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Pulmonary hypertension (PH) in chronic hemolytic anemias is complex.
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Diagnostic criteria appear to differ from that of PH in other conditions.
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PH may result in morbidity and mortality; limited studies detail optimal treatment.
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To date, limited studies have defined pathophysiologic treatment targets.
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More studies should establish definitive guidelines for diagnosis and treatment.
Abstract
Pulmonary hypertension has emerged as a major cause of morbidity and mortality in patients with hemoglobinopathies and chronic hemolytic anemias. These hematological diseases include – but are not limited to – sickle cell disease (SCD), thalassemia, paroxysmal nocturnal hematuria, and hereditary spherocytosis. Although most studies have been based on the use of echocardiography as a screening tool for pulmonary hypertension as opposed to the gold standard of right heart catheterization for definitive diagnosis, the association between chronic hemolytic anemia and pulmonary hypertension is evident. Studies have shown that patients with SCD and a tricuspid regurgitant velocity (TRV) ≥ 2.5 m/sec are at increased risk of pulmonary hypertension and are at increased mortality risk. Additional markers of risk of pulmonary hypertension and increased mortality include a pro-BNP >160 pg/mL combined with a 6-min walk distance of <333 m. There is currently a lack of concrete data to support the use of targeted oral pulmonary arterial hypertension therapy in chronic hemolytic anemia. As a result, management is generally targeted towards medical optimization of the underlying anemia. This literature review aims to discuss the pathophysiology, diagnostic and prognostic tools, recent studies and current protocols that are essential in guiding management of pulmonary hypertension in chronic hemolytic anemias.
]. Pulmonary hypertension associated with chronic hemolytic anemia had been previously classified within the Group 1 category (pulmonary arterial hypertension), but was re-categorized into Group 5, conditions of unclear or multifactorial origin, at the Fifth World Symposium on Pulmonary Hypertension in 2013 [
]. Depending on hemodynamics, pulmonary hypertension can also be characterized as pre-capillary or post-capillary patterns measured at right heart catheterization. Pre-capillary pulmonary hypertension is defined as when the pulmonary capillary wedge pressure is ≤ 15 mmHg, whereas post-capillary pulmonary hypertension is when the PAWP (or LVEDP) is >15 mmHg [
]. A distinction between pre-capillary and post-capillary hypertension is often key to guiding management.
Table 1Classification of pulmonary hypertension.
Adapted from: Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, et al. Updated Treatment Algorithm of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. 2013; 62 (25, Supplement):D60-D72. This classification may change somewhat following the 6th World Symposium of Pulmonary Hypertension, Nice France, February 2018
As indicated in their current classification within Group 5, there are multiple possible mechanisms that underlie the pathogenesis of pulmonary hypertension in hematological diseases. Pulmonary hypertension caused by hematological diseases can be associated with pre-capillary etiologies, post-capillary etiologies, or a combination. The mechanisms may be associated with hemolysis and its consequences, chronic anemia leading to high cardiac output, or with a hypercoagulable state. Nitric oxide normally plays a key role as a potent vasodilator and modulator of endothelial proliferation, along with having anti-inflammatory properties [
]. Depletion of nitric oxide and its precursor, Arginine, has been shown to correlate with a higher incidence of pulmonary hypertension. Intravascular hemolysis releases free hemoglobin and arginase-1, which both cause decreased nitric oxide signaling via different pathways. Free hemoglobin directly inactivates nitric oxide, while arginase-1 depletes a substrate of NO synthase, L-arginine. Both pathways lead to a decrease in nitric oxide and impair vascular endothelial function, which may result in pre-capillary pulmonary hypertension [
]. Hemolysis also enhances reactive oxygen species and the oxidation of hemoglobin has been shown to activate Toll-Like Receptor 4, promote vaso-occlusion and acute lung injury, particularly in SCD. The activation of these sterile-inflammatory molecules via the heme-TLR4 pathway have been termed damage-associated molecular pattern molecules (DAMPs) [
]. Aside from hemolysis, chronic anemia may also cause a high cardiac output state that leads to left-sided heart disease, left ventricular dysfunction, and predisposes patients to post-capillary pulmonary hypertension. Hemolysis also causes oxidative damage to tissues, activating platelets and the coagulation cascade, resulting in vasculopathy and hypercoagulability [
]. As a result, patients are at an increased risk of developing deep venous thrombosis and pulmonary embolism, which may lead to one of the major categories of pulmonary hypertension (Group 4). It should be noted that patients with Group 1 PAH have also been shown to have increased hypercoagulability due to thrombotic arteriopathy, abnormalities of serum coagulation factors, anti-thrombotic factors, and fibrinolytic system that leads to a pro-thrombotic state. Furthermore, patients with SCD are prone to develop in situ thrombosis at the level of the small pulmonary vessels from recurrent vaso-occlusive crisis, which could also result in pulmonary hypertension [
Histopathologically in pulmonary arterial hypertension, all three layers of the pulmonary arterial wall – the intima, adventitia, media, and adventia – are affected via medial hypertrophy, migration of smooth muscle cells from the media to endothelial cells, and intimal proliferation [
]. The adventitia itself is thickened due to the expansion of cells in the media due to the accumulation of immune cells, such as fibroblasts and macrophages [
]. All groups of pulmonary hypertension may exhibit these histopathological findings, with Group 2 disease also showing prominently enlarged pulmonary veins and capillaries and Group 4 disease having organized thrombi replacing the intima of the proximal or distal elastic pulmonary arteries and attach to the medial layer [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. As pulmonary hypertension in chronic hemolytic diseases is secondary to hemolysis, hypoxia, hypercoagulability or a combination of these factors, they may show any of the histopathological features described above.
