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Pulmonary hypertension associated with sickle cell disease

Pulmonary hypertension associated with sickle cell disease
Literature review current through: Sep 2023.
This topic last updated: Sep 29, 2023.

INTRODUCTION — Sickle cell disease (SCD) refers to a group of syndromes in which the sickle mutation is coinherited with a mutation at the other beta globin allele that reduces or abolishes normal beta globin production. These include sickle cell anemia (homozygous sickle mutation), sickle-beta thalassemia, hemoglobin SC disease, and others.

Pulmonary hypertension (PH) is a relatively frequent and severe complication of SCD and an independent risk factor for mortality [1-3]. The prevalence, pathogenesis, screening, and treatment of PH associated with SCD are discussed here. A discussion of other aspects of SCD and overviews of the pulmonary complications of SCD and of PH in patients without SCD are provided separately. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of the management and prognosis of sickle cell disease" and "Overview of the pulmonary complications of sickle cell disease" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

CLASSIFICATION — Patients with PH are classified into one of five groups based upon etiology (table 1). Patients in the first group are considered to have pulmonary arterial hypertension (group 1 PAH), while patients in the remaining four groups are considered to have PH (groups 2, 3, 4, and 5). When all five groups are discussed collectively, the term PH is used. SCD is placed in group 5, as there are some patients with hemodynamics consistent with PAH, while others have features of PH related to left-sided heart disease (group 2) or thromboembolic disease (group 4) [4]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Group 1 – PAH

Group 2 – PH due to left heart disease

Group 3 – PH due to chronic lung disease and/or hypoxemia

Group 4 – PH due to pulmonary artery obstructions (eg, chronic thromboembolic PH)

Group 5 – PH due to unclear multifactorial mechanisms (eg, SCD, beta-thalassemia, myeloproliferative disorders, sarcoidosis, and metabolic disorders)

PREVALENCE — Echocardiographic screening studies have identified evidence of elevated pulmonary pressures, defined as a tricuspid regurgitant jet velocity (TRV) ≥2.5 m/sec (equivalent to a pulmonary artery systolic pressure of approximately 36 mmHg), in 30 to 40 percent of adults with hemoglobin SS (HbSS) and 10 to 28 percent of adults with HbSC disease [5-8]. Additionally, up to 22 percent of HbSS children and adolescents have this echocardiographic finding [9], including children as young as three years of age [10]. However, echocardiographic estimates of pulmonary pressures are substantially less accurate than right heart catheterization, with a positive predictive value of 31 percent [11]. Three prospective studies utilizing right heart catheterization have defined the prevalence of PH in SCD (using a definition of mean pulmonary artery pressure ≥25 mmHg) to be between 6 and 10.5 percent [7,12,13].

PATHOGENESIS — The exact pathogenesis of PH in SCD is not known, but a number of potential contributing factors have been implicated, including endothelial injury from recurrent sickling, acute and chronic inflammation, hypercoagulability and thrombosis, chronic intravascular hemolysis, and altered bioavailability of the potent vasodilator nitric oxide (NO) [14-18]. Vascular remodeling caused by chronically elevated left heart pressures from diastolic dysfunction may also contribute, similar to PH group 2, which is purely due to left heart disease (table 1) [11].

One theory is that hemolysis results in increased plasma levels of cell-free hemoglobin (Hb) in excess of the binding capacity of the Hb scavengers, haptoglobin and hemopexin. This excess of cell-free Hb may rapidly deplete circulating NO, although there is continuing disagreement over the impact of this process on NO bioavailability [18-20]. In addition to these effects on endothelial regulation, increased levels of cell-free Hb may also contribute to endothelial and vascular smooth muscle dysfunction [21]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Pathogenetic mechanisms'.)

NO bioavailability in SCD is additionally impacted by a number of other factors:

Elevated plasma levels of arginase, also released from red cells, limit the bioavailability of L-arginine, the substrate for NO synthesis, by increasing its breakdown to ornithine (figure 1) [17,22-24]. In one study, plasma arginase activity was significantly elevated in 228 patients with SCD as compared with 36 controls; the highest activity was seen in those with secondary PH [25]. Lower bioavailability of arginine, as reflected by a low ratio of arginine to ornithine, was associated with markers of inflammation and soluble adhesion molecules, greater severity of PH, and a significantly increased risk of mortality (RR 2.5, 95% CI 1.2-5.2).

Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, may also be an independent risk factor for endothelial dysfunction [26]. In a study of 177 patients with SCD and 29 controls, ADMA levels correlated with markers of hemolysis, low oxygen saturation, PH, and early death. (See "Overview of possible risk factors for cardiovascular disease", section on 'Asymmetrical dimethylarginine'.)

