Gaetano Giuffrida

ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission

Acquired thrombotic thrombocytopenic purpura (TTP) is often due to anti-ADAMTS13 antibodies that inhibit the proteolytic activity of the plasma metallo-protease and/or accelerate its clearance. Survivors of an acute episode of TTP with severely reduced levels of ADAMTS13 and /or with anti-ADAMTS13 antibodies during remission are at high risk of developing another epidode of TTP. Background From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established. Design and Methods In 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients. Results Median values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p=0.007; antigen: 36% vs. 58%; p=0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p=0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p=0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p=0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence. Conclusions Survivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.

Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.

Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice

Gaucher disease is a rare autosomal recessive disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal enzyme beta-glucocerebrosidase that causes accumulation of glucosylceramide in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Severity and progression may vary independently among these domains, necessitating individualized therapy. Skeletal involvement is highly prevalent and often associated with intense pain, impaired mobility, and reduced quality of life. Enzyme replacement therapy improves parameters in all affected domains, but skeletal involvement requires longer treatment and higher dosages to obtain significant results. Despite numerous papers on bone complications in patients with Gaucher disease, there are no specific indications on how to assess properly bone involvement in such condition, the frequency of assessment, the use of markers for osteoblast and osteoclast activity, or the administration of bisphosphonates or other symptomatic drugs in adult and pediatric patients. Starting from a re-evaluation of cases with bone involvement, we have identified some common errors in the diagnostic approach and management. The aim of this paper was to propose a methodological and critical approach to the diagnosis, follow-up and treatment of bone disease in patients with Gaucher disease type 1.

Bone turnover markers in patients with type 1 Gaucher disease

Bone complications occur frequently in Gaucher disease (GD) and reduce the quality of life of these patients. Skeletal involvement is an important indication for treatment to ameliorate symptoms and reduce the risk of irreversible and debilitating disease. Bone biomarkers have been used to assess disease status and the response to therapy in a number of bone disorders. Here, we examine the literature for evidence of abnormalities in bone turnover markers in patients with type 1 GD to assess whether they might be useful for the assessment of bone involvement in GD. We have found that bone biomarkers in GD show highly variable results which do not currently support their routine use for clinical assessment of bone status, as an indication for therapy initiation, or for monitoring the response to therapy. A greater understanding of bone markers and their relation to the bone manifestations of GD is required.

Minimal disease activity in Gaucher disease: Criteria for definition

Gaucher disease type I is a metabolic disorder caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of glucocerebroside in macrophages, thus causing damage in different organ systems. Enzyme replacement therapy with imiglucerase improves organ impairment and clinical manifestations, but patients differ in response to treatment. While clinical remission is the most desirable therapeutic outcome, a more realistic goal in patients with high disease burden is reasonably good clinical status despite persistence of residual biochemical or imaging abnormalities. Therefore, the concept of minimal disease activity--used in certain haematological or rheumatologic conditions--needs to be introduced in Gaucher disease, with a level of disease activity that patients and physicians consider a useful treatment target. In this paper, we propose specific parameters and criteria for defining minimal disease activity in Gaucher disease and its stability over time, based on three major systemic domains typically involved: haematological, visceral, and skeletal. Biomarker parameters were not included as criteria, because currently they do not adequately reflect disease evolution in individual patients. Neurological and respiratory domains were also excluded, as their involvement per se indicates severe disease unlikely to respond to enzyme replacement therapy and achieve minimal disease status. Our goal in defining minimal disease activity and stability is to identify a tool to facilitate treatment decisions in clinical practice.

Percutaneous transluminal angioplasty and stent implantation for aortic coarctation in haemophilia A patient with high‐titre factor VIII inhibitors

G. GIUFFRIDA,* R. LOMBARDO,* N. L. PARRINELLO,* M. R. CINGARI,* E. DI FRANCESCO,* A. M. TRIOLO,* G. P. USSIA,† A. A. ARCIDIACONO,† S. SCANDURA† and F. DI RAIMONDO* *Divisione Clinicizzata di Ematologia con Trapianto di Midollo Osseo, Centro di riferimento regionale per la prevenzione, diagnosi e cura delle malattie rare della coagulazione nel bambino e nell’adulto Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Ospedale Ferrarotto, Universit a di Catania; and †Interventional Structural and Congenital Heart Disease Programme, Invasive Cardiology, Istituto di Cardiologia, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Ospedale Ferrarotto, Universit a di Catania, Catania, Italy

Percutaneous transluminal aortic valve implantation for severe aortic valve stenosis in a patient with severe haemophilia A

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Erratum to: Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice

The authors of the above-mentioned paper noticed some errors subsequent to publication and would like to make the following corrections: On page 1199, under the heading Dual Energy X-ray Absorptiometry (Table 1), the sentence ‘‘The gold standard for quantitative assessment of bone mineral status in adults is dual energy X-ray absorptiometry (DXA), performed at the lumbar spine (L1–L4) and hip (total hip or femoral neck).’’ should read ‘‘The gold standard for quantitative assessment of bone mineral status in adults is dual energy X-ray absorptiometry (DXA), performed at the lumbar spine (L1–L4) and hip (total hip and femoral neck).’’ Here, the word ‘or’ in the second brackets is replaced by ‘and’. In the original supplementary material, the references cited in Supplementary Tables 1 and 2 were not updated during editing and as such do not correlate with the reference list in the published manuscript. These have been updated in the electronic supplementary material associated with this erratum. The online version of the original article can be found under doi:10.1007/s12325-014-0174-0.

Reference ranges for biventricular volumes and ejection fraction and for left ventricular mass in adult thalassemia intermedia patients without myocardial iron overload

Background Thalassemia intermedia (TI) patients were shown to have significantly higher cardiac output and cardiac volumes with respect to thalassemia major (TM) patients. So, to compare biventricular parameters in TI patients with established ranges from TM may be misleading. The aim of this study was to establish the ranges for normal biventricular volumes and ejection fraction (EF) and for left ventricular (LV) mass assessed by cardiovascular magnetic resonance (CMR) in TI.