Cardiopulmonary testing in adult patients with ß-thalassemia major in comparison to healthy subjects.

ß-Thalassemia patients often have a reduced capacity of exercise and abnormal respiratory function parameters, but the reasons are unclear. In order to identify the causes of the exercise limitation, we performed a cardiopulmonary exercise testing (CPET) in a group of 54 adult ß-thalassemia major (TM) patients without pulmonary arterial hypertension and in a group of healthy control subjects. All subjects underwent cardiac echocardiography and carried out pulmonary function tests. TM patients also filled an IPAQ questionnaire on usual physical activity (PA).Overall, TM patients have a diminished exercise performance in comparison to control subjects. In fact, peak oxygen uptake (V'O2 peak), expressing maximum exercise capacity, was decreased in 81.5% of the patients; similarly, anaerobic threshold (V'O2@AT) and O2 pulse also resulted lowered. In multivariable regression models adjusted for gender, age, BMI, and mean haemoglobin, V'O2 peak and O2 pulse were positively associated with cardiac iron overload (T2*). No ventilatory limitation to exercise was observed. The most important causes of exercise limitation in these patients were muscular deconditioning and reduced cardiac inotropism due to iron deposition. Only 15/54 (27.8%) TM patients used to perform vigorous physical activity. These results suggest that a program of regular physical activity may be useful to increase the tolerance to effort and therefore to improve the quality of life in these patients.

Skeletal involvement in type 1 Gaucher disease: Not just bone mineral density.

Gaucher disease is characterized by multi-organ infiltration of phospholipid-laden macrophages. Bone involvement is characterized by typical deformities, osteopenia/osteoporosis, pathological fractures, and bone marrow infiltration (avascular osteonecrosis, infarction). Estimation of skeletal disease includes bone quality that contributes substantially to bone strength. We studied 23 type 1 Gaucher patients (median age 22years, range 3-73) on Enzyme Replacement Therapy from 2months to 26years (median 7years); 4 patients had pathological fractures, 10 bone infarctions, 6 avascular osteonecrosis. We noninvasively assessed bone quality by trabecular microarchitecture and macroscopic geometry, using two innovative dual-energy X-ray absorptiometry tools: Trabecular Bone Score (TBS) and Hip Structural Analysis (HSA). Bone quality parameters distinguished the patients with skeletal complications. TBS was significantly lower in patients with avascular osteonecrosis (p=0.049) and pathological fractures (p=0.024), while it could not identify those with bone infarctions. Among HSA parameters, the Cross Sectional Area of the intertrochanteric region and the Buckling Ratio of the narrow neck allowed the distinction of patients with avascular osteonecrosis. BMD was low in 11 patients (50%); neither BMD nor HSA were associated with pathological fractures. The combined evaluation of bone quality and bone quantity is useful to identify GD patients with more severe skeletal involvement.

Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT).

A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection has been implicated in the development of liver fibrosis. Hepatic siderosis and fibrosis were assessed in 99 transfusion-dependent thalassemia (TDT) patients using transient elastography (TE) and liver iron concentration (LIC) assessed by T2*MRI at baseline and after 4 years. Data were analyzed retrospectively. At baseline, the overall mean liver stiffness measurement (LSM) was 7.4 ± 3.2 kPa and the mean LIC was 4.81 ± 3.82 mg/g dw (n = 99). Data available at 4 ± 1.5 years showed a significant reduction in LSM (6.6 ± 3.2 kPa, p 0.017) and hepatic siderosis measured by LIC (3.65 ± 3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurement (n = 41) and subjects treated with a stable dose of deferasirox over the entire period of observation (n = 39). A reduction of LSM, yet not statistically significant, was achieved in patients on combined deferoxamine + deferiprone, while the group on deferoxamine (n = 11) remained stable over time. HCV-RNA positivity was found in 33 patients at T0, 20 of which were treated during the observation period. Patients who underwent anti-HCV therapy showed a more evident reduction in LSM (9 ± 3 vs 7 ± 3.1 kPa, p 0.016). Adequate chelation therapy is mandatory in order to prevent liver disease progression in TDT. Patients could benefit from regular non-invasive assessment of liver fibrosis by TE to indirectly monitor treatment adequacy and therapeutic compliance.

Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

Pregnancy in patients with thalassemia major: a cohort study and conclusions for an adequate care management approach.

An improvement in quality of life and survival occurred among thalassemia major (TM) patients: pregnancy in such patients has become a reality. Safe pregnancy and delivery require efforts to ensure the best outcomes. Between 2007 and 2016, 30 TM patients had 37 pregnancies. We analyzed the hematological parameters before, during, and after pregnancies and in 19 patients a cardiovascular magnetic resonance (CMR) T2* was performed. The mean age at first pregnancy was 30 ± 4 years; the current mean age is 35 ± 5 years. Twenty-four patients (80%) had a single pregnancy, five patients (17%) had two pregnancies, and one patient (3%) became pregnant three times. Seventeen pregnancies (46%) were spontaneous, 20 (64%) needed gonadotrophin-induced ovulation and/or reproductive technologies. All pregnancies resulted in live births. Seven were twin pregnancies (19%). The mean gestational hemoglobin was 9.2 ± 0.5 g/dl, lower than pre- and postpregnancy (9.8 ± 1 g/dl, p = ns and 9.6 ± 1 g/dl, p = 0.02, respectively). Median ferritin levels increased progressively (1071, range 409-5724 ng/ml, before pregnancy vs 2231, range 836-6918 ng/ml, after pregnancy, p < 0.0001). CMR before pregnancy showed a normal cardiac T2* (mean 35.34 ± 8.90 ms) and a mean liver iron concentration (LIC) of 3.37 ± 2.11 mg/g dry weight (dw). After pregnancy, the mean cardiac T2* was 31.06 ± 13.26 ms and the mean LIC was significantly increased (9.06 ± 5.75 mg/g dw, p = 0.0001). Pregnancy is possible and safe in thalassemia major. During pregnancy, iron accumulates, especially in the liver; a prompt resumption of chelation after delivery is mandatory.

A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients.

Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. We evaluated by T2* cardiovascular magnetic resonance (CMR) the efficacy of DFX in preventing and removing cardiac and liver iron load and cardiac volume changes, along 5 years in adult thalassemia major (TM) patients. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4 years) were included in this study. Repeated CMR was performed to assess myocardial and liver iron load (baseline t0, after 2.5 years t1, after 5 years t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p = 0.0001). At baseline evaluation, a cardiac T2* value <20 ms was detected in six patients (26 %): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population, a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132 ± 31 ml vs t2: 124 ± 22 ml, p = 0.033; ESV, t0: 48 ± 14 ml vs t2: 41 ± 10 ml, p = 0.0007). A significant reduction in liver iron concentration (LIC) was detected at t1 (5.36 ± 3.58 mg/g dw at baseline vs 3.35 ± 2.68 mg/g dw at t1, p = 0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2, and mean LIC value is reduced of 29 %. After 5 years of treatment, DFX continually and significantly reduced myocardial and liver iron overload, and it prevented further iron deposition.

Spine bone texture assessed by trabecular bone score (TBS) to evaluate bone health in thalassemia major.

Due to the increasing survival of thalassemic patients, osteopathy is a mounting clinical problem. Low bone mass alone cannot account for the high fracture risk described; impaired bone quality has been speculated but so far it cannot be demonstrated noninvasively. We studied bone quality in thalassemia major using trabecular bone score (TBS), a novel texture measurement extracted from spine dual-energy X-ray absorptiometry (DXA), proposed in postmenopausal and secondary osteoporosis as an indirect index of microarchitecture. TBS was evaluated in 124 adult thalassemics (age range 19-56 years), followed-up with optimal transfusional and therapeutical regimens, and in 65 non-thalassemic patients (22-52 years) undergoing DXA for different bone diseases. TBS was lower in thalassemic patients (1.04 ± 0.12 [range 0.80-1.30]) versus controls (1.34 ± 0.11 [1.06-1.52]) (p < 0.001), and correlated with BMD. TBS and BMD values correlated with age, indicating that thalassemia negatively affects both bone quality and quantity, especially as the patient gets older. TBS was 1.02 ± 0.11 [0.80-1.28] in the osteoporotic thalassemic patients, 1.08 ± 0.12 [0.82-1.30] in the osteopenic ones and 1.15 ± 0.10 [0.96-1.26] in those with normal BMD. No gender differences were found (males: 1.02 ± 0.13 [0.80-1.30], females 1.05 ± 0.11 [0.80-1.30]), nor between patients with and without endocrine-metabolic disorders affecting bone metabolism. Our findings from a large population with thalassemia major show that TBS is a valuable tool to assess noninvasively bone quality, and it may be related to fragility fracture risk in thalassemic osteopathy.

