Papers by Elvira Grandone
Blood, 2000
Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic ... more Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic diathesis of variable severity. Although more than 100 families with this disorder have been described, genetic defects have been characterized in few cases. An investigation of a young propositus, offspring of a consanguineous marriage, with undetectable levels of functional and quantitative fibrinogen, was conducted. Sequence analysis of the fibrinogen genes showed a homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the third intervening sequence (IVS) of the γ-chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), c...
Prothrombotic Genetic Risk Factors and the Occurrence of Gestational Hypertension with or without Proteinuria
Thrombosis and Haemostasis, 1999
SummaryGestational hypertension with or without proteinuria is a multi-factorial disease in which... more SummaryGestational hypertension with or without proteinuria is a multi-factorial disease in which the presence of a hypercoagulable state has been suggested. The prothrombin G20210A, the Factor V (FV) Leiden mutations, and the C677T 5-10 methylenetethrahydrofolate reductase (MTHFR) polymorphism were investigated in 140 women with gestational hypertension and in 216 normotensive women from Southern Italy. Nine controls (4.1%) and 16 cases (11.4%; OR: 2.96, 95% CI: 1.27-6.91) carried the prothrombin A20210 allele. FV Leiden mutation was observed in 4 controls (1.8%) and 11 cases (7.9%; OR: 4.53, 95% CI: 1.41-14.53). The TT MTHFR genotype was found in 36 controls (16.6%) and 34 cases (24.4%; OR: 1.61, 95%CI: 0.96-2.74). The impact of potential confounding variables was evaluated using a logistic regression analysis. Nulliparity, Factor V Leiden and prothrombin A20210 carrier status resulted to be independent risk factors of having gestational hypertension with or without proteinuria. I...
Blood transfusion = Trasfusione del sangue, Jan 3, 2015
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific au... more Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about half of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as haematological malignancies, such as chronic lymphocytic leukaemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. Apart from standard immunosuppressive treatments, rituximab has been proven to be effective in AHA. The aim of this review is to provide a systematic description of data available in the literature on this topic. To do so, we performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words "rituximab" and "acquired h(a)emophilia". Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. The review...
BMJ open, Jan 6, 2015
To evaluate in an Italian cohort the incidence of venous thromboembolic events (VTE) in pregnanci... more To evaluate in an Italian cohort the incidence of venous thromboembolic events (VTE) in pregnancies after assisted reproductive technologies (ART). Thrombosis and Haemostasis Unit at I.R.C.C.S. 'Casa Sollievo della Sofferenza', S. Giovanni Rotondo. A prospective cohort of 998 women advised to undergo ART was referred by local fertility clinics from April 2002 to July 2011. Follow-up information was obtained during the check-up and/or by phone interviews. In a cohort of women who consecutively gave birth (n=3339) after spontaneous conception in our Institution, information on the diagnoses of pregnancy-related venous thromboses was obtained by linkage to a patient administrative register. We calculated the incidence of VTE and superficial venous thrombosis in successful ART cycles and compared it with that of the general population conceiving spontaneously. Overall, 684 ART cycles were carried out by 234 women, who achieved a clinical pregnancy; in case of more than one succe...
Thrombosis Research, 2015
In this article, we address issues about thrombotic risk and use of antithrombotic prophylaxis du... more In this article, we address issues about thrombotic risk and use of antithrombotic prophylaxis during assisted reproductive technologies (ART) and during pregnancies after ART. Many aspects of these complications remain not completely understood and data about incidence, pathogenesis, duration and magnitude of the risk, role of thrombophilias and thromboprophylaxis in determining first events and recurrences are lacking. The role of known or possible risk factors and the efficacy of antithrombotic prophylaxis will be discussed.
