemolytic anemia and decreasing arterial hemoglobin saturation, likely because of increased cardiac output and altered perfusion of the pulmonary vasculature, which may lead to impaired ventilation-perfusion matching.^45,46

Two Primary Phenotypes of SCD

There appears to be 2 distinct SCD clinical phenotypes: a vaso-occlusive phenotype and a hemolytic phenotype.⁴⁷ Although these distinctions occur on a spectrum and vary at the individual patient level, they are helpful to approach individuals with SCD from a clinical perspective. The vaso-occlusive phenotype is characterized by persistent leukocytosis, higher hemoglobin levels and bony pain, in which case recurrent episodes of acute chest syndrome tend to occur. The hemolytic phenotype is characterized by chronic kidney disease, cutaneous leg ulcers, priapism, and strokes, as well as vascular dysfunction, in which case PH tends to develop more frequently.⁴⁸

Hemodynamic Prof iles of PH in SCD

During the Sixth World Symposium in Pulmonary Hypertension the definition of precapillary PH was changed to a mPAP > 20 mm Hg and PVR ≥ 240 dynes·sec/cm⁵.^8,49,50 Because of chronic anemia, patients with SCD have baseline increases in cardiac output and low vascular resistances. At baseline, PVR in patients with SCD ranges from 68 to 74 dynes·sec/cm⁵, as compared to nonanemic healthy volunteers of 80 to 120 dynes·sec/cm⁵. As a result, a PVR > 160 dynes·sec/cm⁵ has been proposed as abnormal in patients with SCD.⁵¹

Studies using the former definition of PH (mPAP ≥ 25 mm Hg) suggest that the prevalence of PH in SCD is 6% to 11%.^52–55 (Table 1) Given the large body of literature published prior to this updated definition of disease, a significant number of individuals with SCD could be classified as having SCD-related PH. Approximately half of patients have precapillary PH (defined as mPAP ≥ 25 mm Hg and pulmonary artery occlusion pressure [PAOP] ≤ 15 mm Hg), and half have postcapillary PH (defined as mPAP ≥ 25 mm Hg and PAOP > 15 mm Hg).^52–56 Another clinical and hemodynamic phenotype that is common in SCD is one in which group 2 PH is present but the pulmonary vasculature has been remodeled and the transpulmonary gradient (mPAP-PAOP) and PVR rise.^57,58 Therefore, although the mPAP is >20 mm Hg and PAOP is >15 mm Hg, the PVR is ≥240 dynes·sec/cm⁵; this is now termed combined precapillary and postcapillary PH.⁸

Table 1. Hemodynamic profiles in SCD patients with and without pulmonary hypertension ^a

View Fullscreen

PH in SCD may occur secondary to isolated pathologic remodeling of the pulmonary arterioles, beginning with vasoconstriction, hyperplasia of intima and smooth muscle and progressing to severe angioproliferation, occlusion, and recanalization, termed the plexiform lesion.⁵⁹ When disease is restricted to the pulmonary arterioles, mean pulmonary pressures increase but left ventricular end-diastolic pressures (measured on RHC by PAOP) are normal ( ≤15 mm Hg). According to autopsy studies, pulmonary vascular lesions characteristic of precapillary PH have been found in one-third to two-thirds of patients with SCD.^33,34

Group 2 PH, defined by mPAP > 20 mm Hg and PAOP > 15 mm Hg, with a normal PVR, arises from left heart disease. In chronic anemia, the left ventricle compensates with an increase in stroke volume and chamber dilatation, leading to increased wall stress and an increase in left ventricular mass. This hypertrophy leads to impaired filling, which is characteristic of diastolic dysfunction, also known as heart failure with preserved ejection fraction.^41,43 Heart failure with reduced ejection fraction is much less common in patients with SCD, but is still an important cause of group 2 PH. Many patients with PH due to diastolic dysfunction also have an increased transpulmonary gradient consistent with combined precapillary and postcapillary PH. Importantly, diastolic dysfunction is associated with decreased exercise capacity and independently associated with increased mortality in individuals with SCD, despite adjusting for tricuspid regurgitant velocity (TRV).^40,41

The majority of patients with SCD have hemodynamic profiles consistent with group 1 and group 2 disease. High-output heart failure may occur because of longstanding elevated cardiac output in the setting of anemia, although this is a rare etiology of PH. Advanced lung disease and pulmonary fibrosis leading to PH (group 3 PH) is exceedingly rare, even if patients develop recurrent episodes of acute chest syndrome (ACS) over time. However, patients should be screened and treated for obstructive sleep apnea or nocturnal hypoxemia if present.