The treatment of some hematological disorders themselves could also predispose patients to the development of pulmonary hypertension. Patients with hemoglobinopathies, such as SCD and β-thalassemia, are occasionally managed with blood transfusions. This may lead to iron-overload, especially in transfusion-dependent patients, which may induce myocardial iron deposition and/or interstitial pulmonary fibrosis and, ultimately, affect the left ventricular systolic or diastolic function and pulmonary vascular resistance [
]. Splenectomy, whether via surgery or auto-infarction, is also a risk factor for pulmonary hypertension, particularly chronic thromboembolic pulmonary hypertension (CTEPH). This is postulated to be due to an increased susceptibility to thrombosis resulting from high platelet counts and platelet aggregation or an increased amount of damaged red blood cells and adhesion to endothelium after splenectomy. The spleen is also responsible for clearing circulating microparticles, which are involved with inflammatory modulation, cytokine secretion, and expression of adhesion molecules [
]. Splenectomy causes decreased clearance of microparticles, resulting in inflammation and vascular remodeling that has been hypothesized to result in pulmonary hypertension [
]. Circulating microparticles of platelet and erythrocyte origins have been shown to impair endothelial vaso-relaxation by decreasing nitric oxide production during times of oxidative stress, thereby, altering pulmonary vascular tone and predisposing to the development of pulmonary hypertension [
]. These effects of splenectomy, coupled with the intrinsic complications of hemolytic disorders as described above, further predispose patients to pulmonary hypertension [
The clinical presentation of pulmonary hypertension is often non-specific, mainly manifesting as dyspnea (particularly on exertion), fatigue, and, in more advanced disease, signs and symptoms of heart failure [
]. As a result, a high clinical suspicion is required for diagnosis, especially in at-risk patient populations. Right heart catheterization remains the gold standard diagnostic tool for pulmonary hypertension, with a mean pulmonary artery pressure ≥25 mmHg meeting the definition criterion. A subclass of pulmonary hypertension, pulmonary arterial hypertension (PAH), has an additional criteria of a pulmonary capillary wedge pressure ≤15 mm Hg [
ACCF/AHA 2009 expert consensus document on pulmonary Hypertension. A report of the American College of Cardiology foundation task force on Expert Consensus documents and the American heart association developed in collaboration with the American College of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
]. Patients with chronic anemia have a reduced blood viscosity, which with an increased cardiac output, result in a lower pulmonary vascular resistance (PVR) compared with non-anemic patients. This is because measurement of PVR is inversely proportional to cardiac output. As a result, patients with increased cardiac output would have a lower PVR at baseline. Due to this physiology, patients with high cardiac output secondary to anemia should have an alternate definition of pulmonary hypertension. For sickle cell patients, the American Thoracic Society's Ad Hoc Committee on Pulmonary Hypertension of SCD has suggested >2 Wood units to be diagnostic of elevated pulmonary vascular resistance [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. However, few guidelines are available for other types of hemolytic anemias and whether this revised definition can be generalized to include other hemoglobinopathies remain in question.
