Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia.

BACKGROUND: Heart disease represents the main determinant of survival in beta-thalassemia, but its particular features in the two clinical forms of the disease, thalassemia major (TM) and thalassemia intermedia (TI), are not completely clarified. METHODS: We compared clinical and echocardiographic global parameters in 131 TM patients who received regular chelation transfusions and were highly compliant with treatment (mean age, 28 +/- 6 years [+/- SD]), and 74 age-matched, TI patients who did not receive chelation transfusions. RESULTS: Congestive heart failure was encountered in five patients with TM (3.8%; age range, 25 to 29 years) and in two patients with TI (2.7%; age range, 37 to 40 years). Systolic left ventricular (LV) dysfunction (ejection fraction < 55% or shortening fraction < 35%) was only encountered in patients with TM (8.4%). Considerable pulmonary hypertension (systolic tricuspid gradient > 35 mm Hg) was only present in TI (23.0%). In the remaining patients without evident heart disease, cardiac dimensions, LV mass, LV shortening and ejection fractions, and cardiac output were significantly higher in patients with TI. LV afterload was higher in patients with TM. LV diastolic early transmitral diastolic peak flow velocity (E)/late transmitral diastolic peak flow velocity (A) ratio was also higher in TM. Systolic and mean pulmonary artery pressures and total pulmonary resistance were higher in both young and old TI patients. CONCLUSION: Regular lifelong transfusion and chelation therapy in TM prevented premature heart disease and pulmonary hypertension, although LV dysfunction still occurred and led to heart failure. The absence of regular therapy in TI, in contrast, preserved systolic LV function but allowed pulmonary hypertension development, which also led to heart failure, starting within the fourth decade of life, a decade later compared to TM.

Does heterozygous beta-thalassemia confer a protection against coronary artery disease?

Six hundred and thirty-eight patients who presented with clinical symptoms and/or electrocardiographic findings suggestive of stable angina pectoris were studied; they were also investigated by coronary arteriography. Hemoglobin electrophoresis was performed on all patients to detect the presence of the beta-thalassemia trait. Results were analyzed by logistic regression analysis to determine whether the latter confers any protective effect against advanced coronary artery disease (aCAD; defined as the presence of atheromas in coronary arteries, resulting in stenosis at least 70%). The role of the currently accepted risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) in developing aCAD were reconfirmed, while at the same time it was found that beta-thalassemia heterozygosity is associated with a reduced risk against aCAD (odds ratio 0.39, 95% confidence interval 0.16-0.98). The lipoprotein and blood rheology profile of these individuals may be the underlying causes of this protective effect.

Suboptimal erythropoietic response to hypoxemia in idiopathic pulmonary fibrosis.

BACKGROUND AND STUDY OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory process characterized by severe derangement of gas exchange in the advanced stages of disease. However, erythrocytosis is infrequent in IPF. The aim of this study was to investigate the potential relation between the blunted erythropoietic response and the chronic inflammation. SUBJECTS: Nine patients (6 men and 3 women) with IPF and profound hypoxemia (PO(2) < 65 mm Hg) and 34 sex- and age-matched healthy volunteers participated in the study. METHODS: We evaluated the hematologic parameters, serum erythropoietin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels. We also studied the development of burst-forming unit-erythroid (BFU-E)-derived colonies in semisolid methylcellulose cultures in blood samples from all patients. RESULTS: Hemoglobin and serum erythropoietin levels were almost comparable between the two studied groups. On the contrary, serum TNF-alpha, IL-6, and IL-8 values were significantly higher in patients with IPF (p < 0.05, p < 0.01, and p < 0.001, respectively). IPF sera induced a significant growth inhibition of erythroid bursts arising from mononuclear cells of either patients or control subjects compared with heat-inactivated AB serum (p < 0.05 and p < 0.01, respectively). Moreover, there was an apparent increment in the number of BFU-E colonies when patients' mononuclear cells were cultured in comparison with those of healthy subjects (p < 0.05). CONCLUSIONS: Our findings suggest that in IPF there is an increased number of primitive erythroid progenitors, which fail to proliferate and differentiate in vivo, suggesting a kind of ineffective erythropoiesis. As a consequence, hemoglobin levels do not rise in proportion to the severity of hypoxemia. Cytokines released from alveolar macrophages seem to have not only local but also systemic effects, since the serum of these patients directly suppressed erythropoiesis; however, the suboptimal erythropoietic response to hypoxia cannot be entirely attributed to this suppression. It is possible that several other factors interfere, synergistically or additively.

