Publications by authors named "Erica De Candia"

37 Publications

Direct oral anticoagulants and therapeutic adherence: do not let your guard down.

Acta Cardiol 2021 Apr 26:1-7. Epub 2021 Apr 26.

Department of Diagnostic Imaging, Radiotherapy, Oncology and Haematology, Hemorrhagic and Thrombotic Diseases Center, Foundation "A. Gemelli" IRCCS University Hospital, Rome, Italy.

Background: Direct oral anticoagulants (DOAC) and vitamin K antagonist drugs (VKA) are recommended for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism. Undoubtedly, DOAC have contributed to improve quality of life of these patients, but unfortunately, available 'real world' data show a very high variable compliance to DOAC.

Aims And Objectives: to evaluate predictors that adversely affect therapeutic adherence in patients naive to DOAC.

Methods And Population: this study was conducted on an outpatient population in oral anticoagulant therapy in a period between January 2019 and February 2020. Patients naiveto DOAC and treated for at least 6 months were enrolled. Non-Italian-speaking patients, cognitive or psychiatric disorders, refusal to participate or non-consent to the interview were exclusion criteria. A socio-demographic scale and the 8-item Morisky scale (MMAS-8) questionnaire assessed therapeutic adherence.

Results: One hundred two DOAC-naïve patients were selected from a population of 407 patients on the first visit at our centre. The population was homogeneously represented for gender (males 48%). The mean age was 79.5 years. Atrial fibrillation (65.7%) resulted the main reason for DOAC prescription and a polypharmacy was detected in 47.1% of the patients. Moreover, an optimal adherence to DOAC therapy was assessed in less than 30% of patients.

Conclusions: Polypharmacy, patient's isolation, such as a low education level were statistically associated with a low therapeutic adherence. Therapeutic adherence remains an unsolved problem for anticoagulated patient. To identify patients at higher risk of poor compliance and therapeutic failure and establish targeted care pathways is a priority.
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http://dx.doi.org/10.1080/00015385.2021.1908702DOI Listing
April 2021

The ISTH bleeding assessment tool as predictor of bleeding events in inherited platelet disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology.

J Thromb Haemost 2021 May;19(5):1364-1371

Department of Internal Medicine, IRCCS Policlinico S. Matteo Foundation, University of Pavia, Pavia, Italy.

Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study).

Objectives: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients.

Methods: Patients with IPD, type 1 VWD (VWD-1) and age- and sex-matched healthy controls enrolled in the BAT-VAL study were prospectively followed-up for 2 years and bleeding episodes requiring treatment were recorded.

Results: Of the 1098 subjects initially enrolled, 955 were followed-up and 124 suffered hemorrhages during follow-up, 60% of whom had inherited platelet function disorders (IPFD). Total number of events was significantly higher in IPFD (n = 235) than VWD-1 (n = 52) or inherited thrombocytopenia (IT; n = 20). Events requiring transfusions were 66% in IPFD, 5.7% in VWD-1, and 3% in IT. Baseline BS was significantly higher in IPFD patients with a bleeding event at follow-up than in those without (p < .01) and the percentage of subjects suffering a bleeding event increased proportionally to baseline BS quartile. A significant association between the BS and the chance of suffering severe bleeding was found in the overall, IPFD, and VWD-1 populations. Similar results were obtained for the pediatric population.

Conclusions: Inherited platelet function disorder patients with high BS at enrollment are more likely to suffer from bleeding events requiring treatment at follow-up. Moreover, the higher the baseline BS quartile the greater the incidence of subsequent events, suggesting that independently from diagnosis a high BS is associated with a greater risk of subsequent hemorrhage.
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http://dx.doi.org/10.1111/jth.15263DOI Listing
May 2021

Heparin induced thrombocytopenia: position paper from the Italian Society on Thrombosis and Haemostasis (SISET).

Blood Transfus 2021 Jan 28;19(1):14-23. Epub 2020 Dec 28.

IRCCS "Ca' Granda Maggiore" Hospital Foundation, "Angelo Bianchi Bonomi" Haemophilia and Thrombosis Center and "Fondazione Luigi Villa", Milan, Italy.

