P Noris

Policlinico San Matteo Pavia Fondazione IRCCS, Ticinum, Lombardy, Italy

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Publications (97)527.37 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and non syndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found ten (eight novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies we demonstrated that all but one amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk of bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.
    Blood 10/2014; · 9.78 Impact Factor
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    ABSTRACT: Abnormalities of platelet size are considered one of the distinguishing features of inherited thrombocytopenias (ITs) and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know on this matter mainly derives from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all the 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in distribution width of platelet diameters and the percentage of platelets with increased or reduced diameters. Based on these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cut-off values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.
    Blood 07/2014; · 9.78 Impact Factor
  • Patrizia Noris, Carlo L Balduini
    Blood 06/2014; 123(26):4014. · 9.78 Impact Factor
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    ABSTRACT: Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data was gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%) or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.
    Human Mutation 06/2014; · 5.21 Impact Factor
  • Carlo L Balduini, Patrizia Noris
    Haematologica 06/2014; 99(6):953-955. · 5.94 Impact Factor
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    ABSTRACT: Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy, and the course of pregnancy was not different from that of healthy subjects in terms of miscarriages, fetal bleeding and preterm births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but two of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8 to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of risk of abnormal blood loss was increased with respect to the general population. However, no mother died or received hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery lower than 50 x 10(9)/L.
    Haematologica 04/2014; · 5.94 Impact Factor
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    ABSTRACT: Point mutations in the 5' UTR of ankyrin repeat domain 26 (ANKRD26) are associated with familial thrombocytopenia 2 (THC2) and a predisposition to leukemia. Here, we identified underlying mechanisms of ANKRD26-associated thrombocytopenia. Using megakaryocytes (MK) isolated from THC2 patients and healthy subjects, we demonstrated that THC2-associated mutations in the 5' UTR of ANKRD26 resulted in loss of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 transcription factor (FLI1) binding. RUNX1 and FLI1 binding at the 5' UTR from healthy subjects led to ANKRD26 silencing during the late stages of megakaryopoiesis and blood platelet development. We showed that persistent ANKRD26 expression in isolated MKs increased signaling via the thrombopoietin/myeloproliferative leukemia virus oncogene (MPL) pathway and impaired proplatelet formation by MKs. Importantly, we demonstrated that ERK inhibition completely rescued the in vitro proplatelet formation defect. Our data identify a mechanism for development of the familial thrombocytopenia THC2 that is related to abnormal MAPK signaling.
    The Journal of clinical investigation 01/2014; · 15.39 Impact Factor
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    ABSTRACT: MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with non-congenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the non-congenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N and C-terminal deletions had low risk of non-congenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD. This article is protected by copyright. All rights reserved.
    Human Mutation 11/2013; · 5.21 Impact Factor
  • Blood 09/2013; 122(11):1987-9. · 9.78 Impact Factor
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    Carlo L Balduini, Patrizia Noris
    British Journal of Haematology 08/2013; · 4.94 Impact Factor
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    ABSTRACT: The most frequent forms of inherited thrombocytopenia (IT) are characterized by platelet size abnormalities and it has been suggested that this parameter is useful for their differentiation from immune thrombocytopenia (ITP). Recently, a monocentric study identified cut-off values for mean platelet volume (MPV) and mean platelet diameter (MPD) with good diagnostic accuracy in this respect. To validate these cut-off values in a different and larger case series of patients, we enrolled 130 subjects with ITP and 113 with IT in six different centres. The platelet count and MPV was each measured by the instrument routinely used in each institution. In some centres, platelet count was also measured by optical microscopy. MPD was evaluated centrally by image analysis of peripheral blood films. The previously identified cut-off value for MPV had 91% specificity in distinguishing ITP from inherited macrothrombocytopenias (mono and biallelic Bernard-Soulier, MYH9-related disease), while its sensitivity was greatly variable depending on the instrument used. With an appropriate instrument, specificity was 83%. The diagnostic accuracy of MPD was lower than that obtained with MPV. We concluded that MPV is a useful parameter for differentiating ITP from IT provided that it is measured by appropriate cell counters.
    British Journal of Haematology 07/2013; 162(1). · 4.94 Impact Factor