Given that patients with SCD are at high risk of developing thromboembolism, they are at higher risk for developing CTEPH (group 4 PH), characterized by recurrent pulmonary thromboemboli followed by fibrotic remodeling of the occluded pulmonary vasculature.⁵⁹ Scintigraphic evidence suggestive of CTEPH occurs in approximately 5% of patients with SCD and severe PH,⁶⁰ and may be associated with more severe hemodynamic abnormalities, lower exercise capacity, and higher mortality.⁶¹ Identification of CTEPH is important as these patients require lifelong anticoagulation. Specific medications may be approved for therapeutic use,⁶² and surgical options may be available, including pulmonary artery balloon angioplasty or pulmonary endarterectomy.^63–67

Screening for Cardiovascular Disease

The American Thoracic Society published guidelines recommending that adult patients with SCD undergo screening echocardiography and/or NT-proBNP testing to assess the risk of death and of having PH for further diagnosis and intensification of sickle cell-specific therapies.⁵¹ (Figure 1) Patients with a TRV value of 2.5 to 2.9 m/s are further risk stratified by 6-minute walk testing and plasma NT-proBNP testing, with abnormal values suggesting the need for RHC. Patients with values >2.9 m/s should undergo RHC, particularly if there is evidence of right heart dysfunction. Patients with PH should be screened for CTEPH. If patients develop symptoms suggestive of PH, initial screening with echocardiography and RHC may later be pursued.

View Figure

• Download as Powerpoint
• Download Figure

Mortality

The first study establishing a link between PH based on RHC and increased mortality was published in 2003. This study described a 55% mortality over 23 months and found that mPAP was inversely related to survival. Furthermore, for every increase in mPAP of 10 mm Hg, there is a 1.7-fold increase in the hazard ratio of death in patients with SCD.⁷³ Mortality is significantly higher in patients with PH defined by RHC, with significant correlation between hemodynamic markers and increased risk of death.^52–55 (Table 2) This has been validated by multiple subsequent studies, which have also found that an elevated transpulmonary gradient, diastolic pulmonary gradient (pulmonary artery diastolic pressure-PAOP), PVR, NT-proBNP, WHO functional class, and lower 6-minute walk test were all associated with increased mortality.^55,69,71

Table 2. Univariate and multivariate analysis of mortality risk factors in SCD ^a

View Fullscreen

Treatment Options

Data are limited on specific management of patients with SCD and PH; most treatment recommendations are extrapolated from data derived from other forms of PH or expert opinion.⁵¹ Generally, maximization of SCD-specific therapy, treatment of hypoxia with supplemental oxygen therapy and treatment of associated cardiopulmonary conditions (for example, HIV, iron overload, nocturnal hypoxemia, thromboembolic disorders, left ventricular disease, and chronic liver disease) are warranted. Chronic red blood cell transfusions have been shown to reduce pulmonary pressures and increase 6-minute walk distance and functional classification in patients with SCD and PH.⁷⁹

In SCD patients with PAH, namely, patients with a mPAP ≥ 25 mm Hg, PAOP ≤ 15 mm Hg and relatively high PVR ( >160 dynes·sec/cm⁵), PAH-specific therapy may be considered. There are no long-term data on specific treatment of PH in SCD, and choice of agent is empirical and based on the safety profile of the medication and physician preference. Sildenafil and other phosphodiesterase 5 inhibitors function by inhibiting the metabolism of cyclic guanosine monophosphate, the second messenger that mediates the effects of NO. Sildenafil has been shown to improve pulmonary pressures and 6-minute walk distance in phase II studies,⁸⁰ but increased hospitalization due to painful crises was shown in one larger, randomized, double-blind, placebo-controlled trial.⁵⁶ Sildenafil is only recommended in patients with well-controlled and maximized SCD-specific therapy. Riociguat, a small molecule activator of soluble guanylate cyclase, is approved for the treatment of PAH and CTEPH, but its extrapolated use in individuals with SCD-related PH is limited to 1 case series of 6 patients.⁶²

There is also limited published evidence with endothelin receptor agonists in the treatment of SCD-related PH. One retrospective study evaluating the use of ambrisentan and bosentan included 14 individuals with SCD-related PH found that therapy was well tolerated: there was a significant improvement in 6-minute walk distance, a trend toward lower BNP and TRV, and 3 individuals had decreases in their mPAP based on RHC. Therapy was stopped in 2 because of adverse reactions, but both tolerated the switch to the other endothelin-receptor agent.⁸¹ However, the following year 2 randomized, double-blind, placebo-controlled studies were performed, the ASSET-1 and ASSET-2 trials.⁸² Unfortunately, because of slow patient enrollment and site initiation, the studies were terminated prematurely. Preliminary analyses suggested that bosentan was well tolerated, with a trend toward increased CO and decreased PVR observed.

Prostacyclin-based therapies are the most effective agents for the treatment of traditional forms of PAH. Acutely, administration of epoprostenol decreases pulmonary artery pressure and PVR, and increases cardiac output.⁷³ Over time, prostacyclin-based therapy may reduce pulmonary pressure, increase 6-minute walk distance, and improve functional class.⁸³ However, its use remains off-label, with no prospective studies performed in patients with SCD.

Stem cell transplantation is the only curative option for individuals with SCD but is limited because of limited numbers of unaffected matched sibling donors and concerns regarding long-term toxicities.^84–88 Furthermore, bone marrow and lung transplantation have been shown to normalize pulmonary pressures and improve short-term outcome measures,^89,90 but may be associated with significant morbidity and mortality. Gene therapy remains an appealing option but remains limited in its application with further studies ongoing.^91,92