Heparin induced thrombocytopenia (HIT) is a rare immune mediated adverse drug reaction occurring after exposure to heparin. It is a serious and potentially fatal condition, which may be associated with the development of arterial or venous thrombotic events. Although known for many years, HIT is still often misdiagnosed. Pre- test clinical probability, screening for anti-PF4/heparin antibodies and documentation of their platelet activating capacity are the cornerstones of diagnosis. However, both clinical algorithms and test modalities have limited predictive values and limited diffusion so that the diagnosis and management is challenging in the clinical practice. For this reason, there is an unmet need for novel rational non-anticoagulant therapies based on the pathogenesis of HIT.The present paper reports the position of the Italian Society on Haemostasis and Thrombosis (SISET) in order to increase awareness of HIT among clinicians and other health care professionals and to provide information on the most appropriate management.
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http://dx.doi.org/10.2450/2020.0248-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850929PMC
January 2021

Nonalcoholic fatty liver disease (NAFLD) severity is associated to a nonhemostatic contribution and proinflammatory phenotype of platelets.

Transl Res 2021 May 7;231:24-38. Epub 2020 Nov 7.

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, Roma, Italy; UOSD Malattie Emorragiche e Trombotiche, Dipartimento di Diagnostica per immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation.
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http://dx.doi.org/10.1016/j.trsl.2020.11.003DOI Listing
May 2021

Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D'D3 and D4 domains.

Blood Adv 2020 07;4(14):3405-3415

Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia Agostino Gemelli, Università Cattolica S. Cuore, Rome, Italy.

We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G>A and (2) c.6532G>T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D'D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient's daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C>T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q/2178S promote conformational transitions in the VWF molecule, causing a type 2B-like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.
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http://dx.doi.org/10.1182/bloodadvances.2020002334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391138PMC
July 2020

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome.

Blood 2020 10;136(17):1956-1967

Service d'Hématologie Biologique, Hospices Civils de Lyon, Lyon, France.

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.
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http://dx.doi.org/10.1182/blood.2019004776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582559PMC
October 2020

COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET).

Blood Transfus 2020 May 8;18(3):167-169. Epub 2020 Apr 8.

IRCCS "Ca' Granda Maggiore" Hospital Foundation, "Angelo Bianchi Bonomi" Haemophilia and Thrombosis Center and "Fondazione Luigi Villa", Milan, Italy.

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http://dx.doi.org/10.2450/2020.0083-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250682PMC
May 2020

Hemophilia A and von Willebrand deficiency: therapeutic implications.

Blood Coagul Fibrinolysis 2020 09;31(6):397-401

Servizio di Malattie Emorragiche e Trombotiche, Area di Ematologia.

: Hemophilia A is an X-linked bleeding disorder caused by a deficiency of factor VIII. Depending on the factor VIII activity in patient's plasma, we can have three different forms of hemophilia A: mild (5-40 IU/dl), moderate (1-5 IU/dl) and severe (<1 IU/dl). The most common symptoms include recurrent bleeding episodes of soft tissues and joints. The treatment is based on the prophylactic use of clotting factor concentrates to prevent bleeding episodes. We describe three cases of patients with initially diagnosis of hemophilia A that show different clinical severity, undergoing prophylactic therapies with low benefit. In these patients, the dosage of von Willebrand antigen revealed either low level or absence of this factor, which in one case was caused by the occurrence of a type III form of von Willebrand disease.
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http://dx.doi.org/10.1097/MBC.0000000000000908DOI Listing
September 2020

Data on the application of early coagulation support protocol in the management of major trauma patients.

Data Brief 2019 Dec 7;27:104768. Epub 2019 Nov 7.

UOSD Shock e Trauma, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.

This article provides additional data on the application of early coagulation support protocol in the management of major trauma patients. Data come from a retrospective analysis reported in the article "Early coagulation support protocol: a valid approach in real-life management of major trauma patients. Results from two Italian centres" [1]. Data contain information about the relationship between differences in resource use and mortality outcomes, and patient demographic and clinical features at presentation. Furthermore, a comparison between resource consumption, the probability of multiple transfusions and the mortality outcomes among propensity-score matched patients is reported.
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http://dx.doi.org/10.1016/j.dib.2019.104768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861613PMC
December 2019

Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC.

