Pulmonary Hypertension in Thalassemia Patients

Pulmonary hypertension (PH) is defined in children as a mean pulmonary arterial pressure (PAP) greater than 25 mmHg at rest or 30 mmHg during physical activity, with increased pulmonary artery capillary wedge pressure and an increased pulmonary vascular resistance greater than 3 Wood units × M2. it is the main cause of morbidity and mortality in the group of thalassemia, if no treatment leads to right ventricular heart failure and death. The development of pulmonary arterial hypertension (PAH) is assumed to be the result of many multifactorial pathogenic mechanisms including chronic hemolysis, iron overload, hypercoagulability, and erythrocyte dysfunction as a result of splenectomy, inflammation and nitric oxide (NO) depletion. PAH symptoms are non-specific, their signs consist of right ventricular lift, an accentuated pulmonary component of the second heart sound, a (gallop rhythm) right ventricular third heart sound, and parasternal heave meaning a hypertrophied right ventricle. The diagnosis of PAH requires a clinical suspicion based on symptoms and physical examination. Echocardiography is frequently used to screen for PAH, monitor progression over time and allow identification of patients for whom diagnostic right heart catheterization (RHC) is warranted and its treatment includes hemoglobinopathy specific treatment and PAH specific therapy.

Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

Frequency, Pattern, and Associations of Renal Iron Accumulation in Sickle Beta-Thalassemia

Background: Chronically transfused homozygous sickle cell disease (HbSS) patients were shown to have higher kidney iron deposition than thalassemia major patients, not associated to total body iron and mainly caused by chronic hemolysis. Kidney iron deposition has not been explored in sickle beta-thalassemia (Sβ-thal), resulting from the inheritance of both sickle cell and beta-thalssemia genes. Aim: This multi center study aimed to study frequency, pattern, and associations of renal iron accumulation in sickle beta-thalassemia. Methods: Thirty-three Sβ-thal patients (36.49±14.72 years; 13 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) network were considered. Moreover, 20 healthy subjects, 14 HbSS patients and 71 thalassemia major (TM) patients were included as comparison groups. Hepatic, cardiac, pancreatic, and renal iron overload was quantified by the gradient-echo T2* technique. In each kidney T2* was measured in anterior, posterolateral, and posteromedial parenchymal regions and the global T2* value was calculated as the average of the two kidneys T2* values. Results. Global renal T2* were significantly higher in healthy subjects versus both Sβ-thal patients (49.68±10.09 ms vs 43.19±8.07 ms; P=0.013) and HbSS patients (49.68±10.09 ms vs 26.21±17.07 ms; P&lt;0.0001). Sβ-thal patients showed comparable age, sex, frequency of regular transfusion, hematochemical parameters, and hepatic, cardiac and pancreatic iron load than HbSS patients, but they had a significant lower frequency of renal iron overload (global renal T2*&lt;31 ms) (9.1% vs 57.1%; P=0.001). Regularly transfused patients (16 Sβ-thal and 10 HbSS) were compared with TM patients, homogeneous for age and sex, but TM started regular transfusions significantly earlier and they were more frequently chelated. No significant difference was detected in terms of hepatic and cardiac iron levels, but TM patients had significantly lower pancreas T2* values than both the other two groups and significantly higher global renal T2* values than HbSS patients (42.87±9.43 ms vs 24.39±15.74 ms; P=0.001). In Sβ-thal patients no significant difference was detected between T2* values in left and right kidneys, and global renal T2* values were not associated to age, gender, splenectomy, and they were comparable between regularly transfused and non transfused patients. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (Figure 1). Conclusion. Renal iron deposition is not common in Sβ-thal patients, with a prevalence significantly lower compared to that of HbSS patients, but with a similar underlying mechanism due to the chronic hemolysis. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

Diagnosis, Monitoring, and Management of Pyruvate Kinase Deficiency in Children

Pyruvate kinase (PK) deficiency is an important cause of hereditary non-spherocytic hemolytic anemia caused by a defect in the glycolytic pathway in red blood cells. PK deficient erythrocytes have impaired ATP production and resultant difficulty maintaining normal cell integrity and function, leading to mild to severe anemia due to increased extravascular hemolysis and splenic destruction. Sequelae of chronic hemolysis can result in severe and occasionally life-threatening complications such as hepatobiliary disease, iron overload, bone and cardiopulmonary disease, as well as often markedly impaired quality of life. While the mainstay of management of PK deficiency involves supportive care, comprehensive screening recommendations and disease modifying therapies in development are likely to significantly improve the management of patients. Here, we provide a case-based comprehensive review of the diagnostic evaluation, complications, monitoring recommendations and management of PK deficiency in children.