Echocardiography is the main screening tool for pulmonary hypertension by measuring the tricuspid regurgitation velocity (TRV), with a TRV ≥ 3.0 m/sec beginning to suggest increased pulmonary arterial pressures in the general population. The TRV threshold for the SCD population to suggest increased pulmonary arterial pressures, on the other hand, is lower at TRV ≥2.5 m/sec as SCD patients have been shown to have increased mortality at this threshold [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. However, echocardiographic findings are not diagnostic for pulmonary hypertension because hemodynamic effects could cause discrepancies in result interpretations. For instance, patients with hemoglobinopathies are prone to developing a hyperdynamic circulation because of an increased cardiac output secondary to chronic anemia. Hence, there are higher incidences of false-positive readings on echocardiography [
]. A TRV of 3.0 m/sec is 3 standard deviations above the population mean and identifies approximately ¾ of patients with a mPAP≥25 mmHg while a TRV≥2.5 m/sec identifies groups with borderline pulmonary hypertension of mPAP 20–25 mmHg. There is a positive correlation between TRV and prediction of pulmonary hypertension in hemolytic anemia, with a TRV ≥2.5 m/sec shown to have an increased risk for mortality [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. Studies have shown that the prevalence of pulmonary hypertension has been overestimated based on these echocardiographic criteria and that using a TRV>2.9 m/sec or a TRV between 2.5 and 2.8 m/sec combined with either a pro-BNP >164.5 pg/ml or 6-min walk distance of <333 m are better markers for referral for right heart catheterization and increases the likelihood of pulmonary hypertension [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. As such, while a pro-BNP 165 pg/ml to 300 pg/ml is still with the normal range, pro-BNP> 164.5 pg/ml has been associated with an increased risk of pulmonary hypertension when combined with TRV, as described above [
]. While a higher TRV combined with pro-BNP or 6MWD greater identifies patients with mPAP ≥25 mmHg, the increased mortality risk of patients with a TRV≥2.5 m/sec is evident and should be monitored closely. Despite being a good screening tool, there are no definitive routine screening guidelines in asymptomatic patients with hemolytic diseases [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. However, using echocardiography to screen for pulmonary hypertension is useful in high-risk patients and those with unexplained dyspnea and fatigue [
Aside from heart catheterization and echocardiography, a few serological markers and the 6-min walk test have been proposed to risk stratify and potentially monitor the progression of pulmonary hypertension of certain types of hemolytic anemia. Lactate dehydrogenase (LDH) is a well-established marker for intravascular hemolysis. A study of 213 sickle cell patients by Kato et el demonstrated the association of LDH and multiple markers of hemolytic severity as well as the depletion of nitric oxide [
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease.
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease.
]. The evidence of LDH correlation with pulmonary hypertension was also illustrated in a study by Hill et el of 29 patients with paroxysmal nocturnal hemoglobinuria (PNH), an acquired hemolytic disorder with the highest levels of intravascular hemolysis observed [
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
]. This study suggested an LDH >2.0 times the upper limit of normal to place patients at increased risk of developing pulmonary hypertension. Hill et el also demonstrated a decrease in LDH levels with treatment of PNH with eculizumab [
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
]. Another proposed biochemical marker for risk for pulmonary hypertension is NT-proBNP, as it has been shown to be a sign of both left and right ventricular and cardiac dysfunction [
]. Serum concentrations >160 pg/ml are suggestive of an increased risk of pulmonary hypertension, as defined in the 2014 American Thoracic Society Clinical Guidelines on Management of Pulmonary Hypertension in SCD [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. Notably, the positive predictive value of the correlation between a TRV ≥ 2.5 m/sec and pulmonary hypertension is only 25%. However, combining the measurements of NT-proBNP level of 160 pg/mL with a 6-min walk distance of <333 m and TRV ≥2.5 m/sec increases the positive predictive value for pulmonary hypertension to 62% [
]. Table 2 summarizes the general diagnosis, screening, and prognosis tools used in patients with chronic hemolytic anemias who are at risk of pulmonary hypertension.
Table 2Diagnostic, screening, and prognostic tools.
