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S. Allali et al.
include compound heterozygous conditions, such as hemoglobin C (HbC) with HbS (HbSC), HbS with b-tha- lassemia (HbS/b0-thalassemia or HbS/b+-thalassemia), and HbS with other b-globin variants resulting in suffi- cient HbS expression to cause sickling. Under deoxygena- tion, sickle hemoglobin (HbS) polymerizes and erythro- cytes undergo a rapid but reversible change in shape, resulting in both chronic hemolysis and small-vessel obstruction, which have long been recognized as the main contributors to SCD pathophysiology.17 Paradoxically, tissue injury is exacerbated by reperfusion- enabled re-entry of oxygen during the ischemia/reperfu- sion process (I/R). I/R is responsible for systemic inflam- mation, hypercoagulability, and endothelial dysfunction via various mechanisms.18 Endothelial vasoregulatory dysfunction is observed from childhood,19,20 and chronic anemia is responsible for concomitant increased blood flow. The association of macrovascular hyperemia and microvascular hypoperfusion, that Hebbel et al. referred to as the sickle cell “perfusion paradox”, is extremely challenging for major organs such as the brain, kidney, and heart, which may fail to respond and adapt to the need for increased oxygen.18 Moreover, systemic inflam- mation is amplified by the release of free heme and hemoglobin during hemolysis, inducing oxidative stress, cell death, and vascular integrity damage.21 Heme was notably shown to be a potent activator of endothelial cells, leading to an increased expression of major adhe- sion molecules such as P-selectin.21 Finally, each organ (and, indeed, each patient) represents a unique combina- tion of hypoxia, inflammatory and oxidative stress, acti- vation of innate immunity, hyperviscosity and hyperco- agulability in response to genetic and environmental age- dependent drivers. Organ defense may be adapted for a certain length of time, or 'over-adapted', for example, when neoangiogenesis induces the generation of a net- work of collateral vessels which are prone to ruptures, provoking ocular or cerebral hemorrhages. Sickling-relat- ed acute events may be regressive with unsickling but endothelial damage is most often irreversible.
Chronic organ injuries will be presented here according to their impact on mortality in adult patients.
Cardiovascular abnormalities
Main cardiovascular disorders in SCD are pulmonary hypertension (PHT) and left ventricular dysfunction. These are the main contributors to SCD-related mortality in adults, accounting for >30% of all deaths among SCD patients in the US.22 They are more frequent and severe in patients with HbSS or HbS/b0-thalassemia.23,24
Pulmonary hypertension
In addition to the pathophysiology common to all organ injuries described above, increased cardiac output resulting from chronic anemia is a risk factor for PHT in SCD. Hypoxia induces smooth muscle cell and intimal proliferation, and in situ thrombosis can increase pul- monary vascular resistance. These factors contribute to the development of PHT and right heart enlargement, which ultimately leads to right heart failure. In addition, post-capillary PHT is promoted by diastolic dysfunction, which may be related to myocardial fibrosis. In children, however, PHT seems to be mostly related to increased
cardiac output while pulmonary vascular resistance remains normal.25
Historically, PHT in adults and children was defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg but the current threshold proposed by the 6th World Symposium on Pulmonary Hypertension is >20 mmHg.26 Prevalence in adults with SCD ranges from 10% to 33% when measured by right heart catheterization (RHC) or echocardiography, respectively.24 Pulmonary artery sys- tolic pressure (PASP) is assessed on echocardiography by the quantification of the tricuspid regurgitant jet velocity (TRV) using the modified Bernoulli equation. Raised TRV was shown to be a risk factor for death in adults.10,27,28 However, the positive predictive value of TRV for diag- nosing PHT in adults remains controversial. No study has assessed the correlation between TRV and RHC in SCD children. Given the risk of RHC procedure in this patient population, it is only recommended when TRV is >3 m/s and is only to be carried out in experienced pediatric cen- ters.26 In a meta-analysis using a threshold of TRV ≥2.5 m/s, 21% (95%CI: 17-26%) of children and adolescents were considered to have elevated PASP, which was posi- tively associated with age.29 Nevertheless, TRV ≥2.5 m/s may be observed as early as three years of age in SCD children.30 Several studies have shown the influence of hemolysis on the occurrence of PHT in children.31-34 Hemoglobin oxygen desaturation is frequently reported in SCD children, especially at night and after exercise, but its association with elevated TRV is more controver- sial.31,34
In contrast with adults, increased TRV in SCD children has not so far been associated with increased mortality in adulthood. In a cross-sectional study of 483 adolescents and adults with SCD, raised TRV was associated with poor exercise capacity.35 Furthermore, one study of 160 HbSS patients aged 3-20 years showed that baseline ele- vation in TRV was associated with a 4.4-fold increase in the odds of a 10% or more decline in age-standardized 6- minute-walk distance over a median of 22 months.32 Importantly, evaluation of PHT should not be based on a single assessment of TRV, as demonstrated in a follow-up cohort of 120 children with SCD, in which an improve- ment in TRV values was observed over a period of 15±9 months in half of the patients, although there was no clear explanation for this.36
Screening and prevention
US recommendations suggest performing an echocar- diography when symptoms are suggestive of PHT, whereas many European experts recommend measuring TRV once a year in children, usually after five years of age.37,38 In cases of elevated TRV, the cardiopulmonary risk should be evaluated by a full workup including electrocar- diography (ECG), chest radiography, functional respirato- ry tests with 6-minute-walk distance measurement, car- diopulmonary exercise test, overnight oxygen saturation monitoring, polysomnography for obstructive sleep apnea, and measurement of brain natriuretic peptide (BNP) and N-terminal pro-BNP levels. TRV ≥2.5 m/s should suggest the need to optimize SCD treatment, although prospective controlled studies have not demon- strated the benefits of hydroxyurea and chronic transfu- sion on PHT. Retrospective data suggest either improve-
ment of PHT with hydroxyurea39 or no effect of the drug.31,33
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haematologica | 2021; 106(6)