Increased oxidant-related metabolism of NO can reduce the availability of NO to act as a vasodilator. The predominant activities of NO as a vasodilator and inhibitor of platelet aggregation occur when it reacts with thiols, primarily on albumin, to form S-nitrosothiols [27]. Altered redox biology occurs in SCD, and increased concentrations of the oxidative molecules including singlet oxygen, hydroxyl radical, hydrogen peroxide, and superoxide exist within the red blood cells of these patients [28,29]. These oxidative molecules can react with NO to create nitrate, nitrite, and peroxynitrite, which do not share the vasodilatory properties of NO and can be toxic [30].

While much attention has been paid to the role of hemolysis in the pathogenesis of PH in SCD, it is likely that other factors (eg, the impact of local hypoxia on vascular remodeling, genetic variability, and thrombosis) play a role in pathogenesis.

CLINICAL PRESENTATION — The diagnosis of PH is difficult in patients with SCD because of the many potential causes of dyspnea in SCD. As an example, both PH and worsening anemia can produce exertional dyspnea, fatigue, palpitations, light-headedness, and syncope/near-syncope in patients with SCD. Chest pain is not uncommon during vaso-occlusive pain episodes and may be difficult to link to potential PH, especially in patients with SCD who have chronic pain.

Common PH symptoms, including dyspnea on exertion, fatigue, chest pain, lower extremity edema, syncope or near-syncope, and palpitations, may be observed in SCD patients with or without PH. On the other hand, patients with SCD may not report dyspnea on exertion because they ascribe the symptom to anemia or deconditioning. Sometimes, careful questioning is needed to elicit a history of dyspnea (table 2). (See "Approach to the patient with dyspnea".)

Physical examination may reveal findings consistent with those observed in PH patients without SCD, such as a pronounced pulmonic component of the second heart sound. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

SCREENING AND RISK STRATIFICATION — The rationale for screening SCD patients for PH stems from the link between an elevated tricuspid regurgitant jet velocity (TRV) on Doppler echocardiography and mortality in SCD, although this remains an area of controversy and further research is needed to clarify the optimal approach for early detection of PH [1,31,32]. While outcomes studies have not identified a benefit from screening, risk stratification based on TRV helps to guide clinical decision making. An elevated TRV measured by Doppler echocardiography identifies adults with SCD who are at increased risk for mortality [6]; in children ≥8 years old, an elevated TRV identifies those at greater future risk for reduced exercise capacity [9]. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Given the often delayed appearance of symptoms and the increased morbidity and mortality risks associated with elevated pulmonary pressures by echocardiogram (regardless of a PH diagnosis), our practice, consistent with guidelines from the American Thoracic Society, is to screen patients with SCD as follows (algorithm 1) [2]:

A one-time transthoracic Doppler echocardiogram is suggested in asymptomatic children with SCD who are aged 8 to 18 years old (possibly sooner in those with severe hemolytic anemia) [33]. Based on the TRV result, the patient may require additional evaluation as described below and in the algorithm. (See 'Evaluation for PH' below.)

Once individuals with SCD reach adulthood (18 years of age), Doppler echocardiography is recommended every one to three years, using the shorter intervals for those with respiratory symptoms, TRV ≥2.5 m/sec on prior echocardiogram, greater frequency of pain episodes, prior thromboembolic events, or greater severity of hemolytic anemia [2].

An expert panel from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) found insufficient evidence to recommend for or against screening for PH in asymptomatic individuals with SCD; however, the panel emphasized the importance of evaluating symptoms suggestive of PH (eg, exercise intolerance, fatigue, peripheral edema, chest pain) with echocardiography [34,35]. The American Society of Hematology guidelines advise against routine echocardiography for screening but support a comprehensive assessment for symptoms and signs that might be clues to the development of PH (eg, dyspnea or chest pain at rest or with exertion, exercise limitation, syncope or presyncope, sleep-disordered breathing, history of venous thromboembolism, hypoxemia at rest or with exertion) [36].

EVALUATION FOR PH — PH is typically suspected in SCD patients who have exertional dyspnea, oxygen desaturation, more severe hemolytic anemia, or elevated tricuspid regurgitant jet velocity (TRV; ≥2.5 m/sec) on screening echocardiography [24,34,37]. The ability of echocardiography to predict PH increases with increasing TRV. A TRV between 2.5 and 3 m/sec identifies only 31 percent of patients with a mean pulmonary artery pressure (mPAP) ≥25 mmHg, whereas a TRV ≥3 m/sec identifies approximately 66 to 77 percent of patients with PH [7,11,12].