ACCF/AHA 2009 expert consensus document on pulmonary Hypertension. A report of the American College of Cardiology foundation task force on Expert Consensus documents and the American heart association developed in collaboration with the American College of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
Sickle ce (SCD) is caused by a single nucleotide mutation on amino acid 6 of the β-globin chain, converting a glutamic acid codon (GAG) to a valine codon (GTG) [
]. This leads to structurally abnormal hemoglobin that polymerizes, resulting in hemolysis, vaso-occlusion, chronic inflammation, and up-regulation of hypoxic responses [
]. SCD manifests with varying degrees of severity depending on genetic and non-genetic factors, such as co-inheritance of the alpha-thalassemia, fetal hemoglobin, climate, and air quality [
]. Sub-Saharan Africa has the highest prevalence of SCD with about 230,000 affected births per year, contributing to approximately 70–80% of the global total of approximately 300,000 with a projection to 400,000 affected births in 2050 with homozygous HbS sickle cell anemia [
]. As a malaria endemic area, there is a high frequency of SCD in Sub-Saharan that is postulated to be due to the advantage of heterozygous mutations constituting an advantage against fatal malaria [
Screening for pulmonary hypertension was recommended by the ATS in 2014 to be every 1–3 years or when patient is at increased risk (as defined as an initial documented TRV ≥2.5 m/sec) or develops symptoms of pulmonary hypertension, a decreased 6MWD, or elevated NT-proBNP. This was based upon a longitudinal study by Ataga et el, that noted a 13% incidence of pulmonary hypertension in 3 years' time in patients who initially did not have a diagnosis of pulmonary hypertension [
]. However, the National Heart, Lung and Blood Institute in 2014 concluded “there was there is insufficient evidence to make a recommendation supporting regular screening with Doppler echocardiography.” [
] These conflicting recommendations suggest that there needs to be a larger registry in order to ascertain definitive guidelines for the role of screening. It is important to note that even mild elevations of pulmonary artery systolic pressures (30–40 mmHg) have high morbidity and mortality in SCD with pre-capillary pulmonary hypertension [
]. This had been suggested by a study by Mehari et el, analyzing 84 patients with pulmonary hypertension diagnosed by right heart catheterization and subsequent functional measurements of the 6-min walk test and WHO functional class [
Measurements of right ventricular dysfunction by elevated right atrial pressure, increased pulmonary arterial pressures, and decreased cardiac index have been suggested by the NIH as prognostic markers for pulmonary arterial hypertension, however, other markers are advocated for pulmonary hypertension in SCD [
]. Mehari et el demonstrated that standard hemodynamic markers of the severity of pre-capillary pulmonary hypertension, pulmonary vascular resistance and transpulmonary gradient, are associated with increased mortality in this patient population. They further emphasized that despite a high mortality rate in post-capillary hypertension, PAWP was not a significant predictor of mortality. These combined findings suggest that the severity of pre-capillary hypertension has a high association with mortality in SCD population. The study demonstrated a decreased 5-year survival rate of 63% from diagnosis compared to 80% of patients without pulmonary hypertension [
The ATS ad hoc committee guidelines regarding the treatment of pulmonary hypertension in SCD in 2014 are summarized in Fig. 1. Management includes administration of hydroxyurea to reduce sickling of hemoglobin and hemolysis. Chronic transfusion is recommended where patients are unresponsive to hydroxyurea or are at increased risk for mortality, signified by increased pro-BNP >160 pg/ml and TRV ≥2.5 m/sec. A study in 2015 of 26 patients by Detterich et el demonstrated that chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in SCD [
]. The study used ultrasound measurement of flow-mediated dilatation of the brachial artery (FMD) and TRV as surrogate markers of systemic and pulmonary vasculopathy. Detterich et el demonstrated that TRV was inversely correlated with FMD and that a single blood transfusion in chronically transfused patients improved FMD. They further speculated that the transfused blood storage time may affect endothelial function [
1. Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, et al. An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease. American Journal of Respiratory and Critical Care Medicine. 2014; 189 (6):727-40.
2. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016; 127 (7):820–8.
Sickle cell anemia predisposes patients to a hypercoagulability state that could lead to either venous thromboembolism or thrombosis in situ via the various mechanisms described above. In addition, pulmonary arterial emboli are frequently present in patients with acute chest syndrome, with one study of 144 patients demonstrating that 17% of patients had pulmonary thrombi on CT scan [
