A Zanella

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Lombardy, Italy

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Publications (173)687.35 Total impact

  • Alberto Zanella, Wilma Barcellini
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    ABSTRACT: Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment.
    Haematologica 10/2014; 99(10):1547-1554. · 5.94 Impact Factor
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    ABSTRACT: The clinical outcome, response to treatment, and occurrence of acute complications, were retrospectively investigated in 308 primary autoimmune hemolytic anemia (AIHA) cases and were correlated with serological characteristics and severity of anemia at onset. Patients had been followed-up for a median of 33 months (range 12-372); 60% were warm AIHA, 27% cold hemagglutinin disease, 8% mixed, and 5% atypical (mostly DAT-negative). The latter two categories showed more frequently a severe onset (Hb levels ≤6 g/dL) along with reticulocytopenia. The majority of warm AIHA received first line steroid therapy only, whereas patients with mixed and atypical forms were more frequently treated with 2 or more therapy lines, including splenectomy, immunosuppressants and rituximab. The cumulative incidence of relapse was increased in more severe cases (HR 3.08, 95% CI 1.44-6.57 for Hb ≤6 g/dL, p<0.001). Thrombotic events were associated to Hb levels ≤6 g/dL at onset, intravascular hemolysis and previous splenectomy. Predictors of a fatal outcome were severe infections particularly in splenectomized cases, acute renal failure, Evans' syndrome and multi-treatment (4 or more lines). The identification of severe and potentially fatal AIHA in a largely heterogeneous disease requires particular experienced attention by clinicians.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: We studied monosomy and deletions of chromosome 7 in 208 patients with myeloid disorders; we found 39 patients (19%) with monosomy or deletion of chromosome 7: 24 patients with chromosome 7 deletion and 15 with monosomy 7. In the 24 patients with chromosome 7 deletions, studied with copy-number variants, short-tandem repeats, microsatellites, single nucleotide polymorphisms, and deletion polymorphisms, the most common deleted region was 7q31.1 (20 patients). Deletion polymorphism studies performed in these 20 patients showed an interstitial deletion of at least 140 kilobase in 6 patients; the deletion spans between the genes forkhead box P2 and Myo D family inhibitor domain containing. Because both genes do not seem to be involved in leukogenesis, we suggest to look carefully into this deletion for the presence of tumor suppressor genes and microRNAs.
    Human pathology 02/2014; 45(2):368-71. · 3.03 Impact Factor
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    ABSTRACT: ABSTRACT Toll-like receptors (TLR) represent major agents of innate immunity and initiators of adaptive immunity. TLR4 and TLR9 gene expression was related with the occurrence of infections, autoimmunity and disease progression in 95 B-CLL patients, grouped according to stage, therapy, and known prognostic markers, and followed prospectively (median 33.6 months, range 25-50). A retrospective analysis (median 6.8 years, range 6-26) was also performed. TLR4 gene expression was decreased and TLR9 increased in patients versus controls, the former being more pronounced in advanced and multi-treated disease, and in patients with unmutated IgVH and unfavorable cytogenetic. Patients with reduced TLR4 had an increased risk of disease progression and development of autoimmune complications. No relationship was found between reduced TLR4 expression and infectious episodes, which were observed in advanced stages and treated patients. These findings suggest that impaired innate immunity identifies B-CLL patients with poor prognosis and reduced ability to silence autoreactive phenomena.