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    ABSTRACT: The number of recognized causes of inherited thrombocytopenias has grown in the past 10 years and there are now more than 18 thrombocytopenic disorders with characterized genetic mutations. Moreover, the pathogenic mechanisms of many forms of inherited thrombocytopenia have been identified and prognosis of different disorders, ranging from unfavorable to very good, has been defined. In addition, for some inherited thrombocytopenias, therapies are now available to improve both survival and quality of life for persons with these conditions. Therefore, it is important to recognize when a low platelet count reflects an inherited disorder, and establish a correct diagnosis; however, this remains a challenge because documented evidences about these diseases are scarce. In this review, we address how to diagnose inherited thrombocytopenia, how to differentiate these conditions from immune thrombocytopenia, present a new and simple diagnostic algorithm, and discuss the different therapeutic options. We also emphasize that further research on these disorders is needed, as about half of patients with inherited thrombocytopenias have a disease that is not yet characterized.
    Seminars in Thrombosis and Hemostasis 02/2013; · 4.22 Impact Factor
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    ABSTRACT: ANKRD26-related thrombocytopenia (ANKRD26-RT) is an autosomal-dominant thrombocytopenia caused by mutations in the 5'UTR of the ANKRD26 gene. ANKRD26-RT is characterised by dysmegakaryopoiesis and an increased risk of leukaemia. PaCSs are novel particulate cytoplasmic structures with selective immunoreactivity for polyubiquitinated proteins and proteasome that have been detected in a number of solid cancers, in the epithelia of Helicobacter pylori gastritis and related preneoplastic lesions, and in the neutrophils of Schwachman-Diamond syndrome, a genetic disease with neutropenia and increased leukaemia risk. We searched for PaCSs in blood cells from 14 consecutive patients with ANKRD26-RT. Electron microscopy combined with immunogold staining for polyubiquitinated proteins, 20S and 19S proteasome showed PaCSs in most ANKRD26-RT platelets, as in a restricted minority of platelets from healthy controls and from subjects with other inherited or immune thrombocytopenias. In ANKRD26-RT platelets, the PaCS amount exceeded that of control platelets by a factor of 5 (p<0.0001). Immunoblotting showed that the higher PaCS number was associated with increased amounts of polyubiquitinated proteins and proteasome in ANKRD26-RT platelets. PaCSs were also extensively represented in ANKRD26-RT megakaryocytes, but not in healthy control megakaryocytes, and were absent in other ANKRD26-RT and control blood cells. Therefore, large amounts of PaCSs are a characteristic feature of ANKRD26-RT platelets and megakaryocytes, although these novel cell components are also present in a small subpopulation of normal platelets. The widespread presence of PaCSs in inherited diseases with increased leukaemia risk, as well as in solid neoplasms and their preneoplastic lesions, suggests a link of these structures with oncogenesis.
    Thrombosis and Haemostasis 12/2012; 109(2). · 5.76 Impact Factor
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    ABSTRACT: MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.
    European journal of medical genetics 10/2012; · 1.57 Impact Factor
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    ABSTRACT: Background. The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of α-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. Design and Methods. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α- granule secretory proteins. Results. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Conclusions. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
    Haematologica 10/2012; · 5.94 Impact Factor
  • C L Balduini, A Pecci, P Noris
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    ABSTRACT: The chapter of inherited thrombocytopenias has expanded greatly over the last decade and many "new" forms deriving from mutations in "new" genes have been identified. Nevertheless, nearly half of patients remain without a definite diagnosis because their illnesses have not yet been described. The diagnostic approach to these diseases can still take advantage of the algorithm proposed by the Italian Platelet Study Group in 2003, although an update is required to include the recently described disorders. So far, transfusions of platelet concentrates have represented the main tool for preventing or treating bleedings, while haematopoietic stem cell transplantation has been reserved for patients with very severe forms. However, recent disclosure that an oral thrombopoietin mimetic is effective in increasing platelet count in patients with MYH9 -related thrombocytopenia opened new therapeutic perspectives. This review summarizes the general aspects of inherited thrombocytopenias and describes in more detail MYH9 -related diseases (encompassing four thrombocytopenias previously recognized as separate diseases) and the recently described ANKRD26 -related thrombocytopenia, which are among the most frequent forms of inherited thrombocytopenia.
    Hamostaseologie 09/2012; 32(4). · 1.59 Impact Factor