Combination of deferasirox and deferoxamine in clinical practice: an alternative scheme of chelation in thalassemia major patients.

The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs' starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 µM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable dose of DFO (32 ± 4 mg/kg/day). Combined or alternated DFX/DFO can be considered when monotherapy is not able to remove the iron overload or in the presence of adverse events.

Effect of hydroxyurea on extramedullary haematopoiesis in thalassaemia intermedia: case reports and literature review.

Extramedullary haematopoiesis (EH) is the production of blood cell precursors outside the bone marrow that occurs in various disorders, such as thalassaemia, sickle cell anaemia, hereditary spherocytosis, polycythaemia vera, myelofibrosis and other haematological diseases. In chronic anaemia, it is a physiological response to increased erythropoietin. In some other conditions, such as myeloid metaplasia, polycythaemia vera or chronic myeloid leukaemia, EH is due to a clonal disorder of haematopoiesis that enables progenitor cells to escape from the marrow and lodge in other organs. EH usually involves the liver, spleen and lymph nodes or it can be paravertebral, intrathoracic, pelvic. It is often asymptomatic but can sometimes lead to symptomatic tumour-like masses. Treatment options are still controversial and limited, including hypertransfusion regimen, surgical treatment, radiotherapy and hydroxyurea (HU). We describe intrathoracic and symptomatic pelvic EH masses in a 48-year-old woman and intrathoracic bilateral masses causing respiratory insufficiency with pleural effusion in a 42-year-old male, both affected by thalassaemia intermedia. Both patients showed a clinical improvement with hydroxyurea therapy and occasional blood transfusions.

Segmental duplications involving the alpha-globin gene cluster are causing beta-thalassemia intermedia phenotypes in beta-thalassemia heterozygous patients.

We describe two cases of simple heterozygosity for the common beta degrees -thalassemia mutation beta 39 (C-->T), both presenting with a thalassemia intermedia phenotype. In both cases synergic effect deriving from membrane defects or red cell enzyme deficiencies were excluded. In one case a triplication of the alpha-globin genes was found which did not justify the severity of the transfusion-dependent phenotype. Multiplex ligation-dependent probe amplification (MLPA) analysis of the alpha-globin gene cluster revealed two new rearrangements, consisting of a full duplication of the alpha-globin genes locus including the upstream regulatory element. In one case the duplication was in the presence of the common anti-alpha(3.7) triplication in trans, resulting in a total of 7 active alpha-globin genes. In the other case the duplicated allele and the normal allele in trans resulted into a total of 6 active alpha-globin genes. We report the clinical and hematological data and the molecular analysis and discuss the occurrence of alpha-globin genes duplication defects in cases of beta-thalassemia heterozygotes with thalassemia intermedia phenotypes.

Heparin induced thrombocytopenia: pathogenetic, clinical, diagnostic and therapeutic aspects.