    Leukemia & lymphoma 10/2013; · 2.61 Impact Factor
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    ABSTRACT: to evaluate the sustained response to low-dose (LD)-rituximab in autoimmune hemolytic anemia (AIHA), the ex vivo effect on anti-RBC antibody production by mitogen-stimulated direct antiglobulin test (MS-DAT), and the in vitro dose-effect of the drug on the production of anti-RBC antibodies. 32 patients, 18 warm (W)AIHA and 14 cold hemagglutinin disease (CHD), were treated with LD-rituximab (100 mg fixed dose x4 weekly infusions) along with a short course of oral prednisone. Complete clinical examination, blood counts and hemolytic markers were performed at enrollment, and at month 6, 12, 24, and 36. Hematologic parameters significantly improved at all time points compared to enrollment. The overall response was 90%, 100%, 100% and 89% and the relapse free survival 87%, 79%, 68% and 68% at 6, 12, 24 and 36 months, respectively. Response rates were slightly better in WAIHA than in CHD, and relapse risk was greater in cold than warm forms (HR 2.1, 95% CI 0.6 -7.9). Four patients were retreated (one patient twice), all achieving a response, lasting a median of 18 months (range 9-30). Treatment was well tolerated without adverse events or infections. Anti-RBC antibody production by MS-DAT significantly decreased over time. In vitro studies showed that rituximab effectively inhibited anti-RBC antibody production at 50 μg/mL, 1/6 of the drug concentration after therapy with standard doses. These data confirm that LD-rituximab treatment is effective and induces sustained responses in AIHA, and that a lower dose of the drug is enough to down-regulate autoantibody production. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 09/2013; · 2.55 Impact Factor
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    ABSTRACT: Hereditary spherocytosis (HS) and pyruvate kinase (PK) deficiency are the most common causes of congenital hemolytic anemia. We describe a case of HS with defective PK activity initially misdiagnosed as PK deficiency. Hematologic investigation, SDS-PAGE analysis of red cell membrane proteins and sequencing of the PKLR gene were performed. The molecular characterization of the PKLR gene showed a heterozygous mutation 994G > A (Gly332Ser) associated with the promoter substitution -148C > T, whose role in the pathophysiology of PK deficiency is debated. Further investigations revealed spectrin deficiency; the family study demonstrated that the hemolysis was exclusively attributable to HS. The present case pinpoints to the need for extensive family investigations to correctly diagnose chronic hemolytic anemia, in particular when molecular characterization does not fully explain the clinical phenotype.
    Clinical laboratory 01/2013; 59(3-4):421-4. · 0.92 Impact Factor
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    Paola Bianchi, Elisa Fermo, Alberto Zanella
    Haematologica 12/2012; 97(12):e50-1. · 5.94 Impact Factor
  • Paola Bianchi, Elisa Fermo, Alberto Zanella
    Haematologica 12/2012; 97(12):e52. · 5.94 Impact Factor
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    ABSTRACT: Phosphoglycerate kinase (PGK) is a key glycolytic enzyme that catalyzes the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to MgADP, to form 3-phosphoglycerate and MgATP. Two isozymes encoded by distinct genes are present in humans: PGK-1, located on Xq-13.3, encodes a ubiquitous protein of 417 amino acids, whereas PGK-2 is testis-specific. PGK1 deficiency is characterized by mild to severe hemolytic anemia, neurological dysfunctions and myopathy; patients rarely exhibit all three clinical features. Nearly 40 cases have been reported, 27 of them characterized at DNA or protein level, and 20 different mutations were described. Here we report the first Italian case of PGK deficiency characterized at a molecular and biochemical level. The patient presented during infancy with hemolytic anemia, increased CPK values, and respiratory distress; the study of red blood cell enzymes showed a drastic reduction in PGK activity. In adulthood he displayed mild hemolytic anemia, mental retardation and severe myopathy. PGK-1 gene sequencing revealed the new missense mutation c.1112T>A (p.Ile371Lys). The mutation was not found among 100 normal alleles, and even if located in the third to the last nucleotide of exon 9, it did not alter mRNA splicing. The p.Ile371Lys mutation falls in a conserved region of the enzyme, near the nucleotide binding site. The mutant enzyme shows reduced catalytic rates toward both substrates (apparent k(cat) values, 12-fold lower than wild-type) and a decreased affinity toward MgATP (apparent K(m), 6-fold higher than wild-type). Moreover, it lost half of activity after nearly 9-min incubation at 45°C, a temperature that did not affect the wild-type enzyme (t(1/2)>1 h). The possible compensatory expression of PGK2 isoenzyme was investigated in the proband and in the heterozygote healthy sisters, and found to be absent. Therefore, the highly perturbed catalytic properties of the new variant p.Ile371Lys, combined with protein instability, account for the PGK deficiency found in the patient and correlate with the clinical expression of the disease.