The evaluation of patients with these findings includes pulmonary function tests with a diffusing capacity, ventilation/perfusion scanning, a six-minute walk test (6MWT), N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), and transthoracic Doppler echocardiography in those who have not had a recent study [1,7,14,38,39]. However, none of these noninvasive tests is diagnostic for PH; a right heart catheterization (RHC) is required for diagnosis (algorithm 1). (See 'Diagnosis' below.)

The following discussion reviews the accuracy of these tests for identifying PH and the interpretation of the results in patients with SCD. The role of these studies in the evaluation of PH from other etiologies is described separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)

Transthoracic doppler echocardiography — Doppler echocardiography provides an estimate of pulmonary artery and right ventricular systolic pressures via the TRV, and assesses left and right ventricular size, thickness, and function. Although much attention has been given to the association of a TRV of ≥2.5 m/sec with increased mortality risk in SCD [6], each component of the echocardiogram helps to inform the clinician of PH risk [36]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

A prospective French study performed echocardiography on 398 SCD adults, of whom 96 underwent RHC [7]. An elevated TRV was noted in 27 percent, but only 6 percent had PH confirmed by right heart catheterization. Using a TRV of >2.9 m/sec increased the positive predictive value to 64 percent but also increased the false negative rate to 42 percent. This false negative rate was improved by using a 6 minute walk distance of <333 meters and an NT-pro-BNP level >164.5 pg/mL. A 2016 meta-analysis of the studies with RHC and echocardiographic data revealed that 53 of 173 patients (31 percent) with a TRV >2.5 m/sec actually had PH, confirming the low positive predictive value of transthoracic Doppler echocardiography [11].

Elevated pulmonary artery pressures are also noted in children, particularly those with more severe hemolysis and/or frequent episodes of acute chest syndrome (ACS), and are associated with a subsequent decline in exercise tolerance [10]. The PUSH trial demonstrated that children and adolescents with an elevated TRV and a high hemolytic component were at highest risk for a decreased 6MWT after two years of follow-up [9].

For patients with a TRV ≥3 m/sec, we proceed to RHC (algorithm 1). For patients with a TRV 2.5 to 2.9 m/sec, we proceed to RHC if there are other findings suggestive of PH, such as symptoms or physical signs including unexplained hypoxemia, a decreased 6MWT distance, or an elevated NT-pro-BNP. In the absence of these other findings, we increase the frequency of subsequent Doppler echocardiograms to annually. These criteria are slightly different from those used for patients with pulmonary arterial hypertension (PAH). Our preference to use 2.5 m/sec as the TRV to consider RHC is based upon an increased mortality associated with this finding in SCD patients. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

N-terminal-pro-brain natriuretic peptide — Plasma concentrations of NT-pro-BNP are typically elevated in patients with PH and correlate with severity; similar findings pertain in SCD.

Two studies evaluated the use of NT-pro-BNP to assess for PH and mortality risk in SCD. One study included two separate cohorts of consecutive SCD adults [14]. In one cohort, the degree of NT-pro-BNP elevation correlated with mortality; among patients with NT-pro-BNP levels of ≤30 pg/mL, 31 to 159 pg/mL, and ≥160 pg/mL, respectively, mortality was 6, 7, and 26 percent. The mortality risk among adults with an NT-pro-BNP level ≥160 pg/mL was 5.1 (95% CI 2.1-12.5) times greater than that observed among patients with a NT-pro-BNP level <160 pg/mL. In the other cohort, the degree of NT-pro-BNP elevation also correlated with mortality; among patients with NT-pro-BNP levels of ≤30 pg/mL, 31 to 159 pg/mL, and ≥160 pg/mL, respectively, mortality was 6, 17, and 49 percent. The risk of mortality was 2.9 (95% CI 1.2-6.6) times greater among patients with an NT-pro-BNP level ≥160 pg/mL compared with those with lower levels [14]. These findings were confirmed by a study of 330 adults recruited as part of the Cooperative Study of Sickle Cell Disease, in which an NT-pro-BNP level ≥160 pg/mL was associated with a relative risk of death of 6.24 (95% CI 2.9-13.3) compared with those with lower levels [40]. (See "Natriuretic peptide measurement in non-heart failure settings", section on 'Pulmonary hypertension'.)