J Thromb Haemost 2020 03 16;18(3):732-739. Epub 2019 Dec 16.

Department of Internal Medicine, IRCCS Policlinico S. Matteo Foundation, University of Pavia, Pavia, Italy.

Background: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups.

Objectives: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC).

Patients/methods: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries.

Results: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD-1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC.

Conclusions: The ISTH-BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD-1. Therefore, the ISTH-BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.
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http://dx.doi.org/10.1111/jth.14683DOI Listing
March 2020

Early coagulation support protocol: A valid approach in real-life management of major trauma patients. Results from two Italian centres.

Injury 2019 Oct;50(10):1671-1677

UOSD Shock e Trauma, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.

Introduction: Early coagulation support (ECS) includes prompt infusion of tranexamic acid, fibrinogen concentrate, and packed red blood cells for initial resuscitation of major trauma patients. The aim of this study was to determine the effects, in terms of blood product consumption, length of stay, and in-hospital mortality, of the ECS protocol, compared to the massive transfusion protocol (MTP) in the treatment of major trauma patients.

Patients And Methods: A retrospective analysis was conducted using the registry data of two Italian trauma centres. Adult major trauma patients with, or at risk of, active bleeding who were managed according to the MTP during the years 2011-2012, or the ECS protocol during the years 2013-2014 and were considered at risk of multiple transfusions, were enrolled. The primary endpoint was to determine whether the ECS protocol reduces the use of blood products in the acute management of trauma patients. Secondary endpoints were the outcome measures of length of stay in ICU, length of stay in hospital, and mortality at 24-hours and 28-days after hospital admission.

Results: Among the 518 major trauma patients admitted to the trauma centres during the study period, 235 patients (118 in the pre-ECS period and 117 in the ECS period) matched one of the inclusion criteria and were enrolled in the study. Compared with the pre-ECS period, the ECS period showed a reduction in the average consumption of packed red blood cells (-1.87 units, 95% confidence interval [CI], -2.40, -1.34), platelets (-1.28 units; 95% CI, -1.64, -0.91), and fresh frozen plasma (-1.69; 95% CI, -2.14, -1.25) in the first 24-hours. Furthermore, during the ECS period, we recorded a 10-day reduction in the hospital length of stay (-10 days, 95% CI, -11.6, -8.4) and a non-significant 28-day mortality increase.

Conclusions: The ECS protocol was effective in reducing blood product consumption compared to the MTP and confirmed the importance of early fibrinogen administration as a strategy of rapid coagulation. This novel approach may be adopted in real-life management of major trauma patients.
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http://dx.doi.org/10.1016/j.injury.2019.09.032DOI Listing
October 2019

Antithrombotic prophylaxis for surgery-associated venous thromboembolism risk in patients with inherited platelet disorders. The SPATA-DVT Study.

Haematologica 2020 07 26;105(7):1948-1956. Epub 2019 Sep 26.

Department of Transfusion and Cell Transplantation Kitasato University School of Medicine, Sagamihara, Japan.

Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery.
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http://dx.doi.org/10.3324/haematol.2019.227876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327644PMC
July 2020

Eltrombopag for the treatment of inherited thrombocytopenias: a phase II clinical trial.

Haematologica 2020 03 4;105(3):820-828. Epub 2019 Jul 4.

Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia

Patients with inherited thrombocytopenias often require platelet transfusions to raise their platelet count before surgery or other invasive procedures; moreover, subjects with clinically significant spontaneous bleeding may benefit from an enduring improvement of thrombocytopenia. The hypothesis that thrombopoietin-mimetics can increase platelet count in inherited thrombocytopenias is appealing, but evidence is scarce. We conducted a prospective, phase II clinical trial to investigate the efficacy of the oral thrombopoietin-mimetic eltrombopag in different forms of inherited thrombocytopenia. We enrolled 24 patients affected by -related disease, -related thrombocytopenia, X-linked thrombocytopenia/ Wiskott-Aldrich syndrome, monoallelic Bernard-Soulier syndrome, or -related thrombocytopenia. The average pre-treatment platelet count was 40.4 ×10/L. Patients received a 3- to 6-week course of eltrombopag in a dose-escalated manner. Of 23 patients evaluable for response, 11 (47.8%) achieved a major response (platelet count >100 ×10/L), ten (43.5%) had a minor response (platelet count at least twice the baseline value), and two patients (8.7%) did not respond. The average increase of platelet count compared to baseline was 64.5 ×10/L (<0.001). Four patients with clinically significant spontaneous bleeding entered a program of long-term eltrombopag administration (16 additional weeks): all of them obtained remission of mucosal hemorrhages, with the remission persisting throughout the treatment period. Treatment was globally well tolerated: five patients reported mild adverse events and one patient a moderate adverse event. In conclusion, eltrombopag was safe and effective in increasing platelet count and reducing bleeding symptoms in different forms of inherited thrombocytopenia. Despite these encouraging results, caution is recommended when using thrombopoietinmimetics in inherited thrombocytopenias predisposing to leukemia. ClinicalTrials.gov identifier: NCT02422394.
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http://dx.doi.org/10.3324/haematol.2019.223966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049343PMC
March 2020

Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing.

Blood Adv 2019 06;3(11):1702-1713

INSERM U970, Paris Cardiovascular Research Centre, Paris, France.

The bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by deletion selectively in MKs. Moreover, S1P expression and signaling were both undetectable in mature MKs in situ, and MK deletion did not affect platelet aggregation or spreading. When deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted deletion and was reversed by compound deletion of either or , suggesting that this phenotype arises from increased S1P export and S1P activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P, and can further suppress thrombopoiesis through S1P when aberrantly secreted in the hematopoietic niche.
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http://dx.doi.org/10.1182/bloodadvances.2019031948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560353PMC
June 2019

Carbamazepine interaction with direct oral anticoagulants: help from the laboratory for the personalized management of oral anticoagulant therapy.

J Thromb Thrombolysis 2019 Oct;48(3):528-531

Unità Operativa Malattie Emorragiche e Trombotiche, Area di Ematologia, Fondazione Policlinico Universitario "Agostino Gemelli", IRCCS, Rome, Italy.

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants (DOACs) and antiepileptic drugs due to drug-drug interactions leading to potential risk of DOACs subtherapeutic concentration and treatment failure. Herein we report a significant interaction between carbamazepine (CZP) and apixaban, causing subtherapeutic concentration of the drug in a patient with atrial fibrillation who had a transient ischemic attack (TIA) episode. Another anti-Xa DOAC, edoxaban, administered to the patient after TIA occurrence did not show significant interaction with CZP. In addition to confirm that cautions should be used when antiepileptic and DOACs are concomitantly prescribed, the present case also demonstrates that, in the management of certain subsets of patients who need anticoagulant treatment, measurement of DOAC plasma concentration can help guide a personalized management and avoid adverse clinical outcomes.
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http://dx.doi.org/10.1007/s11239-019-01866-1DOI Listing
October 2019

Ibrutinib does not affect ristocetin-induced platelet aggregation evaluated by light transmission aggregometry in chronic lymphocytic leukemia patients.

Haematologica 2018 03 14;103(3):e119-e122. Epub 2017 Dec 14.

Servizio Malattie Emorragiche e Trombotiche, Polo Oncologia ed Ematologia, Istituto di Medicina Interna, Rome, Italy

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http://dx.doi.org/10.3324/haematol.2017.179044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830396PMC
March 2018

Bleeding risk of surgery and its prevention in patients with inherited platelet disorders.

Haematologica 2017 07 6;102(7):1192-1203. Epub 2017 Apr 6.

Hematology Department, S. Bortolo Hospital, Vicenza, Italy.

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.
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http://dx.doi.org/10.3324/haematol.2016.160754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566025PMC
July 2017

Portal vein thrombosis occurrence in a cirrhotic patient during treatment with rivaroxaban.

Liver Int 2017 08 30;37(8):1251. Epub 2017 Mar 30.