]. The same study further investigated those patients with Doppler ultrasound of the lower extremities, revealing no deep venous thrombosis. These findings suggest that pulmonary thrombosis in patients with acute chest syndrome could be an in situ phenomenon, rather than embolic. The incidence of venous thromboembolism itself in SCD is approximately 3.5 times that of non-sickle cell African population [
]. The incidence of chronic thromboembolic pulmonary hypertension (CTEPH) in SCD population is not known and estimates are only based on small studies, with one study of 27 patients showing 22% (6/27) with ventilation-perfusion scan defects and 11% (3/27) with patterns consistent with CTEPH [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. Indefinite anticoagulation in such patients is associated with a 13.8% decrease in recurrent VTE and with a possible decrease in mortality, in contrast to a 2.4% increased risk of bleeding [
]. The role of pulmonary endarterectomy in SCD and other hemoglobinopathies are more practically challenging due to increased risk of sickling during cardiopulmonary bypass, which causes a hypoxic and hypothermic environment, potentially causing a higher risk of circulatory arrest [
Balloon pulmonary angioplasty (BPA) is an emerging interventional therapeutic procedure that has been advocated to treat patients that are unable to undergo pulmonary endarterectomy (PEA), especially in cases that are inoperable or with peripherally located thrombi. In general, less than 60% of patients with CTEPH can undergo pulmonary PEA and 17–31% of patients have persistent or recurrent pulmonary hypertension post-procedure [
]. BPA was initially described in 2001 by Feinstein et el, and although it provided significant improvement in hemodynamics and exercise tolerance, it was still inferior to pulmonary endarterectomy [
]. However, a team lead by Mizoguchi et el studying 68 patients with inoperable CTEPH developed refined BPA techniques that was able to significantly decrease pulmonary arterial pressure to a mPAP <25 mmHg with comparable complications to PEA [
]. Current European Society of Cardiology/European Respiratory Society guidelines state that BPA may be considered in inoperable patients or carry an unfavorable risk/benefit ratio with BPA, patients with persistent or recurrent pulmonary hypertension post-PEA, or those that need rescue therapy after early failure of PEA [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. In regards to its application to the sickle cell population, thus far, only 1 case report of BPA has been documented in a sickle cell patient as a palliative approach, which was uncomplicated and lead to successful discharge of patient on post-op day #5 [
]. Despite the fact that further studies are needed to confirm the use of BPA as an alternative therapeutic option to PEA, it remains a viable option to consider in SCD with CTEPH, particularly as the prevalence of in situ thrombi appears greater than VTE disease and the significantly increased mortality rate in patients with CTEPH (over 1/3 of perioperative deaths and approximately ½ of long-term deaths are associated with persistent pulmonary hypertension) [
Limited large-scale studies have been completed on targeted pulmonary arterial hypertension therapy (i.e. prostacyclin agonists, endothelin receptor antagonists, soluble guanylate cyclase stimulators, and phosphodiesterase-5 inhibitors) in SCD populations, and at present, no clear benefit has been demonstrated.
The Walk-Phasst trial aimed at the use of sildenafil with 74 subjects was prematurely terminated due to an apparent increased incidence of serious adverse events in the treatment group [
]. However, it is important to note that myalgias, back pain, and limb pain, have been recorded to have increased incidence in patients treated with sildenafil for both PAH initially and in the long-term follow-up study [
]. Whether these symptoms of myalgia, back pain, and limb pain may be a class effect of phosphodiesterase-5 inhibitors as opposed to a true sickle cell crisis needs to be differentiated in future studies. In regards to endothelin receptor agonists, the ASSET trials were randomized trials comparing the efficacy of Bosentan to placebo in SCD with pre-capillary pulmonary hypertension (ASSET-1 with 14 subjects) and post-capillary pulmonary hypertension (ASSET-2 with 12 subjects). Although there were small-scale studies and had no apparent toxicity issues, these trials were, unfortunately, prematurely terminated due to sponsorship withdrawal [
Exercise capacity and hemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.
]. The use of intravenous prostacyclin on SCD with pre-capillary pulmonary hypertension diagnosed on RHC has been studied by Castro et el on 20 patients. In this study, 8 patients were initiated on intravenous prostacyclin at cardiac catheterization to test reversibility of their pulmonary hypertension, which demonstrated acute decrease in pulmonary vascular resistance [
]. Thus far, the last group of targeted-PAH therapy, the soluble guanylate cyclase stimulators have not yet been studied in the SCD population.