NT-pro-BNP can also be used as a screening test for PH when Doppler echocardiography is not available or not able to obtain adequate images [2]. A serum NT-pro-BNP level ≥160 pg/mL detects PH with a sensitivity and specificity of 57 and 91 percent, respectively [14]. Of note, measurements may be misleading in patients with renal insufficiency or left heart failure [2].

Six-minute walk test with oximetry — We perform oximetry at rest and with exertion in all patients with dyspnea, decreased exercise tolerance, fatigue, chest pain, lower extremity edema, syncope or near-syncope, and/or palpitations [36]. Measuring pulse oxygen saturation (SpO2) during ambulation on a flat surface (eg, 6MWT) and during stair climbing is critical for identifying patients whose SpO2 <94 percent or decreases by more than 7 percentage points with exertion; these patients need a more complete evaluation for PH. 6MWTs provide information about oxygen desaturation and distance walked, which can be helpful in assessing exercise capacity. (See 'Diagnosis' below and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)

In a controlled observational study, a 6MWT was performed in 17 patients with SCD without PH and 26 patients with SCD and PH [38]. Patients with SCD and PH walked a shorter distance during the 6MWT (320 versus 435 meters). The 6MWT distance inversely correlated with the mPAP as measured by RHC. In a separate study of 310 patients with SCD, SpO2 declined in 68 percent of children with an elevated TRV compared with 32 percent of those with a normal TRV [41]. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)

The 6MWT has not been rigorously tested as a screening tool for PH complicating SCD. As chronic anemia and deconditioning can contribute to reduced exercise tolerance in these patients, caution is needed when interpreting the results. On the other hand, using a six-minute walk distance of <333 meters, combined with an NT-pro-BNP ≥160 pg/mL, may help improve the diagnostic accuracy of echocardiography [7,36].

DIAGNOSIS — While PH may be suspected on the basis of exertional dyspnea and the results of noninvasive testing (eg, elevated N-terminal-pro-brain natriuretic peptide ≥160 pg/mL, six-minute walk distance <333 m, elevated tricuspid regurgitant velocity [TRV]), a definitive diagnosis requires right heart catheterization (RHC) (algorithm 1) [36]. (See 'Evaluation for PH' above.)

PH is now defined as a resting mean pulmonary artery pressure (mPAP) >20 mmHg [42]. While 6 to 11 percent of SCD patients have PH based on an mPAP ≥25 mmHg, the hemodynamic features vary across patients. In approximately 40 percent of patients, there is predominantly precapillary PH [4]. In the rest, the hemodynamic characteristics have at least a component of postcapillary PH (table 3). Some patients have hemodynamic features of both. The details of right heart catheterization in the diagnosis of PH are reviewed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

Precapillary PH – Precapillary PH associated with SCD is defined similarly to other types of Group 1 pulmonary arterial hypertension (PAH): an mPAP >20 mmHg with a mean pulmonary artery occlusion pressure (PAOP) or left ventricular end-diastolic pressure ≤15 mmHg, plus an increased pulmonary vascular resistance (PVR).

However, the definition of an increased PVR is different in SCD-related PAH compared with other types of Group 1 PAH because patients with SCD have an anemia-induced elevation of their cardiac output and reduction in their blood viscosity at baseline [43]. These factors result in a lower baseline PVR than is observed in non-anemic patients (60 to 80 dynes-sec/cm5). In the absence of a consensus definition of an elevated PVR in SCD, most clinicians consider values that are two to three standard deviations above normal (ie, approximately >160 dynes-sec/cm5 [2 Wood units]) as indicative of a high PVR. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

Postcapillary PH – Postcapillary PH (group 2) occurs in SCD when the left atrial pressure and, therefore, the pulmonary venous pressure (ie, the mean PAOP or left ventricular end-diastolic pressure) is >15 mmHg (in the absence of mitral valve disease) without an increase in PVR [44]. These hemodynamic features are generally observed in the setting of diastolic dysfunction of the left ventricle, although rare cases of left-sided systolic dysfunction and valvular disease have been observed [8,11,45]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Cardiac complications'.)

Combined pre- and postcapillary PH – Patients with SCD frequently have hemodynamic features of both pre- and postcapillary PH, characterized by an mPAP >20 mmHg, a PAOP ≥15 mmHg, and an increased PVR. An elevated transpulmonary gradient (>12 mmHg) reflective of a reactive post-capillary PH is often noted [45]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Cardiac complications'.)