Internal Medicine, Gastroenterology and Hepatology, Agostino Gemelli Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/liv.13406DOI Listing
August 2017

NETosis in arterial and venous thrombosis: a one size fits all mechanism?

Authors:
Erica De Candia

Intern Emerg Med 2017 Feb 9;12(1):9-11. Epub 2017 Jan 9.

Servizio Malattie Emorragiche e Trombotiche, Area di Ematologia, Fondazione Policlinico Agostino Gemelli, Istituto di Medicina Interna, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy.

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http://dx.doi.org/10.1007/s11739-016-1600-xDOI Listing
February 2017

Abnormal proplatelet formation and emperipolesis in cultured human megakaryocytes from gray platelet syndrome patients.

Sci Rep 2016 Mar 18;6:23213. Epub 2016 Mar 18.

Department of Internal Medicine, Policlinico Agostino Gemelli, Catholic University, Rome, Italy.

The Gray Platelet Syndrome (GPS) is a rare inherited bleeding disorder characterized by deficiency of platelet α-granules, macrothrombocytopenia and marrow fibrosis. The autosomal recessive form of GPS is linked to loss of function mutations in NBEAL2, which is predicted to regulate granule trafficking in megakaryocytes, the platelet progenitors. We report the first analysis of cultured megakaryocytes from GPS patients with NBEAL2 mutations. Megakaryocytes cultured from peripheral blood or bone marrow hematopoietic progenitor cells from four patients were used to investigate megakaryopoiesis, megakaryocyte morphology and platelet formation. In vitro differentiation of megakaryocytes was normal, whereas we observed deficiency of megakaryocyte α-granule proteins and emperipolesis. Importantly, we first demonstrated that platelet formation by GPS megakaryocytes was severely affected, a defect which might be the major cause of thrombocytopenia in patients. These results demonstrate that cultured megakaryocytes from GPS patients provide a valuable model to understand the pathogenesis of GPS in humans.
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http://dx.doi.org/10.1038/srep23213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796794PMC
March 2016

Impact of Gut Microbiota on Obesity, Diabetes, and Cardiovascular Disease Risk.

Curr Cardiol Rep 2015 Dec;17(12):120

Institute of Internal Medicine, Policlinico Gemelli Hospital, Catholic University of Sacred Heart of Rome, Rome, Italy.

Gut microbiota has been recently established to have a contributory role in the development of cardiometabolic disorders, such as atherosclerosis, obesity, and type 2 diabetes. Growing interest has focused on the modulation of gut microbiota as a therapeutic strategy in cardiovascular diseases and metabolic disorders. In this paper, we have reviewed the impact of gut microbiota on metabolic disorders and cardiovascular disease risk, focusing on the newest findings in this field.
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http://dx.doi.org/10.1007/s11886-015-0671-zDOI Listing
December 2015

Megakaryocytic emperipolesis and platelet function abnormalities in five patients with gray platelet syndrome.

Platelets 2015 25;26(8):751-7. Epub 2015 Mar 25.

f Department of Internal Medicine , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Roma , Italy.

The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic α-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2-3) and extensive emperipolesis, with many (36-65%) MKs containing 2-4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease.
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http://dx.doi.org/10.3109/09537104.2014.994093DOI Listing
June 2016

Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders.

Blood 2014 Aug 2;124(6):e4-e10. Epub 2014 Jul 2.

Department of Internal Medicine, University of Pavia-Istituto Di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy;

Abnormalities of platelet size are 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 about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of 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 cutoff 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.
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http://dx.doi.org/10.1182/blood-2014-03-564328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126341PMC
August 2014

Functional role of protease activated receptors in vascular biology.

Vascul Pharmacol 2014 Aug 9;62(2):72-81. Epub 2014 Jun 9.