Despite small studies showing potential efficacy of targeted PAH therapy in SCD, further studies are needed to affirm their potential and no targeted PAH therapy has, thus far, been approved by the Food and Drug Administration (FDA) for use in SCD. As such, the use of targeted PAH therapy on SCD patients with only isolated risk factors of elevated TRV or pro-BNP levels is not recommended [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. A trial of targeted PAH therapy is only suggested in select patients with pre-capillary pulmonary hypertension as documented on right heart catheterization [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. In such cases, the trial of an oral endothelin receptor antagonist may be preferred over a phosphodiesterase-5 inhibitor due to better tolerance of side effects [
Thalassemia is an inherited disorder of defective alpha-globulin or beta-globulin of hemoglobin A subunits. The alpha-thalassemia gene is located on chromosome 16 and four alleles control the synthesis of α-globulin (α1 −/− and α2 −/−) and the number of allele deletions is associated with the severity of the disease [
]. If only one allele is deleted, then a carrier would result. Two allele deletion results in α-trait, which causes a mild anemia, while three allele deletions leads to HbH or Bart's disease that causes severe hemolytic anemia. An overproduction of α-globulin leads to increased destruction of red blood cells in bone marrow and peripheral blood [
Worldwide, approximately 20% of the population is an alpha-thalassemia carrier. Annually, there are approximately 56,000 births with thalassemia major [
]. Data on the incidence and prevalence of pulmonary hypertension documented by right heart catheterization is limited in thalassemia, and epidemiologic data can only be extrapolated from echocardiographic results. One study of 80 patients with either HgH or Bart's disease found that 4% of the patients had a TRV>2.95 m/sec. Another study of 198 patients with HgH or Bart's disease showed that 7% of patients had a TRV>2.5 m/sec and 2% TRV>3.0 m/sec [
The beta globulin gene is located on chromosome 11 and has one allele on each chromosome. An increased production of beta-globulin due to decreased alpha-globulin results in heterodimerization of hemoglobin molecules and impaired oxygen delivery [
]. There are two forms of β-Thalassemia, Thalassemia Intermedia (TI) with 1 gene affected and Thalassemia Major (TM) with 2 genes affected, which is transfusion dependent. Both TI and TM are associated with pulmonary hypertension. Studies using echocardiography to suggest evidence of pulmonary hypertension with peak systolic tricuspid regurgitation gradient greater than 30 mmHg (TRV>2.75 m/sec) suggested a prevalence of 40–50% in TI and a wide range of 10–75% in TM [
]. Notably, pulmonary hypertension has been shown to be absent in a study of 202 patients with TM that had undergone intense transfuse on and chelation therapy since early infancy [
]. These mechanisms, in addition to advanced age and significant anemia, were demonstrated to be significant risk factors by a study by Teawtrakul et el with 219 patients with primarily non-transfusion dependent thalassemia [
]. The authors suggested that the genotype of thalassemia may be an independent risk factor for pulmonary hypertension, with a higher risk in patients with β-thalassemia compared to patients with α-thalassemia and combined α and β-thalassemia [
]. This study also found evidence of a risk of pulmonary hypertension based on echocardiographic measurements of TRV>2.9 m/sec (derived from their study of 219 patients, in which the majority patients with TRV>2.9 m/sec had PH confirmed by right heart catheterization), with an incidence of 10.96% and recommended echocardiography screening in all patients ≥10 years old [
Diagnosis and assessment of pulmonary hypertension in thalassemia are similar to that suggested in SCD. This should consist of the 6-min walk test and pro-BNP levels (prognostic markers), echocardiography, and right heart catheterization. Management is directed at hemoglobinopathy-targeted treatment and general supportive therapy. As with SCD, pulmonary hypertension specific therapies have only been tried in small series or case reports. However, chronic transfusion therapy and concomitant chelation therapy has been shown to prevent pulmonary hypertension in both forms of thalassemia [
]. The OPTIMAL CARE study, which observed treatment complications in 584 thalassemia intermedia patients, also demonstrated that transfusion and chelation therapy along with hydroxyurea was protective for pulmonary hypertension, whereas splenectomy was associated with a higher risk of pulmonary embolism and pulmonary hypertension [
Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study.
Since targeted pulmonary hypertension therapy with phosphodiesterase-5 inhibitors, endothelin-1 receptor antagonists, prostacyclin analogues, and soluble guanylate cyclase stimulators have no definitive proven benefit, their use should be restricted to patients with clear hemodynamic characterization of pre-capillary pulmonary hypertension [
]. Although there is insufficient data to make general recommendations, some small-scaled studies have shown potential benefits of targeted PH therapies in β-thalassemia patients. Sildenafil has been shown to improve NYHA functional class and echocardiographic evidence of pulmonary hypertension (13.3% decrease of the TRV) after a 12-week course in a study by Morris et el with 10 patients (5 with TM and 5 with TI) with PH defined as having a TRV >2.5 m/sec [
]. An additional study also using a 12-week course of Sildenafil in 4 patients with thalassemia intermedia and 2 patients with thalassemia major with a baseline tricuspid gradient of 45 mmHg also showed improvement in NYHA functional class and 6 min walk test [
Efficacy and safety of sildenafil for the treatment of severe pulmonary hypertension in patients with hemoglobinopathies: results from a long-term follow up.