Once PH is diagnosed, further evaluation is needed to identify contributors to PH that might require focused treatment, such as hypoxemia due to sleep-disordered breathing including obstructive sleep apnea (OSA), in situ thrombosis, venous thromboembolism, HIV infection, or portal hypertension (table 1 and algorithm 1). Because of the known association of OSA with PH in non-SCD populations, the clinical guidelines for diagnosis of PH in SCD recommend a formal sleep study for all SCD patients with an elevated TRV or PH [2]. In addition, the evaluation for other contributors to PH typically includes laboratory testing (liver function tests, antinuclear antibody, HIV serology), pulmonary function testing, and a radionuclide ventilation-perfusion scan. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

MANAGEMENT — The optimal therapy for PH due to SCD is not known. As these patients are often quite complicated, it is recommended that they be managed at PH centers with experience in the care of patients with SCD [34,37]. A general approach to these patients involves the use of SCD-specific therapies with consideration of specific treatments for PH. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'.)

Supportive care and treatment of comorbidities — Supplemental oxygen is administered to patients with decreased oxyhemoglobin saturation, aiming for a pulse oxygen saturation ≥90 percent at rest and exertion, based on the experience in other forms of PH. Suspected obstructive sleep apnea (OSA) is evaluated via polysomnography and treated accordingly. In a small case series of children with SCD, treatment of OSA, nocturnal hypoxemia, and asthma reduced the elevated tricuspid regurgitant jet velocity (TRV), suggesting that mortality risk can be modified with early intervention [46]. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing' and "Overview of the pulmonary complications of sickle cell disease", section on 'Asthma'.)

Diuretics are used to treat right ventricular volume overload complicating PH [44], but diuresis must be done carefully to minimize the risk of volume depletion-induced red blood cell sickling. The risk of this complication may be reduced by hydroxyurea or chronic transfusion therapy.

Proteinuria or microalbuminuria are common in SCD-related PH [31] and may improve with angiotensin converting enzyme (ACE)-inhibitor therapy [47]. (See "Sickle cell disease effects on the kidney", section on 'Prevention and management (sickle nephropathy)'.)

SCD-specific treatments — Hydroxyurea and chronic transfusion therapy are SCD-specific treatments that may be of benefit in SCD-associated PH, based on indirect evidence. Given the risks of red blood cell transfusions (eg, febrile and allergic reactions, volume overload, iron overload, infection, alloimmunization), hydroxyurea is preferred as first line therapy. In general, these therapies are not given concurrently [2].

Hydroxyurea – Hydroxyurea increases fetal hemoglobin concentration in patients with SCD and reduces the frequency of acute pain episodes and other complications [48]. Hydroxyurea is the mainstay of treatment for SCD, as discussed separately (see "Hydroxyurea use in sickle cell disease"). In addition, consensus clinical guidelines for PH in SCD recommend the use of hydroxyurea for all SCD patients with documented PH, an elevated TRV, or increased N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) who are not already taking hydroxyurea [2]. The administration of hydroxyurea in SCD is described separately.

As both PH and an elevated TRV are risk factors for mortality in SCD and as hydroxyurea reduces hemolysis which is key to the pathogenesis of PH in SCD, it is likely that use of this medication is beneficial in these patient groups. However, this question has not been addressed in a large-scale clinical trial.

Evidence in favor of hydroxyurea comes from a longitudinal study of 299 SCD patients in which hydroxyurea use was associated with improved survival over time periods up to 17.5 years [49]. In this study, 87 percent of the deaths due to pulmonary complications occurred in patients not taking hydroxyurea.

ACS and vaso-occlusive episodes increase pulmonary pressures acutely and can precipitate right-sided heart failure; patients with ACS and right heart failure are at increased risk of death both during and after that hospitalization [7,16]. Thus, reducing the frequency of ACS with hydroxyurea is thought to decrease the likelihood of development or progression of PH based upon the well-characterized association of episodes of ACS and death from PH and cor pulmonale [7].

Chronic transfusion therapy – Chronic transfusion therapy (also called prophylactic or preventive transfusion) is effective in reducing the incidence of stroke and ACS. There are no clinical trials assessing the benefit of chronic transfusion in the management of PH [50,51]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

In accord with consensus guidelines, chronic transfusion therapy can be used in SCD patients who have an increased risk for mortality (ie, right heart catheterization [RHC]-confirmed PH, a TRV ≥2.5 m/s, or an NT-pro-BNP ≥160 pg/mL) and do not have a response to or do not tolerate hydroxyurea therapy [2]. The rationale for this practice is that chronic transfusion reduces the frequency of ACS in patients who continue to have episodes of ACS despite hydroxyurea therapy; and reducing the frequency of ACS is likely to reduce the incidence of death and possibly the progression of PH [2]. In a series of 13 patients with SCD and severe dyspnea due to PH, regularly scheduled exchange transfusions were associated with improved symptoms and decreased pulmonary vascular resistance but no improvement in the six-minute walk distance [51,52].