Hemothorax due to extramedullary erythropoietic masses.

We describe a 27-year-old male patient suffering from beta-thalassemia intermedia who presented with a nontraumatic spontaneous hemothorax due to extramedullary hemopoietic foci. In reviewing the literature, four similar reports were found. The details of this unusual entity are discussed.

Red cell macrocytosis in hypoxemic patients with chronic obstructive pulmonary disease.

Macrocytosis is a common finding in patients with chronic obstructive pulmonary disease (COPD). The cause for the elevation of mean corpuscular volume (MCV) in these patients remains elusive. In an attempt to determine the extent of macrocytosis in COPD patients and search for possible causative factors, we evaluated the hematologic parameters, F-cell percentage, blood gases and serum erythropoietin (Epo) Levels in 32 COPD clinically stable patients and 34 sex- and age-matched non-smoker healthy volunteers. An increased MCV was observed in almost half of the hypoxemic COPD cases (14/32 or 43.75%), while erythrocytosis developed to a lesser degree (37.5%). The erythropoietic response did not correlate with the severity of hypoxia. Moreover, no significant correlation was found between macrocytosis and hypoxemia or erythrocytosis and red cell size. In some cases the two phenomena occurred independently. The F-cell percentage was significantly elevated in the COPD group (P < 0.01) and was associated with MCV values (n = 32, r5 = 0.41, P < 0.05). This finding supports the hypothesis we put forward to explain the macrocytosis often observed in COPD, i.e., that the acute erythropoietic stress occurring repeatedly in these patients as a result of the frequent exacerbations may lead to waves of release of relatively immature, large red cells from the marrow, including an increased number of F-cells, reflecting the recruitment of normally dormant BFU-E (bursts forming units of erythrocyte precursors), which maintain the program for gamma-chain synthesis. The fact that erythrocytosis and macrocytosis, both being triggered by hypoxemia, do not occur consistently in all COPD patients indicates that many other factors may also intervene.

Extramedullary hematopoiesis-related pleural effusion: the case of beta-thalassemia.

BACKGROUND: Thalassemia intermedia has a later clinical onset and a milder anemia than thalassemia major, characterized by high output state, left ventricle remodeling, and age-related pulmonary hypertension. Bone deformities, extramedullary hematopoiesis (EMH), and spleen and liver enlargement are the consequences of hypoxia and enhanced erythropoiesis. The EMH-related pleural effusion is rarely referred to in the literature of thalassemia. METHODS: We reviewed the thalassemia patients' medical records hospitalized for pleural effusion in our Department, within the last 6 years. RESULTS: Eight (4 men) thalassemia intermedia patients admitted for symptomatic pleural effusion were identified. Common clinical findings on admission were dyspnea and apyrexia. Their mean hemoglobin level was 7.15 +/- 0.64 g/dL. Radiology revealed intrathoracic EMH and pleural effusion in all patients: exudative in seven patients and massive hemothorax in one. Cytologic fluid analysis was negative for malignancy. Fluid and serum cultures, antibodies, and stains were negative for viral, bacterial, and fungal infection. The hemothorax case was successfully treated with repeated aspirations, transfusions, and hydroxyurea. Although repeated thoracentesis and radiation could not control the effusions in the rest of the cases, pleurodesis was successful in 5 patients, without serious adverse events. Treatment was further accomplished with hydroxyurea. No relapses were observed in the mean 30 month follow-up period. CONCLUSIONS: Afebrile, EMH-related pleuritis represents a potentially life-threatening complication in thalassemia. Therapy should be individualized and treatment is emerging. Pleurodesis seems to be an effective and safe therapeutic option for exudative effusions, while transfusion-chelation therapy combined with hydroxyurea may be helpful in suppressing increased erythropoiesis.

A comparative study of the role of erythropoietin in the pathogenesis of deficient erythropoiesis in idiopathic pulmonary fibrosis as opposed to chronic obstructive pulmonary disease.