    Molecular Genetics and Metabolism 05/2012; 106(4):455-61. · 2.83 Impact Factor
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    ABSTRACT: This prospective study investigated the efficacy, safety, and response duration of low-dose rituximab (100 mg fixed dose for 4 weekly infusions) together with a short course of steroids as first- or second-line therapy in 23 patients with primary autoimmune hemolytic anemia (AIHA). The overall response was 82.6% at month +2, and subsequently stabilized to ∼ 90% at months +6 and +12; the response was better in warm autoimmune hemolytic anemia (WAIHA; overall response, 100% at all time points) than in cold hemagglutinin disease (CHD; average, 60%); the relapse-free survival was 100% for WAIHA at +6 and +12 months versus 89% and 59% in CHD, respectively, and the estimated relapse-free survival at 2 years was 81% and 40% for the warm and cold forms, respectively. The risk of relapse was higher in CHD and in patients with a longer interval between diagnosis and enrollment. Steroid administration was reduced both as cumulative dose (∼ 50%) and duration compared with the patient's past history. Treatment was well tolerated and no adverse events or infections were recorded; retreatment was also effective. The clinical response was correlated with amelioration biologic markers such as cytokine production (IFN-γ, IL-12, TNF-α, and IL-17), suggesting that low-dose rituximab exerts an immunomodulating activity. This study is registered at www.clinicaltrials.gov as NCT01345708.
    Blood 01/2012; 119(16):3691-7. · 9.78 Impact Factor
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    ABSTRACT: Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.
    PLoS ONE 01/2012; 7(2):e32065. · 3.53 Impact Factor
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    ABSTRACT: The laboratory diagnosis of hereditary spherocytosis commonly relies on NaCl-based or glycerol-based red cell osmotic fragility tests; more recently, an assay directly targeting the hereditary spherocytosis molecular defect (eosin-5'-maleimide-binding test) has been proposed. None of the available tests identifies all cases of hereditary spherocytosis. We compared the performances of the eosin-5'-maleimide-binding test, NaCl-osmotic fragility studies on fresh and incubated blood, the glycerol lysis test, the acidified glycerol lysis test, and the Pink test on a series of 150 patients with hereditary spherocytosis grouped according to clinical phenotype and the defective protein, with the final aim of finding the combination of tests associated with the highest diagnostic power, even in the mildest cases of hereditary spherocytosis. The eosin-5'-maleimide-binding test had a sensitivity of 93% and a specificity of 98% for detecting hereditary spherocytosis: the sensitivity was independent of the type and amount of molecular defect and of the clinical phenotype. The acidified glycerol lysis test and Pink test showed comparable sensitivity (95% and 91%). The sensitivity of NaCl osmotic fragility tests, commonly considered the gold standard for the diagnosis of hereditary spherocytosis, was 68% on fresh blood and 81% on incubated blood, and further decreased in compensated cases (53% and 64%, respectively). The combination of the eosin-5'-maleimide-binding test and acidified glycerol lysis test enabled all patients with hereditary spherocytosis to be identified. The eosin-5'-maleimide-binding test showed the greatest disease specificity. Each type of test fails to diagnose some cases of hereditary spherocytosis. The association of an eosin-5'-maleimide-binding test and an acidified glycerol lysis test enabled identification of all patients with hereditary spherocytosis in this series and, therefore, represents a currently effective diagnostic strategy for hereditary spherocytosis including mild/compensated cases.
    Haematologica 11/2011; 97(4):516-23. · 5.94 Impact Factor
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    ABSTRACT: We identified the pyruvate kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with pyruvate kinase deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have pyruvate kinase deficiency did not, because they were heterozygous.
    The Journal of pediatrics 07/2011; 159(4):695-7. · 4.02 Impact Factor
  • Wilma Barcellini, Alberto Zanella
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    ABSTRACT: Autoimmune haematological diseases are characterized by the production of antibodies against blood proteins or cells, and comprise primary immune thrombocytopenia, autoimmune haemolytic anaemia, acquired haemophilia, and thrombotic thrombocytopenic purpura. Current treatments for these disorders include corticosteroids, cytotoxic drugs and splenectomy, which may be associated with significant systemic toxicity and/or morbility. B cells play a key role in both the development and perpetuation of autoimmunity, since they produce autoantibodies but also function as antigen-presenting cells, and release immunomodulatory cytokines. Rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, may be an effective treatment strategy for patients with autoimmune disorders. This article reviews data of the literature, showing that patients with autoimmune haematological diseases can respond to rituximab irrespective of age and number or type of prior treatments. These data suggest that rituximab provides an effective and well-tolerated treatment option for these conditions.