The frequency of transfusion, relative benefits of exchange transfusion rather than simple transfusion, and the use of chelation therapy are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Transfusion in sickle cell disease: Management of complications including iron overload".)

Long-term anticoagulation — Long-term anti-coagulation for treatment of patients with idiopathic pulmonary arterial hypertension (PAH) is controversial (see "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy').

The specific risks and benefits of anticoagulation in patients with SCD-associated PH are not known. Retrospective data suggest that both PH and an elevated TRV are associated with an increased prevalence of venous thromboembolism (VTE) [53]. SCD is a hypercoagulable state with 11 to 12 percent of patients experiencing a VTE by age 40 and a recurrence rate of 31 percent after a primary event [54,55]. It is likely that thrombosis would further compromise pulmonary vascular physiology in these patients. On the other hand, patients with SCD have an increased risk for cerebral and retinal hemorrhage. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Intracranial hemorrhage management' and "Overview of the clinical manifestations of sickle cell disease", section on 'Retinopathy'.)

Based upon consensus clinical guidelines, for patients with SCD-associated PH and VTE but without a known bleeding risk, the benefits of indefinite anticoagulation seem to outweigh the risks, in that recurrent VTEs are likely to be poorly tolerated by patients with PH and SCD [2,36]. If there is no clinical history of VTE, we screen patients with a diagnosis of PH for coexistent thromboembolic disease, usually with a radionuclide ventilation-perfusion scan; V/Q scanning is preferred over computed tomographic pulmonary angiography (CTPA) in suspected cases of PH due to chronic thromboembolic disease because of greater sensitivity in such cases. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Clinical features'.)

In concert with the guidelines, we suggest long-term, rather than short-term, anticoagulation for patients with SCD and PH confirmed by right heart catheterization with prior or current VTE (unrelated to an indwelling catheter) and without known bleeding risk (eg, without low steady state hemoglobin, increased steady state leukocyte count, history of hemorrhage) [2]. (See "Venous thromboembolism: Initiation of anticoagulation" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

PH-specific therapy — PH-specific therapy (also termed PH-targeted therapy) refers to treatment with endothelin receptor antagonists (ie, bosentan, macitentan, ambrisentan), prostanoids (ie, epoprostenol, treprostinil, iloprost), nonprostanoid prostacyclin receptor (IP receptor) agonists (ie, selexipag), soluble guanylate cyclase stimulators (GCS; eg, riociguat), or phosphodiesterase 5 inhibitors (PD5I; sildenafil, tadalafil). In PAH, PH-specific therapy is generally initiated in patients with symptoms consistent with World Health Organization (WHO) functional class II, III, or IV (table 4). In SCD, the recommendations are more complicated because of the frequency of PH related to left-sided heart disease (pulmonary venous hypertension) and the paucity of randomized trial data. An overview of pulmonary vasodilator therapy in PAH is provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'.)

Based upon the data outlined below and the consensus clinical experience of the PH in SCD guidelines committee, we typically initiate PH-specific therapy in carefully selected, symptomatic patients with RHC-confirmed elevation in pulmonary vascular resistance (PVR) and normal PAOP (ie, physiology similar to group 1 PAH) using either an endothelin receptor antagonist or a prostanoid [2]. We recommend against treatment of SCD patients with isolated elevations in TRV or NT-pro-BNP level or those with RHC-confirmed PH due to left-sided heart disease [2].

Not all of the available PH-targeted agents are useful in SCD; we use endothelin receptor antagonists and prostanoids in selective patients as described below. We do not typically use PD5I, and calcium channel blockers (CCB) in patients with SCD and PH. A Phase 2b study of the safety of riociguat in patients with SCD and vasculopathy (systemic hypertension, proteinuria or an elevated TRV) is in progress (NCT02633397). Until the results of this study are known, we cannot comment on the utility of riociguat in SCD-related PH. We use combination oral therapy for most patients who are NYHA Class II/III and intravenous therapy for those who are NYHA Class IV or in right-sided heart failure similar to those with PAH. In our experience, the baseline elevations in cardiac output make the occurrence of a cardiac index (CI) <2.0 extremely rare.

Endothelin receptor antagonist – Endothelin receptor antagonists (ERAs) are effective in other forms of PH and are suggested therapy for SCD patients with RHC-proven PH and moderate disease based on functional class (ie, WHO class II and III) [2,56,57].