Fibrinolysis, 1994
BIOVARIABILITY OVER A 24 WEEK PERIOD IN although infrequent relatively large changes were observe... more BIOVARIABILITY OVER A 24 WEEK PERIOD IN although infrequent relatively large changes were observed. For the PLASMINOGEN ACTIVATOR INHIBITOR-l LEVELS group, the Pearson correlation of values from the first week to rmy Macv, EM, Haves. TE, Tracv. RP, Bovill.EG other week (i.e., weeks 2-8) was approximately 0.5, showing that Laboratory for Clinical Biochemistry Research, Vermont Thrombosis there was little time-dependent change. The figure shows means and
Thrombosis Research, 2012
Monovariate analysis-statistically significant variables related with higher recurrence rates: • ... more Monovariate analysis-statistically significant variables related with higher recurrence rates: • Duration of therapy b 6 months (p = 0.030) • Co-existence of thrombophilic mutations (p = 0.008), whereas each factor tested alone didn't show statistical significance. • Co-existence of MTHFR and Leiden (p = 0,031) • Site of first TE: lower limbs, abdomen and PE (p = 0.046)
BMC Medical Genetics, 2014
Background: Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WF... more Background: Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2. The proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor. Our patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the "asymptomatic" optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.
Thrombosis Research, 2009
The term thrombophilia describes an increased tendency to develop thrombosis and many laboratory ... more The term thrombophilia describes an increased tendency to develop thrombosis and many laboratory markers with different strengths of association with thrombosis have been identified. The main causes of maternal mortality and morbidity in developed countries is venous thromboembolism (VTE) and obstetric complications. During pregnancy and puerperium the risk for VTE increases due to hemostatic imbalance towards a prothrombotic state, and it is further increased in women carriers of thrombophilia; recent studies have also demonstrated an association between thrombophilia and obstetric complications. These complications are, therefore, considered potentially preventable with the prophylactic administration of anticoagulant drugs, although their efficacy is not proven by data from randomized controlled trials. After a systematic comprehensive literature review and using a rigorous methodology, the expert panel formulated recommendations regarding the usefulness of screening for thrombophilia in pregnancy to identify high-risk women and for the management of antithrombotic prophyalxis. When evidence is lacking, consensus-based recommendations are provided.
C0307 Baseline characteristics and management of patients with splanchnic vein thrombosis: Results of an international registry
Thrombosis Research, 2012
Thrombosis Research, Volume 130, Issue null, Pages S188-S189, October 2012, Authors:Walter Ageno;... more Thrombosis Research, Volume 130, Issue null, Pages S188-S189, October 2012, Authors:Walter Ageno; Nicoletta Riva; Sam Schulman; Soo-Mee Bang; Maria Teresa Sartori; Elvira Grandone; Jan Beyer; Giovanni Barillari; Dario Di Minno; Rita Duce; Alessandra Malato; Rita Santoro; Daniela Poli; Peter Verhamme; Ida Martinelli; Pieter Kamphuisen; Adriano Alatri; Doyeun Oh; Elbio D\'Amico.
C0322 Factors associated with therapeutic strategies in patients with splanchnic vein thrombosis: Results of an international registry
Thrombosis Research, 2012
Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications
Thrombosis and Haemostasis, 2009
SummaryInherited or acquired thrombophilias have been largely explored as a cause of pregnancy co... more SummaryInherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancyrelated hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls,195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic...
Setting up a 2D-LC/MS/MS method for the rapid quantitation of the prostanoid metabolites 6-oxo-PGF 1α and TXB 2 as markers for hemostasis assessment
Journal of Mass Spectrometry, 2009
6-oxo-PGF(1alpha) and TXB(2) are the metabolites of the prostanglandin PGI(2) and of the thrombox... more 6-oxo-PGF(1alpha) and TXB(2) are the metabolites of the prostanglandin PGI(2) and of the thromboxane TXA(2), respectively. PGI(2) and TXA(2) are arachidonic acid-derived compounds which regulate the blood hemostasis. Their quick metabolism leads to the 6-oxo-PGF(1alpha) and TXB(2) metabolites in plasma. In order to study on a large base the external factors influencing the hemostatic conditions, there is a need for a fast and reliable assay for quantitating these metabolites. Some methods have been published for the analysis of the arachidonic acid-derived compounds and some are dealing with mass spectrometry but nonspecifically centered on these specific compounds with a fast and cheap protocol, amenable for large-scale studies. Here we describe an analytical strategy that incorporates a two-dimensional chromatography running coupled to tandem mass spectrometry that minimizes the sample preparation and addresses the presence of the TXB(2) anomers for a robust quantitation measurement. After a protein precipitation, 100 microl of the supernatant (corresponding to 50 microl of the original plasma) was injected in a two-dimensional chromatographic system which operates an on-line clean-up and a subsequent chromatographic separation of the targeted analytes with a limit of quantitation (LOQ) of 22 pg/ml for 6-oxo-PGF(1alpha), and and a LOQ of 25 pg/ml for TXB(2).