    European Journal of Internal Medicine 06/2011; 22(3):220-9. · 2.30 Impact Factor
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    ABSTRACT: Febrile nonhemolytic transfusion reactions occur in 0.12% of transfusions, usually during transfusion or within 4 to 6 hours after transfusion and are not medically dangerous. A patient with thalassemia from Togo with asymptomatic malaria in which the infection became clinically manifest only after blood transfusion, mimicking a febrile nonhemolytic transfusion reaction, is presented. Thirty-two hours after transfusion of 2 O D- red blood cell (RBC) units, the patient (phenotype A(2) D+) developed fever and multiorgan failure and was admitted to the intensive care unit. Direct and indirect antiglobulin tests were negative on posttransfusion samples. Blood cultures and infectious diseases testing were negative. No malaria parasites were found at thick blood smear microscopic examination on Days 1 and 2 and the malaria rapid diagnostic test gave inconsistent results. Plasmodium total antibodies were detected in the serum at high levels. On Day 5, routine microscopic examination of blood smear revealed the presence of parasites in a very small number of RBCs. This finding was almost simultaneous to the availability of polymerase chain reaction testing results that were positive for P. falciparum. The sequential agglutination with anti-A antiserum allowed patient's and donors' RBCs to be separated and revealed that the parasitized cells were almost exclusively those of donors (14.4% vs. 0.029%). Malaria infection in implicated donors was excluded. In this patient with thalassemia with asymptomatic malaria, the infusion of two normal RBC units provided a favorable environment for a rapid parasite replication leading to a dramatic acute malaria attack.
    Transfusion 03/2011; 51(3):469-72. · 3.53 Impact Factor
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    Blood transfusion = Trasfusione del sangue 01/2011; 9(3):274-7. · 1.86 Impact Factor
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    ABSTRACT: Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.
    European Journal Of Haematology 07/2010; 85(1):20-5. · 2.55 Impact Factor
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    ABSTRACT: The diagnosis of autoimmune hemolytic anemia (AIHA) is based on a positive direct antiglobulin test (DAT), which is performed using various methods with different sensitivities. Recently, mitogen-stimulated (MS)-DAT was suggested to be able to identify latent anti-erythrocyte autoimmunity. Traditional methods (tube, microcolumn, and solid phase) and MS-DAT were compared in 54 consecutive cases of suspected AIHA, 28 idiopathic AIHA in clinical remission, and 12 difficult-to-diagnose cases of DAT-negative AIHA, and the results (all cases) were correlated with hematologic and hemolytic parameters. DAT tube was confirmed as the gold standard to diagnose AIHA since almost all positive cases showed hemolytic anemia and positive eluates; 10 out of 26 tube-negative cases were positive on microcolumn and solid phase antiglobulin tests, and 22 out of 26 using MS-DAT, although only half of them showed clear signs of hemolysis. Mitogen stimulation increased the amount of IgG bound to red blood cells in all groups; moreover, MS-DAT was the only positive test in 10 cases of AIHA, and mitogen stimulation facilitated the identification of autoantibody specificity in culture supernatants. We conclude that a battery of tests rather than a single test is useful for the diagnosis of AIHA, including MS-DAT as an additional test for selected cases, although the results have to be cautiously interpreted based on the overall clinical context.
    International journal of hematology 06/2010; 91(5):762-9. · 1.17 Impact Factor
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    ABSTRACT: We report two patients with very severe congenital dyserythropoietic anemia presenting with hydrops foetalis, previously classified as "atypical" CDAs since they presented CDAII-like erythroblastic morphological features lacking other diagnostic CDAII markers. Molecular characterization of SEC23B gene, recently described as responsible of CDAII, revealed the presence of Glu109Lys/Arg701Cys and Glu109Lys/Cys66Tyr mutations, respectively. This finding leads to a re-classification of these cases and underlines phenotypic heterogeneity of CDAII, demonstrating for the first time that CDAII may be associated with hydrops foetalis and intrauterine death.