The ERA bosentan has been the subject of two randomized trials comparing bosentan to placebo in SCD patients with RHC-defined elevated PVR and a normal PAOP (the ASSET-1 trial) or pulmonary venous hypertension and a PVR >100 dynes-sec/cm5 (the ASSET-2 trial) [56]. After the randomization of only 14 participants in ASSET-1 and 12 patients in ASSET-2, the trials were prematurely terminated due to slow patient enrollment. As very few patients were enrolled, efficacy endpoints were not assessed other than a nonsignificant increase in cardiac output and a nonsignificant decrease in PVR with bosentan noted in both trials. There were no apparent toxicity issues. Due to known hepatotoxicity, bosentan in particular is avoided in patients with liver disease.

Additional details regarding use of ERAs in PH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Prostanoid pathway agonists – While the evidence is limited to consensus experience and extrapolation from trials in PAH, prostanoids are preferred over ERAs for patients with advanced SCD-associated PH (eg, WHO class IV), evidence of right ventricular failure (depressed CI), or those who have failed ERAs. Side effects include jaw pain, diarrhea, arthralgias, and complications of the delivery systems. A small case series of 11 patients treated with long-term prostanoids suggested improved right ventricular systolic pressures by echocardiography and greater six-minute walk distances [58].

The oral prostacyclin receptor agonist selexipag has not been evaluated in patients with PH and SCD, and its benefits in this setting are unknown.

The use of the various prostanoids in other forms of PH is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Guanylate cyclase stimulants – The GCS (eg, riociguat) increase the sensitivity of the nitric oxide (NO) receptor to endogenous NO, thus enhancing the vasodilator effect of NO. Oral riociguat is beneficial in patients with chronic thromboembolic PH (CTEPH; group 4) and may be of benefit in patients with PAH (group 1). A retrospective series of six patients with SCD related CTEPH treated with riociguat demonstrated improved six-minute walk distance, right ventricular systolic pressure by echocardiography and WHO functional class in 5 of 6 patients; however, these observations require confirmation in a more robust prospective study [59]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Sildenafil – Sildenafil is a PD5I that is effective in other forms of PH but is avoided in SCD-associated PH. The Walk-PHaSST (Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy) trial compared the safety and efficacy of sildenafil to placebo in SCD patients with a TRV ≥2.7 m/s [60]. After 74 (of a targeted 132) participants were enrolled, the study was terminated due to an increase in serious adverse events in the sildenafil group, primarily hospitalization for acute vaso-occlusive pain. This result was different from that reported in prior smaller open-labelled studies [61,62]. A study of long-term PD5I use (defined as >4 months) in 36 patients with RHC-confirmed PH due to SCD demonstrated that these medications are well tolerated in a subset of patients with possible improvement in NYHA Class [63].

Calcium channel blockers – Calcium channel blockers are not recommended in SCD-associated PH. Data evaluating the use of acute vasodilator therapy in this population are quite limited, and it is unknown whether or not these patients respond to calcium channel blocker therapy other than in isolated, anecdotal cases.

Patients should be evaluated at three-month intervals, depending on clinical status and stability; if clinical status fails to improve or worsens, a second or third agent from a different class may be added, understanding that agents are limited and poorly studied in this population. Management of refractory PH with shunts and transplantation is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Right-to-left shunt' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

PROGNOSIS — Both PH and an elevated tricuspid regurgitant jet velocity (TRV; without PH documentation on right heart catheterization) have important prognostic implications for SCD patients.

PH is an independent risk factor for mortality with an approximate 40 percent six year mortality according to one study of 531 patients [12]. In a longitudinal study, 84 patients with PH due to SCD were followed for a median time of 4.7 years [45]. The following were identified as hemodynamic risk factors for mortality: mean pulmonary artery pressure (PAP; hazard ratio [HR] 1.61, 95% CI 1.05-2.45 per 10 mmHg increase), diastolic PAP (HR 1.83, 95% CI 1.09-3.08 per 10 mmHg increase), diastolic PAP - pulmonary arterial wedge pressure (HR 2.19, 95% CI 1.23-3.89 per 10 mmHg increase), transpulmonary gradient (HR 1.78, 95% CI 1.14-2.79 per 10 mmHg increase), and pulmonary vascular resistance (HR 1.44, 95% CI 1.09-1.89 per Wood unit increase). These data suggest that the greater the degree of precapillary PH, the worse the prognosis.