BACKGROUND: Despite the severe derangement of gas exchange in the advanced stages of idiopathic pulmonary fibrosis (IPF), secondary erythrocytosis is either absent or much lower than is seen in chronic obstructive pulmonary disease (COPD) with comparable hypoxemia. This study investigates the differences in erythropoiesis between IPF and COPD, searching for the possible underlying mechanisms. MATERIAL/METHODS: The study included 32 patients with COPD, 18 patients with IPF, all with overt hypoxemia (PO(2) <65 mmHg), and 34 healthy controls. Erythrocytic parameters and serum erythropoietin (EPO) levels were assessed for all subjects. In a number of patients from both groups, the development of erythroid colonies grown from peripheral blood mononuclear cells was assayed in semisolid methylcellulose cultures and compared to cultures of control cells, in the presence of patient or control serum. RESULTS: Hb and serum EPO levels were significantly higher in the COPD group than in IPF patients and controls. However, the number of BFU-E colonies obtained from mononuclear cells of IPF patients was clearly higher than in COPD patients when the same culture medium was used. Unlike COPD sera, IPF sera induced a significant growth inhibition of erythroid bursts arising from mononuclear cells of both patients and controls. CONCLUSIONS: Our findings suggest a kind of ineffective erythropoiesis in IPF. Defective EPO production and inhibitory effect on erythropoiesis exerted by pro-inflammatory cytokines released from alveolar macrophages may be implicated in the suboptimal erythropoietic response. However, the possible involvement of other factors affecting erythropoiesis in IPF requires further investigation.

Hemodynamic assessment of splenomegaly in beta-thalassemia patients undergoing splenectomy.

Splenomegaly is a common finding in beta-thalassemia; however, its hemodynamic features and its potential correlations with high output state and hepatic disorders, both also frequent in thalassemia, have not yet been assessed in these patients. Eight beta-thalassemia patients with the indication for splenectomy and no symptoms or signs of heart disease, aged 25.6+/-5.5 years, were studied. Preoperative assessment included hematological profile, liver biology, hepatitis virus serology, and echocardiography. During splenectomy, splenic artery blood flow and splenic vein pressure were directly measured and liver biopsies were taken. Preoperative echocardiographic data were compared with those of 34 healthy controls. The preoperative cardiac index was significantly elevated in patients (4.8+/-1.3 vs 3.4+/-1.1 l/min per m2 in controls, p<0.001). Splenic blood flow, although increased, was not particularly high, being 285+/-56 ml/min or 0.13+/-0.04 ml/min per g of splenic mass, representing 4.1+/-0.9% of total cardiac output (CO). Splenic vein pressure was considerably elevated (29.7+/-5.5 cmH2O). Hepatic fibrosis, iron deposition, and extramedullary foci were found in all eight biopsies. Serology was positive in five of eight cases. beta-thalassemia patients with extensive splenomegaly requiring splenectomy are characterized by high output state, increased splenic blood flow, which probably makes a limited contribution to CO elevation, and portal hypertension, manifest by increased splenic vein pressure and hepatic histopathological abnormalities.

Decreased expression of membrane alpha4beta1, alpha5beta1 integrins and transferrin receptor on erythroblasts in splenectomized patients with beta-thalassemia intermedia. Parallel assessment of serum soluble transferrin receptors levels.

Dysfunction of cell membrane is a recognized consequence of the pathogenetic process underlying the beta-thalassemia syndromes and it is reasonable to hypothesize that surface structures crucial for the development of erythroid lineage may also be affected. The study included six adult splenectomized patients with beta-thalassemia intermedia. Expression of alpha4beta1 integrin (CD49d/CD29), alpha5beta1 integrin (CD49e/CD29) and transferrin receptor (CD71) on peripheral blood and bone marrow erythroblasts and on erythroid precursors grown in vitro was studied by flow cytometry and immunocytochemistry. Serum soluble transferrin receptor levels (sCD71) were also measured with enzyme-linked immunosorbent assay. In beta-thalassemic patients, significant reduction of CD49d, CD29 and CD71 expression was found in peripheral blood nucleated red cells, compared to patients presenting with erythroblasts in the circulation because of other diseases. Marrow erythroblasts were also deficient for the same molecules against the erythroblasts in iron deficiency anemia. All molecules tested were greatly diminished on erythroid precursors developed in vitro from the patients' cells. Serum sCD71 levels were much higher in thalassemic patients in comparison to both patients with iron deficiency anemia and healthy individuals. The loss of certain integrins and CD71 from erythroid precursors in beta-thalassemia intermedia could be attributed to a generalized membrane dysfunction, perhaps affecting the integrity of their transmembrane domains. The elevation of serum sCD71 levels may be the result of the increased red cell lineage turnover or, alternatively, may indicate increased shedding from the cells to prevent iron overload. In any case, further molecular study of the membrane components is warranted to provide a better understanding of the pathogenetic process in beta-thalassemia syndromes.