Hemostasis and Thrombosis Unit, Department of Internal Medicine, Agostino Gemelli Hospital School of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

Protease activated receptors (PARs) are a small family of G protein-coupled receptors (GPCR) mediating the cellular effects of some proteases of the coagulation system, such as thrombin, or other proteases, such as trypsin or metalloproteinase 1. As the prototype of PARs, PAR1 is a seven transmembrane GPCR that, upon cleavage by thrombin, unmasks a new amino-terminus able to bind intramolecularly to PAR1 itself thus inducing signaling. In the vascular system, thrombin and other proteases of the coagulation-fibrinolysis system, such as plasmin, factor VIIa and factor Xa, activated protein C, are considered physiologically relevant agonists, and PARs appear to largely account for the cellular effects of these enzymes. In the vasculature, PARs are expressed on platelets, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the vessel wall, under physiological conditions, PARs are mainly expressed in ECs and participate in the regulation of vascular tone, by inducing endothelium-dependent relaxation. PAR activation on ECs promotes conversion of these cells into a proinflammatory phenotype, causes increase of vascular permeability, and the exposure/secretion of proteins and cytokines mediating the local accumulation of platelets and leukocytes. These effects contribute to the vascular consequences of sepsis and of diseases such as acute lung injury and acute respiratory distress syndrome. In normal arteries PARs are to a much lesser amount expressed on VSMCs. However, in conditions associated with endothelial dysfunction, PARs mediate contraction, proliferation, migration, hypertrophy of VSMCs and their production of extracellular matrix, thereby contributing to the pathophysiology of atherosclerosis and hypertension. Inhibition of protease-PAR interaction might thus become a potential therapeutic target in various vascular diseases.
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http://dx.doi.org/10.1016/j.vph.2014.06.001DOI Listing
August 2014

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.

Haematologica 2014 Aug 24;99(8):1387-94. Epub 2014 Apr 24.

Division of Angiology and Haemostasis, Department of Medical Specialisations, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

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 did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term 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 2 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 abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo 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 below 50 × 10(9)/L.
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http://dx.doi.org/10.3324/haematol.2014.105924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116839PMC
August 2014

MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.

Hum Mutat 2014 Feb 12;35(2):236-47. Epub 2013 Dec 12.

Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle 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 noncongenital 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 noncongenital 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 noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.
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http://dx.doi.org/10.1002/humu.22476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233870PMC
February 2014

Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency.

Haematologica 2013 Jun 25;98(6):868-74. Epub 2012 Oct 25.

Department of Medical Sciences, University of Trieste, Trieste, Italy.

The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. 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. 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. 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.
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http://dx.doi.org/10.3324/haematol.2012.075861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669441PMC
June 2013

Mechanisms of platelet activation by thrombin: a short history.

Authors:
Erica De Candia

Thromb Res 2012 Mar 2;129(3):250-6. Epub 2011 Dec 2.

Hemostasis and Thrombosis Unit, Department of Internal Medicine, Agostino Gemelli Hospital, Università Cattolica del Sacro Cuore, Rome, Italy.

Platelet activation by thrombin is relevant to arterial thrombosis, therefore it is an attractive target for the development of new antithrombotic drugs. In the 1970s the platelet membrane complex glycoprotein (GP) Ib-V-IX was shown to have a high affinity binding site for thrombin on GPIbα and a substrate cleaved by thrombin, GPV. For several years it was considered to be involved in platelet activation by thrombin. The discovery of the protease activated receptors (PARs) in 1991 was a major breakthrough in the field. The first member of this family of receptors to be discovered was PAR1, a seven transmembrane G-protein coupled receptor which, upon cleavage by thrombin, unmasks a new amino-terminus able to bind intramolecularly to PAR1 itself thus inducing signaling. On human platelets PAR1 and, later PAR4, were demonstrated to mediate most of the platelet responses to thrombin. However, after the discovery of PARs, different groups demonstrated that GPIbα is required to stimulate a full platelet activation by thrombin. A model where thrombin binds to the GPIb receptor prior to proteolysis of the PAR receptors was supported by several lines of evidence. A role for GPV as inhibitor of GPIbα signaling has been shown by using GPV knock-out mice. Crystallographic data suggested that thrombin bound to GPIbα might be able to interact with other GPIbα molecules on the same or other platelets, shedding light on a new role for thrombin binding to GPIbα. Finally, anti-PAR1 molecules were developed which are now in phase II and III clinical studies as antithrombotic drugs.
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http://dx.doi.org/10.1016/j.thromres.2011.11.001DOI Listing
March 2012