Although only a portion of patients with an elevated TRV or N-terminal-pro-brain natriuretic peptide level alone have PH, each of these factors predicts mortality in SCD adults [6]. One possible explanation for this observation is the association between an elevated TRV and relative systemic hypertension, lower extremity ulcers, and kidney disease, suggesting the presence of a more diffuse systemic vasculopathy in these patients [64].

While an elevated TRV is not associated with a higher mortality in children with SCD, longitudinal follow-up of 160 children and adolescents with SCD demonstrated a reduction in exercise capacity (decreased six-minute walk distance) over 22 months in those with an elevated TRV [9]. This observation suggests that children with SCD and an elevated TRV may be at increased risk of cardiopulmonary decline. At this time, we do not know whether early identification and treatment of patients with SCD and elevated TRV without PH improves survival.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults" and "Society guideline links: Pulmonary hypertension in children" and "Society guideline links: Sickle cell disease and thalassemias".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

Classification – Pulmonary hypertension (PH) in sickle cell disease (SCD) is due to unclear, multifactorial mechanisms. PH is associated with increased morbidity and mortality in SCD. The prevalence of PH in SCD is estimated to be between 6 and 10.5 percent. (See 'Classification' above and 'Prevalence' above.)

Clinical presentation – Patients with SCD may not report dyspnea on exertion, as they may ascribe the symptom to anemia or deconditioning. Careful questioning may be needed to elicit a history of dyspnea (table 2). (See 'Clinical presentation' above.)

Screening and risk stratification – As symptom recognition is often delayed in PH complicating SCD, we obtain a baseline transthoracic Doppler echocardiogram in children ≥8 years old and perform Doppler echocardiogram in adults every one to three years, although this is controversial and evidence is lacking. A tricuspid regurgitant jet velocity (TRV) of ≥2.5 m/sec is indicative of increased mortality risk and requires further evaluation (algorithm 1). (See 'Screening and risk stratification' above.)

Diagnosis – Our approach includes (see 'Diagnosis' above):

PH may be suspected based on exertional dyspnea and noninvasive testing (eg, TRV ≥2.5 m/sec, N-terminal-pro-brain natriuretic peptide ≥160 pg/mL, six-minute walk distance less than 333 m).

Definitive diagnosis requires right heart catheterization (RHC) that identifies a resting mean pulmonary artery pressure >20 mmHg. RHC is also used to differentiate precapillary PH with a normal pulmonary artery occlusion pressure (PAOP ≤15 mmHg) from postcapillary PH with an elevated PAOP (>15 mmHg).

Once PH is diagnosed, further evaluation is needed to identify any contributors to PH that might require focused treatment, such as hypoxemia due to obstructive sleep apnea (OSA), in situ thrombosis, venous thromboembolism (VTE), HIV infection, or portal hypertension (algorithm 1). We typically obtain laboratory testing (liver function tests, antinuclear antibody, HIV serology), pulmonary function testing, a radionuclide ventilation-perfusion scan, and polysomnography.

Treatment – Treatment includes:

Supportive treatment for precapillary PH in SCD includes supplemental oxygen and diuretics, as well as treatment of sleep disordered breathing, VTE, and other disease modulators. (See 'Supportive care and treatment of comorbidities' above and 'Long-term anticoagulation' above and "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing'.)

For SCD patients with precapillary PH by RHC, we evaluate for pulmonary embolus (PE), usually with radionuclide ventilation-perfusion lung scanning. For patients with PE, we suggest indefinite anticoagulant therapy rather than a limited duration of therapy (Grade 2C). Anticoagulation may need to be reduced for patients with major bleeding risk factors. (See 'Long-term anticoagulation' above.)

For patients with SCD and PH by RHC or a TRV of ≥2.5 m/sec, we recommend treatment with hydroxyurea (Grade 1B). In practice, most patients with SCD should already be taking hydroxyurea. Chronic transfusion therapy is an alternative for patients who are unable to take hydroxyurea or whose disease does not respond. (See 'Management' above and "Hydroxyurea use in sickle cell disease", section on 'Summary and recommendations' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Summary and recommendations'.)

PH-specific therapy is reserved for SCD patients who are symptomatic (World Health Organization [WHO] class II to IV) and have precapillary PH documented by RHC. For patients with moderate disease (WHO class II to III), we typically initiate therapy with an endothelin receptor antagonist; for patients with advanced disease (WHO class IV), we typically initiate therapy with a prostanoid following guidelines for other forms of PH. We avoid phosphodiesterase-5 inhibitors in SCD due to a possible increase in the frequency of vaso-occlusive pain. (See 'PH-specific therapy' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

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