Journal of Hepatology, 2004
Background/Aims: Portal vein thrombosis in patients with liver cirrhosis is usually associated to... more Background/Aims: Portal vein thrombosis in patients with liver cirrhosis is usually associated to hepatocellular carcinoma. Clinical presentation of non-neoplastic portal vein thrombosis (PVT) in cirrhotic patients has not been specifically studied and risk factors of PVT in this group of patients are still poorly understood. Methods: We studied all patients with PVT and liver cirrhosis admitted to our Unit from January 1998 to December 2002. They were paired (by gender, age and Child-Pugh score) to a group of cirrhotic patients without PVT and screened for acquired and inherited thrombophilic risk factors. These factors together with the site of thrombosis and the severity of the liver disease were correlated to the clinical presentation of PVT. Results: Out of a total of 701 cirrhotic patients admitted to our hospital and routinely screened with Doppler ultrasound, 79 (11.2%) were found to have PVT. Of these, 34 (43%) were asymptomatic and 45 (57%) were symptomatic (31 presented with portal hypertensive bleed and 14 with abdominal pain, 10 of whom had intestinal infarction). Mesenteric vein involvement was never asymptomatic and lead to intestinal ischemia or infarction. Most patients were in class Child-Pugh B and C. Among thrombophilic risk factors studied only the mutation 20210 of the prothrombin gene resulted independently associated to PVT. Conclusions: Portal vein thrombosis may be completely asymptomatic in patients with liver cirrhosis; however in more than half of cases presents with life-threatening complications such as gastrointestinal haemorrhage and intestinal infarction. Cirrhotic patients with PVT usually have an advanced liver disease and the presence of the mutation 20210 of the prothrombin gene increases more than fivefold the risk of PVT.
Does Endothelial Nitric Oxide Synthase Gene Variation Play a Role in the Occurrence of Hypertension in Pregnancy?
Hypertension in Pregnancy, 2003
Nitric oxide is suggested to play a role in the development of preeclampsia. We studied 61 patien... more Nitric oxide is suggested to play a role in the development of preeclampsia. We studied 61 patients with gestational hypertension (GH), 77 with GH and significant proteinuria (urine protein excretion > or = 300 mg/24 h), 82 with essential hypertension (EH) and 188 normotensive women with at least one normal pregnancy. A polymorphism within the constitutive endothelial nitric oxide synthase (ecNOS) gene in various types of hypertension in pregnancy was explored. Allelic and genotypic frequencies did not differ between controls and case groups. A significant difference was observed between the frequency of the rare allele in GH patients and that in EH group (chi2: 4.47, P <.04). This difference approximated the significance when GH subjects with or without proteinuria were grouped (chi2 square: 3.33; P =.068). Cigarette smoking or gravidity did not interact with the ecNOS polymorphism in identifying different types of hypertension in this setting. Our findings argue against an association between ecNOS polymorphism and preeclampsia and support the hypothesis for a different pathogenesis of GH in respect to EH.
Fertility and Sterility, 2004
Fertility and Sterility, 2006
Discrepancies about a possible relationship between prothrombotic mutations and a decreased utero... more Discrepancies about a possible relationship between prothrombotic mutations and a decreased uteroplacental blood flow are present in literature. We prospectively evaluated a cohort of pregnant women (n ϭ 41) with bilateral uterine artery notches and found that women with inherited thrombophilia showed a sixfold higher risk to have an adverse outcome than women without. (Fertil Steril 2006;86:726 -7.