Heparin induced thrombocytopenia (HIT) in addition to bleeding complications are the most serious and dangerous side effects of heparin treatment. HIT remains the most common antibody-mediated, drug-induced thrombocytopenic disorder and a leading cause of morbidity and mortality. Two types of HIT are described: Type I is a transitory, slight and asymptomatic reduction of platelet count occurring during 1-2 days of therapy. HIT type II, which has an immunologic origin, is characterized by a thrombocytopenia that generally onset after the fifth day of therapy. Despite thrombocytopenia, haemorrhagic complications are very rare and HIT type II is characterized by thromboembolic complications consisting in venous and arterial thrombosis. The aim of this paper is to review new aspects of epidemiology, pathophysiology, clinical features, diagnosis and therapy of HIT type II. There is increasing evidence that platelet factor 4 (PF4) displaced from endothelial cells, heparan sulphate or directly from the platelets, binds to heparin molecule to form an immunogenic complex. The anti-heparin/PF4 IgG immune-complexes activates platelets through binding with the Fcgamma RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia and thrombosis. Cytokines are generated during this process and inflammation could play an additional role in the pathogenesis of thromboembolic manifestations. The onset of HIT type II is independent from dosage, schedule, and route of administration of heparin. A platelet count must be carried out prior to heparin therapy. Starting from the fourth day, platelet count must be carried out daily or every two days for at least 20 days of any heparin therapy regardless of the route of the drug administration. Patients undergoing orthopaedic or cardiac surgery are at higher risk for HIT type II. The diagnosis of HIT type II should be formulated on basis of clinical criteria and confirmed by in vitro demonstration of heparin-dependent antibodies detected by functional and antigen methods. However, the introduction of sensitive ELISA tests to measure anti-heparin/PF4 antibodies has showed the immuno-conversion in an higher number of patients treated with heparin such as the incidence of anti-heparin/PF4 exceeds the incidence of the disease. If HIT type II is likely, heparin must be immediately discontinued, even in absence of certain diagnosis of HIT type II, and an alternative anticoagulant therapy must be started followed by oral dicumaroids, preferably after resolution of thrombocytopenia. Further studies are required in order to elucidate the pathogenetic mechanism of thrombosis and its relation with inflammation; on the other hand large clinical trials are needed to confirm the best therapeutic strategies for HIT Type II.

New antithrombotic agents.

The main clinical indications for anticoagulant agents are treatment and prophylaxis of venous and arterial thromboembolism and acute coronary syndromes. For decades, two anticoagulants, heparin and warfarin, have been the principal drugs available. Dicumaroid agents have serious limitations due to their narrow therapeutic range, needing close monitoring. The interaction with food and drugs and the numerous interindividual variations result in unstable effects on coagulation parameters. On the other side, heparins have an exclusive parenteral use and a risk of immunological adverse reactions. Heparin induced thrombocytopenia is the most serious complication. The limitations of existing oral and parenteral anticoagulant agents have prompted the search for alternative anticoagulant drugs. This paper reviews new anticoagulant agents describing their pharmacological and clinical properties. It focuses on the target of their anticoagulant action inside the coagulation pathway, and analyzes the clinical trials providing indications for new clinical anticoagulation strategies. Agents currently under study include direct thrombin inhibitors, indirect activated factor X inhibitors, and inhibitors of tissue factor and activated factor VII. The new anticoagulant agents may demonstrate improvements in effectiveness, safety convenience and cost-effectiveness compared with current anticoagulants.

Coagulation and splenectomy: an overview.

Venous thromboembolic events, such as pulmonary embolism, deep venous thrombosis, and portal vein thrombosis, have been observed in adult thalassemia patients, mainly in beta-thalassemia intermedia. The clinical findings are consistent with the observation of several alterations that indicate a state of activation of the hemostatic mechanisms in thalassemias. These alterations have usually been related to high platelet counts due to splenectomy and/or liver dysfunction. In a retrospective study of a large cohort of adults with thalassemia, we found a larger prevalence of venous thromboembolic events in transfusion-independent patients with thalassemia intermedia (29%) than in regularly transfused patients with thalassemia major (2%); moreover, the higher prevalence occurred particularly in splenectomized thalassemia intermedia patients. More recently, a multicenter study involving 56 tertiary referral centers in 7 countries was planned to assess the magnitude of thrombotic risk in thalassemia patients. The total number of patients who had thrombotic events was 146 (1.65%) out of 8860, with a prevalence of 0.9% in thalassemia major and 4% in thalassemia intermedia. The highest prevalence was confirmed in splenectomized patients. The observation that thrombotic events are more frequent in beta-thalassemia patients who are not receiving regular transfusions (thalassemia intermedia or thalassemia major patients in less developed countries with limited transfusion resources) or in thalassemic patients who have undergone splenectomy strongly supports the procoagulant activity of circulating damaged red blood cells.