]. PNH is an acquired deficiency of GPI-linked surface molecules, CD55 and CD59, which leads to a lack of complement inhibiting surface proteins on red blood cells and platelets [
]. Subsequently, there is unopposed assembly of terminal complement complex, resulting in intravascular hemolysis via the alternate complement pathway [
]. PNH is characterized by a triad of intravascular hemolysis, hypercoagulability, and various degrees of bone marrow failure. The incidence rate of pulmonary hypertension indicated by echocardiography in PNH is 50%, with its pathophysiology driven by nitric oxide depletion from intravascular hemolysis as well as pulmonary emboli, which have been shown to occur in 40% of patients at the time of diagnosis [
Hemolytic anemia in PNH stems from intravascular hemolysis (where red blood cells are lysed in the blood circulation), whereas hemolytic anemia in SCD is mainly via the extravascular pathway (where red blood cells are phagocytosed and broken down by macrophages in the liver and spleen). Due to this difference, PNH has a 10-fold greater degree of hemolysis which is reflected by the relative elevation in plasma hemoglobin [
]. NO depletion in PNH leads to smooth muscle dysfunction, clinically manifesting as abdominal pain (from small vessel spasms), esophageal spasm, and erectile dysfunction. Furthermore, NO depletion disrupts endothelial and platelet function, causing hypertension, a hypercoagulable state, and pulmonary hypertension [
]. Given that hemolysis occurs more dramatically in PNH versus SCD, PNH theoretically should be associated with more prominent complications and treatment should demonstrate improvement. This has been demonstrated by various studies, showing reversal of clinical complications of nitric oxide scavenging – including esophageal spasms, erectile dysfunction, and pulmonary hypertension – with Eculizumab [
]. At present, no therapies are FDA approved for treatment of this population, and further studies will be required to analyze the magnitude of the effects, benefits and risks of pulmonary vasodilator therapy for the treatment of pulmonary hypertension in these specific patient populations.
6.2 Management
Currently, there are no studies of targeted pulmonary hypertension agents used in PH secondary to PNH. However, treatment of PNH has been well established with the use of Eculizumab, an antibody that targets CD5 and inhibits complement-mediated hemolysis [
Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria.
]. The TRIUMPH trial investigated the use of Eculizumab in 87 patients with PNH, by measuring response of biochemical markers (LDH, pro-BNP, and L-arginase) and clinical symptom of dyspnea [
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
]. This international phase 3 randomized, placebo-controlled trial, demonstrated that Eculizumab dramatically reduced intravascular hemolysis, the need for transfusion, and symptoms. Furthermore, it has the link between hemolysis and NO depletion has been demonstrated by measurements of free hemoglobin and reduction in arginase-1 availability in patients with PNH [
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
]. The reversal of the biochemical markers for hemolysis and pulmonary hypertension, coupled with an illustrated association between intravascular hemolysis and NO depletion further solidify the pathogenesis of pulmonary hypertension in PNH [
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
Exercise capacity and hemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.
Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study.
Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study.
Consider a trial of either a prostacyclin agonist or an ERA in patients with RHC-confirmed PAH (neither has been FDA approved)
•
While not FDA approved, trial of PDE5i (sildenafil) has been tried in small-scaled studies and has shown improvement based on TRV and NYHA functional class [
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
ACCF/AHA 2009 expert consensus document on pulmonary Hypertension. A report of the American College of Cardiology foundation task force on Expert Consensus documents and the American heart association developed in collaboration with the American College of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
]. Such disorders include thalassemia, hereditary spherocytosis, hereditary stomatocytosis, autoimmune hemolytic anemia, SCD and others. Splenectomy is performed in patients with hemolytic anemia to ameliorate the extent of hemolysis. The combination of an underlying hematological disorder and splenectomy has been shown to further increase the risk of the development of CTEPH, as compared to patients with splenectomies alone [
]. In a study of 61 patients by Hoeper et el, the prevalence of pulmonary hypertension in patients with splenectomies ranged from 8.6% to 11.5% in contrast with a control group consisting of other pulmonary diseases ranging from 0% to 0.6% [
]. In a retrospective study of 257 patients with CTEPH, 8.6% had a history of splenectomy compared with 2.5% and 0.56% in patients with idiopathic pulmonary hypertension or chronic lung disease requiring lung transplant, respectively [
Hereditary spherocytosis is an inherited hemolytic disorder that occurs most commonly in the northern European population, affecting approximately 1 in 3000 people [
]. Due to a defect in anchoring proteins of red blood cell membranes and resultant decreased membrane surface area, patients with hereditary spherocytosis develop hemolytic anemia due to sequestration of red blood cells in the spleen. Hereditary stomatocytosis is an autosomal dominant condition in which there is inability to regulate the volume of red blood cells, resulting in deformed RBC's and eventual splenic sequestration and hemolytic anemia [
]. While there is evidence that splenectomies are a risk factor for the development of pulmonary hypertension and are performed in these conditions with a frequency of 20 times greater than the general population, there is limited data on the development of pulmonary hypertension in patients with hereditary spherocytosis and stomatocytosis post-splenectomy, specifically [
Given the paucity of data on pulmonary hypertension and post-splenectomy patients with underlying hemolytic disorders, no definitive monitoring and/or treatment guidelines have yet been developed. However, due to the increased risk of developing pulmonary hypertension in patients with concomitant hemolytic disorder and splenectomy, pulmonary hypertension should be in the differential diagnosis for a patient presenting with dyspnea or exercise intolerance, and should be screened for with echocardiography. As mentioned previously, echocardiography may overestimate pulmonary artery pressure in chronic hemolytic disorders, hence, right heart catheterization is the gold standard diagnosis. The age of screening would be based on clinical judgment, as there is a wide range in terms of the number of years post-splenectomy until the development of pulmonary hypertension.