    Blood Cells Molecules and Diseases 04/2010; 45(1):20-2. · 2.26 Impact Factor
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    ABSTRACT: Background / Purpose: We sought to ascertain whether atypical CDAII-like forms presenting as hydrops foetalis could be caused by mutations in SEC23B gene and reclassified as CDAII. Both the investigated patients displayed mutations in SEC23B gene: mutations c.325 G>A/ c.2101 C>T in patient 1 and c.325 G>A/ c.197G>A in patient 2 (Glu109Lys/ Arg701Cys and Glu109Lys/ Cys66Tyr, respectively).Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of disorders characterized by ineffective erythropoiesis. No CDAII cases were previously described associated with hydrops foetalis. In the past we described two cases presenting with hydrops foetalis and very severe anemia that were classified as atypical CDAs since they presented CDAII-like erythroblastic morphological features lacking other diagnostic CDAII markers. Very recently we and others (Bianchi et al. 2009; Schwarz et al. 2009) demonstrated that mutations in SEC23B gene, coding for a protein involved in the coat protein complex responsible for vesicle budding from the endoplasmic reticulum, cause CDA II.Two patients from unrelated families with a history of intrauterine death of hydropic foetuses in previous pregnancies were referred at 20th week gestation following ultrasonic diagnosis of foetal hydrops and severe anemia (2.0 and 1.3 g/dL Hb, respectively). In both cases intrauterine transfusions enabled the delivery of the babies. At birth both of them underwent extensive laboratory evaluation (including red cell metabolism and membrane proteins analysis) that was not informative on the causes of anemia. Ham test was repeatedly normal as for Western blotting analysis for GRP78 and glycosylation pattern of red cell band 3. The bone marrow examination revealed the presence of 30 and 48% of bi- or multinucleated erythroblasts, some of whom presenting typical double outer membranes at transmission electron microscopy. The 20 exons and intronic flanking regions of SEC23B gene were analyzed by direct sequencing. Main conclusion: We report two patients with very severe congenital dyserythropoietic anaemia presenting with hydrops foetalis, previously classified as “atypical” CDAs since they presented CDAII-like erythroblastic morphological features lacking other diagnostic CDAII markers. Molecular characterization of SEC23B gene, recently described as responsible of CDAII, revealed the presence of Glu109Lys/Arg701Cys and Glu109Lys/Cys66Tyr mutations, respectively. This finding leads to a re-classification of these cases and underlines phenotypic heterogeneity of CDAII, demonstrating for the first time that CDAII may be associated with hydrops foetalis and intrauterine death.SEC23B gene analysis allowed the correct classification of two very severe CDA cases associated with hydrops foetalis. This finding indicates that CDAII may result in intrauterine death and its frequency may therefore be underestimated. These cases may present as “atypical” for the lack of band3 hypoglycosylation likely due to the early sequestration of the more severely affected cells.
    51st American Society of Hematology Annual Meeting 2009; 03/2010

Publication Stats

2k Citations
687.35 Total Impact Points

Institutions

  • 2004–2014
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • • Haematology 2
      • • Transfusion and Immunohaematology Centre
      Milano, Lombardy, Italy
  • 2005–2012
    • University of Pavia
      • Department of Biology and Biotechnologies "L. Spallanzani" - interfaculty
      Pavia, Lombardy, Italy
  • 1997–2009
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
    • Ospedale Maggiore di Lodi
      Lodi, Lombardy, Italy
  • 1970–2009
    • University of Milan
      Milano, Lombardy, Italy
  • 2000–2002
    • CILEA Interuniversity Consortium
      Segrate, Lombardy, Italy
  • 1994
    • Azienda Ospedaliera Istituto Ortopedico Gaetano Pini
      Milano, Lombardy, Italy
  • 1976
    • Università degli Studi di Torino
      Torino, Piedmont, Italy