Hemodynamic and biological correlates of glomerular hyperfiltration in sickle cell patients before and under renin–angiotensin system blocker

Glomerular hyperfiltration alone or associated with albuminuria is a well-known feature of sickle cell associated nephropathy. Though, glomerular hyperfiltration is currently considered to be related to a high renal plasma flow and chronic hemolysis, cardiac output influence on measured glomerular filtration rate (mGFR) have not been investigated so far. Thirty seven homozygous sickle cell patients (SCA) from the RAND study investigated before and under angiotensin converting enzyme inhibitor (ACEI) were included. Both mGFR and cardiac index (CI) were high (> 110 ml/min/1.73 m2 and > 3.5 l/m2 in 81% and 97% of cases) with low systemic vascular resistance (SVR) (< 700 dynes/s/cm−5) in 38% of cases. mGFR association with CI and SVR were significant at baseline (respectively ρ: 0.44, p = 0.008 and ρ: − 0.37, p = 0.02) and under ACEI (p = 0.007 and 0.01 respectively), in accordance with previous data showing that hyperfiltration was linked to an increased glomerular perfusion and a glomerulomegaly rather than increased capillary hydrostatic pressure. Of notice, after adjustment on CI, mGFR remained associated with reticulocyte count and albuminuria under ACEI (p = 0.006 and 0.02 respectively). Our results suggest that hyperfiltration is tightly linked to an increased cardiac output which may account for an increased renal blood flow. Chronic hemolysis could be a relevant factor accounting for hyperfiltration potentially acting on glomerular enlargement which appears as a key factor. Our data suggest that cardiac output assessment is a relevant tool in the routine management and monitoring of SCA nephropathy.

To Give or Not to Give: RhD Immunoglobulin for an RHD*39 Pregnant Woman with Sickle Cell Disease

Introduction: Patients with sickle cell disease (SCD) have repeated episodes of red blood cell (RBC) sickling and microvascular occlusion that manifest as pain crises, acute chest syndrome, and chronic hemolysis. These clinical sequelae usually increase during pregnancy. Given the racial distribution of SCD, patients with SCD are also more likely to have rarer RBC antigen genotypes than RBC donor populations. We present the management and clinical outcome of a 21-year-old pregnant woman with SCD and an RHD*39 (RhD[S103P], G-negative) variant. Case Presentation: Ms. S is B positive with a reported history of anti-D, anti-C, and anti-E alloantibodies (anti-G testing unknown). Genetic testing revealed both an RHD*39 and homozygous partial RHCE*ceVS.02 genotype. Absorption/elution testing confirmed the presence of anti-G, anti-C, and anti-E alloantibodies but could not definitively determine the presence/absence of an anti-D alloantibody. Ms. S desired to undergo elective pregnancy termination and the need for postprocedural RhD immunoglobulin (RhIG) was posed. Given that only the G antigen site is changed in an RHD*39 genotype and the potential risk of RhIG triggering a hyperhemolytic episode in an SCD patient, RhIG was not administered. There were no procedural complications. Follow-up testing at 10 weeks showed no increase in RBC alloantibody strength. Discussion/Conclusion: Ms. S represents a rare RHD*39 and partial RHCE*ceVS.02 genotype which did not further alloimmunize in the absence of RhIG administration. Her case also highlights the importance of routine anti-G alloantibody testing in women of childbearing age with apparent anti-D and anti-C alloantibodies.

Chronic osteo-articular changes in patients with sickle cell disease

Background Sickle cell disease (SCD) is an autosomal recessive genetic disease in which a mutation occurs in the β-globin chain gene, resulting in abnormal hemoglobin levels. In an environment with reduced oxygen concentration, red blood cells change their conformation, resulting in chronic hemolysis and consequent anemia and vaso-occlusive crises with injuries to several organs, with a significant impairment of the osteoarticular system. This study aimed to verify the chronic osteoarticular alterations and their association with clinical and laboratory characteristics of patients with SCD with a more severe phenotype (SS and Sβ0), on a steady-state fasis. Methods Fifty-five patients were referred to a medical consultation with a specialized assessment of the locomotor system, followed by laboratory tests and radiographic examinations. Results In total, 74.5% patients had hemoglobinopathy SS; 67.3% were female; and 78.2% were non-whites. The mean patient age was 30.5 years. Most patients (61.8%) reported up to three crises per year, with a predominance of high-intensity pain (65.5%). Radiographic alterations were present in 80% patients. A total of 140 lesions were identified, most which were located in the spine, femur, and shoulders. Most lesions were osteonecrosis and osteoarthritis and were statistically associated with the non-use of hydroxyurea. Conclusions There was a high prevalence of chronic osteoarticular alterations, which was statistically associated only with the non-regular use of hydroxyurea.

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease

Objective: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration–approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. Conclusions: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.