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    ABSTRACT: Background: Renal impairment is common affecting around 40% of acutely ill medical patients and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage. Objective: To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment. Patients/Methods: We carried out a multicenter, investigator-initiated, prospective cohort study. Patients at risk for VTE with a creatinine clearance between 20 and 50 mL/min were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. Primary outcome was the incidence of major bleeding, secondary outcomes were clinically relevant non-major bleeding (CRNMB) and symptomatic VTE. Results: We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL/min, and a mean Charlson co-morbidity index of 8.2. One patient had major bleeding (0.49%, 95% CI 0.03-3.10), 8 had CRNMB (3.88%, 95% CI 1.81-7.78), and 3 developed symptomatic VTE (1.46%, 0.38-4.55). Twenty-three patients (11.17%, 7.36-16.48) died. No independent predictors of bleeding were found at univariate analysis. Conclusions: The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk for both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients. © 2012 International Society on Thrombosis and Haemostasis.
    Journal of Thrombosis and Haemostasis 08/2012; · 6.08 Impact Factor
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    ABSTRACT: The thrombocytopenia of the Paris-Trousseau (TCPT) type is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), abnormal giant alpha-granules in platelets and dysmegakaryopoiesis: it derives from a constitutional deletion of chromosome 11 leading to the loss of FLI1, a transcription factor involved in megakaryocyte differentiation and maturation. A women with an acquired, isolated THC developing over 10 yr showed morphological features typical of TCPT in platelets and bone marrow (BM). Twenty years after the onset of THC, the other hematological parameters are still normal and the patient is well. Clonal hemopoiesis was shown and chromosome analyses performed on BM revealed a clone with 45 chromosomes and a complex unbalanced translocation involving chromosomes 2, 3, and 11. The anomaly was present in the majority of bone marrow cells but only in a few peripheral blood elements. A microarray-based comparative genomic hybridization defined the deleted region of chromosome 11 including the FLI1 locus that was missing. Although our patient presented with nearly all the characteristics of TCPT, her illness was acquired instead of being inherited and the most appropriate diagnosis is that of the unilineage dysplasia 'refractory THC.' This observation suggests that appropriate cytogenetic investigations should be always considered in patients with acquired THC of unknown origin.
    European Journal Of Haematology 07/2012; 89(4):345-9. · 2.55 Impact Factor
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    ABSTRACT:   Inherited thrombocytopenias (ITs) are heterogeneous genetic disorders that frequently represent a diagnostic challenge. The requirement of highly specialized tests for diagnosis represents a particular problem in resource-limited settings. To overcome this difficulty, we applied a diagnostic algorithm and developed a collaboration program with a specialized international center in order to increase the diagnostic yield in a cohort of patients in Argentina. Based on the algorithm, initial evaluation included collection of clinical data, platelet size, blood smear examination and platelet aggregation tests. Confirmatory tests were performed according to diagnostic suspicion, which included platelet glycoprotein expression, immunofluorescence for myosin-9 in granulocytes and platelet thrombospondin-1 and molecular screening of candidate genes. Thirty-one patients from 14 pedigrees were included; their median age was 32 (4-72) years and platelet count 72 (4-147)×10(9) L(-1). Autosomal dominant inheritance was found in nine (64%) pedigrees; 10 (71%) had large platelets and nine (29%) patients presented with syndromic forms. A definitive diagnosis was made in 10 of 14 pedigrees and comprised MYH9-related disease in four, while classic and monoallelic Bernard-Soulier syndrome, gray platelet syndrome, X-linked thrombocytopenia, thrombocytopenia 2 (ANKRD26 mutation) and familial platelet disorder with predisposition to acute myelogenous leukemia were diagnosed in one pedigree each. Adoption of an established diagnostic algorithm and collaboration with an expert referral center proved useful for diagnosis of IT patients in the setting of a developing country. This initiative may serve as a model to develop international networks with the goal of improving diagnosis and care of patients with these rare diseases.
    Journal of Thrombosis and Haemostasis 06/2012; 10(8):1653-61. · 6.08 Impact Factor
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    ABSTRACT: MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance. Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0%) an increase of GGT. The increases ranged from 1.9 ± 0.7 to 2.7 ± 1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95% CIs 2.2-44.8) to 24.7 (14.8-40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency. Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value.
    PLoS ONE 01/2012; 7(4):e35986. · 3.53 Impact Factor

Publication Stats

2k Citations
527.37 Total Impact Points


  • 1991–2014
    • Policlinico San Matteo Pavia Fondazione IRCCS
      Ticinum, Lombardy, Italy
  • 2012–2013
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
  • 1988–2013
    • University of Pavia
      • • Centre of Excellence for Applied Biology
      • • Department of Internal Medicine and Therapeutics
      Pavia, Lombardy, Italy
  • 2007–2012
    • Università degli Studi di Trieste
      Trst, Friuli Venezia Giulia, Italy
  • 2011
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2009
    • Università degli Studi di Perugia
      • Department of Internal Medicine
      Perugia, Umbria, Italy
  • 2006
    • Azienda Ospedaliera di Rilievo Nazionale Santobono Pausilipon
      Napoli, Campania, Italy
  • 2003
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
    • National Institute of Molecular Genetics (INGM)
      Milano, Lombardy, Italy