7.4 Management
With the strong associated risk of splenectomy and pulmonary hypertension in hemolytic disorders, treatment should be focused on the prevention of the need for splenectomy [
]. In particular, 32% of thalassemia patients were shown to develop pulmonary hypertension post-splenectomy (defined as echocardiographic estimate of PAP >35 mmHg) in a study of 68 patients. This was contrasted with patients with thalassemia who were treated with chronic transfusions, where 22% of the patients had an estimated PAP of >29 mmHg, while the rest had estimated PAP <25 mmHg [
]. The benefit of chronic transfusion therapy in thalassemia was further demonstrated in a study by Singer et el, which showed that the TRV remained within normal range in patients who underwent chronic transfusion therapy, regardless of whether or not they had a splenectomy [
]. Since chronic transfusion is associated with iron overload, concomitant therapy with chelating agents is also recommended. Furthermore, because platelet hyperactivity is a key mechanism of hypercoagulability in splenectomized patients, the use of aspirin and hydroxyurea to maintain a platelet level below 400 000μ/L has also been suggested [
Patients with hemolytic disorders and splenectomy would fall into Group 5 of the WHO classification of pulmonary hypertension, although they could develop features of Group 1 and Group 4 (see Table 1). In the absence of overt thromboembolic disease, they could have evidence of Group 1 pulmonary hypertension, in which many are treated with vasodilators [
]. While anticoagulation is indicated in Group 1 and 4 pulmonary hypertension, no current evidence supports its routine use in post-splenectomy patients [
]. The ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension recommends warfarin anticoagulation for a target INR of 1.5–2.5 in patients with Group 1 idiopathic pulmonary hypertension, while the 2015 ESC/ERS Guidelines recommends an INR goal of 2.0–3.0 [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
ACCF/AHA 2009 expert consensus document on pulmonary Hypertension. A report of the American College of Cardiology foundation task force on Expert Consensus documents and the American heart association developed in collaboration with the American College of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
Pulmonary hypertension associated with chronic hemolytic anemias develop via multifactorial mechanisms, hence, their complexity. While their pathophysiology has been well studied and described, it is important to note that most data on the management of these hemolytic disorders with pulmonary hypertension are limited. Not only are these studies limited in size and number, but also by the fact that most are based on echocardiographic estimations of pulmonary hypertension and not by the gold standard right heart catheterization.
The management of pulmonary hypertension in hemolytic disorders comprises of general support measures to treat the underlying hemolytic disorder and PAH-specific therapies. The available randomized controlled trials and small-scaled studies have shown potential benefit and efficacy of certain treatment strategies and PAH-targeted therapy. However, to date, none of these therapies have been fully studied, nor are any of them FDA approved for any of these specific patient populations and their applicability to other hemolytic disorders remain in question. For instance, more studies are needed to elucidate the potential benefit of chronic blood transfusion therapy in SCD patients, particularly when this has been found to be effective in the thalassemia population with pulmonary hypertension. In addition, the role of balloon pulmonary angioplasty may emerge as a valuable treatment option for post-splenectomy or SCD patients with CTEPH, especially when most of the disease are due to peripherally located thrombi. As pulmonary hypertension causes significant morbidity and mortality in hemolytic disorders, further studies would help to ascertain the benefit and efficacy of such treatment strategies as well as potential PAH-targeted therapies, and help to establish more definitive guidelines.
Conflicts of interest
The corresponding author, Dr. Alexandra Haw, has no disclosures.
The co-author, Dr. Harold Palevsky has served as a consultant to Actelion/Janssen, Bayer, GSK, and United Therapeutics. He has also served on a Data and Safety Monitoring Board for Eiger.
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
ACCF/AHA 2009 expert consensus document on pulmonary Hypertension. A report of the American College of Cardiology foundation task force on Expert Consensus documents and the American heart association developed in collaboration with the American College of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
An official American thoracic society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease.
Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
Exercise capacity and hemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.
Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study.
Efficacy and safety of sildenafil for the treatment of severe pulmonary hypertension in patients with hemoglobinopathies: results from a long-term follow up.
Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria.
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