A Platelet Defect Modulates Bleeding in Mild Hemophilia: The Tale of 2 Brothers
Clinical and Applied Thrombosis/Hemostasis, 2009
To the Editor: One open issue in the field of hemophilia is the detection of factors influencing ... more To the Editor: One open issue in the field of hemophilia is the detection of factors influencing the clinical phenotype of the disease. Bleeding tendency in severely affected hemophiliac patients has a dramatic impact on life quality and is the basic parameter to determine mode, dose, and frequency of substitution therapy. In severe hemophiliacs, considerable variation in the frequency and the extent of bleeding is described with consequent large heterogeneity in the rate of musculoskeletal damage. In particular, about 10% of severe hemophiliacs bleed rarely and prophylaxis is not required in such patients. Several factors have been evoked as bleeding modulators in severely affected patients, such as the main thrombophilias, the fibrinolytic activity as well as the levels and the kinetics of other coagulation cascade proteins. Results of such studies are conflicting and have been found to account only for a part of the clinical heterogeneity in severe hemophilia. Less observations exist in both moderate and mild hemophilia. Given the generally acknowledged correlation between severity of the disease and levels of circulating factor VIII (FVIII), mild-to-moderate hemophiliacs present with a variegate clinical picture and worsening in the bleeding tendency are suggestive of inhibitor appearance, which is, in nonsevere hemophilia, still a grey area to explore. In addition, the role of platelets as modifiers of bleeding in hemophiliacs has poorly been considered. An interesting report, though, concerns enhanced bleeding following the intake of herbal moieties disturbing platelet function in hemophiliacs with a low bleeding rate. Primary hemostasis impairment was also suspected to worsen the bleeding pattern in HIV-positive hemophiliacs taking HIV protease inhibitors-based antiretroviral therapy, a finding that has recently been confirmed with platelet aggregation studies performed in nonhemophiliac HIV affected patients. Since our Haemophilia Centre is active in 2005, we have cared for 2 mild hemophiliac brothers (14 and 24 years old, respectively) who were genetically characterized to carry the mutation c.1700 T>C, Ile548Thr in the exon 11 of the FVIII gene, a common mutation in patients with mild hemophilia A. FVIII:C assay was 43% and 37%, respectively. Personal hemorrhagic history was significantly different in the 2 siblings: while the older brother had only 1 bleeding episode all along his life after surgery for a chronic sinusitis, the younger brother frequently referred to our Centre for spontaneous and posttraumatic skeletal muscle bleedings and hemarthroses, the right iliopsoas being the most frequent skeletal muscle location and the left knee the target joint. Annual bleeding rate in this patient was about 6 to 10 bleeding episodes per year. Despite a good laboratory response to desmopressin, which was also From the Centro Emofilia e Trombosi, Università De L’Aquila, Italy (ML, MN, GM); Servizio di Genetica Medica Università degli Studi di Foggia, Italy (RS, VB, VL, MM); and Unità di Aterosclerosi e Trombosi Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy (GF, EG).
Biomedicine & Pharmacotherapy, 1993
In western countries, acute myocardial infarction is the commonest cause of morbidity and mortali... more In western countries, acute myocardial infarction is the commonest cause of morbidity and mortality [19]. An occlusive coronary thrombus on an ulcerated atherosclerotic plaque in the coronary arteries is the etiological event in more than 90% of patients with Q-wave myocardial infarction [38]. The underlying abnormality in non-Q-wave myocardial infarction is often a ruptured atherosclerotic plaque, which acts as a nidus for the deposition and activation of platelets. In this case, thrombosis occurs, but may not be totally occlusive, or an early spontaneous recanalization may occur. On the other hand, some clinical trials showed that a prolonged treatment with antiplatelet drugs significantly reduces the recurrence of coronary ischemia. Thus, atherosclerosis is a necessary condition for myocardial infarction, but it is not sufficient in that it usually needs the occurrence of thrombosis. However, only 2530% of these thrombotic events are prevented by the administration of antiplatelets drugs. In recent years, epidemiological studies identified some hemostatic parameters whose abnormalities may help predict the risk of ischemic events: fibrinogen [14]. plasminogen activator inhibitor-l (PAI-1) [3], lipoprotein(a) [46], anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) [IO], leukocyte count [34], blood viscosity [34]. Some of these, such as fibronogen and PAI-I are acute-phase proteins. It is known that personal conditions or environmental factors, such as excess weight, diabetes mellitus, arterial hypertension, cigarette smoking etc, are associated with a high risk of atherosclerosis and myocardial infarction [29] and are known to affect plasma levels of some acute-phase proteins. Thus, the question is whether these hemostatic variables may help predict thrombosis in individuals. Furthermore, in addition to personal and environmental factors, genetic variations can affect plasma levels of some of these variables. Thus, an additional question is to establish the extent to which abnormalities of these variables is just the epiphenomenon of as yet unknown events in atherosclerosis.
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Papers by Elvira Grandone