Cardiovascular adaptation to chronic anemia in the elderly: an echocardiographic study.

OBJECTIVE: To study the effects of chronic severe anemia on the aging heart. METHODS: We studied 41 elderly patients (mean age 69.8 yr, standard deviation [SD] 3.9 yr) suffering from chronic severe anemia (mean hemoglobin 6.3, SD 0.5 g/dL) with no history of cardiac disease, along with 63 healthy age- and sex-matched controls. Assessment included physical examination, electrocardiogram and Doppler echocardiography. RESULTS: Although heart rates were similar between patients and controls, arterial blood pressures were significantly lower in patients (mean pressure 92.7 mm Hg, SD 7.9, v. mean 102.1 mm Hg, SD 3.5; p < 0.001). No patient was found to have congestive heart failure. Patients with chronic anemia had larger diameters of the left (end-systolic 35.28, SD 4.20, v. 33.73, SD 2.08 mm, p < 0.05; end-diastolic 53.33, SD 4.55, v. 50.37, SD 2.10 mm, p < 0.001) and right ventricles (30.76, SD 3.98, v. 29.04, SD 2.04 mm; p < 0.05), and greater left-ventricular mass (277.64, SD 62.85, v. 212.91, SD 24.87 g; p < 0.001). Fractional shortening did not differ significantly (0.33, SD 0.04, v. 0.33, SD 0.03). The load-independent end-systolic index was lower in patients (2.67, SD 0.56, v. 3.87, SD 0.49 kdyn x m2/cm5; p < 0.001) along with end-systolic stress and total systemic resistance (p < 0.001) than controls, whereas the cardiac index was higher (4.31, SD 1.29, v. 2.73, SD 0.51 L/min/m2; p < 0.001). Differences between the 2 groups in diastolic function indices and pulmonary arterial pressures were not statistically significant. INTERPRETATION: Chronic severe anemia is well tolerated by the aging heart. Neither congestive heart failure nor clearly evident left-ventricular dysfunction were encountered. The heart exhibited an adaptive potential through remodelling by means of the Frank-Starling mechanism and afterload reduction. However, the lower end-systolic index in patients suggests that ventricular performance was marginally compromised. This state of high output was achieved mainly by increased stroke volume, with little contribution from heart rate.

Theophylline treatment may adversely affect the anoxia-induced erythropoietic response without suppressing erythropoietin production.

OBJECTIVE: To investigate the influence of theophylline on erythropoiesis in chronic obstructive pulmonary disease (COPD) and explore the potential underlying mechanisms. METHODS: We evaluated the haematological parameters and erythropoietin (EPO) values in 38 COPD patients, 18 of which had been treated with theophylline (8 mg/kg daily) for at least 1 year, and the other 20 had never received this drug; 38 sex- and age-matched healthy volunteers served as controls. We further studied the development of BFU-E (bursts forming units of erythrocyte precursors) -derived colonies in semisolid methylcellulose cultures in blood samples from 7 patients randomly selected from both groups. In addition, we studied the effects of theophylline on the erythroid cell development by adding this agent to erythroid cell cultures from 6 healthy volunteers at various concentrations. RESULTS: Haemoglobin values were found to be significantly lower in COPD patients treated with theophylline than in those untreated ( P<0.05). Both groups of patients exhibited significantly higher haemoglobin values than normal subjects ( P<0.01 and P<0.001 for treated and untreated patients, respectively). Serum EPO levels did not differ among the three studied groups. Unlike untreated patients and controls, the serum of the theophylline-treated patients produced a significant growth inhibition of erythroid bursts ( P<0.05); the in vitro use of theophylline showed a concentration-dependent inhibition ( P<0.001). CONCLUSION: Our findings confirm the decrease of red cell production, which occurs following administration of theophylline, exclude the possibility of decreased EPO synthesis and suggest a direct inhibitory action of theophylline on erythropoiesis.