Publications by authors named "Flora Peyvandi"

373 Publications

The dominant p.Thr274Pro mutation in the von Willebrand factor propeptide causes the von Willebrand disease type 1 phenotype in two unrelated patients.

Haemophilia 2022 Jan 22. Epub 2022 Jan 22.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Background: von Willebrand factor propeptide (VWFpp) plays an important role in VWF multimerization and storage. VWFpp mutations have been previously associated with types 1, 3 and 2A/IIC von Willebrand disease (VWD).

Aims: To characterize the novel p.Thr274Pro variant identified in two unrelated type 1 VWD patients.

Methods: Phenotype tests were performed to evaluate patients' plasma and platelets following the current ISTH-SSC guidelines. Molecular analysis was performed using next-generation sequencing. The pcDNA3.1-VWF-WT and mutant pcDNA3.1-VWF-Thr274Pro expression vectors were transiently transfected into HEK293 cells to evaluate recombinant (r)VWF constitutive and regulated secretion. For the latter, the transfected cells were stimulated with phorbol-12-myristate-13-acetate. Immunofluorescence staining was performed to assess the localization of WT-rVWF and Thr274Pro-rVWF in endoplasmic reticulum, lysosomes, cis-/trans-Golgi and pseudo-Weibel Palade bodies.

Results: Biochemical characterization of patients' plasma samples indicated a type 1 VWD diagnosis. Both patients were heterozygous for the p.Thr274Pro variant. Hybrid Thr274Pro/WT-rVWF showed a secretion reduction of 36±4% according to patients' plasma VWF:Ag levels, whereas Thr274Pro-rVWF secretion was strongly impaired (21±2%). The amount of rVWF in cell lysates was nearly normal for both Thr274P (62±17%) and Thr274Pro/WT-rVWF (72±23%). The regulated secretion was impaired for Thr274Pro/WT-rVWF, whereas Thr274Pro-rVWF was not released at all. Immunofluorescence staining revealed no particular differences between WT and Thr274Pro-rVWF, although Thr274Pro-rVWF showed less pseudo-Weibel Palade bodies with a rounder shape than WT-rVWF.

Conclusions: The novel p.Thr274Pro mutation has a dominant effect and it is responsible of patients' type 1 VWD phenotype through a combined mechanism of reduced synthesis, impaired secretion and multimerization.
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http://dx.doi.org/10.1111/hae.14494DOI Listing
January 2022

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

Current and Emerging Approaches for Pain Management in Hemophilic Arthropathy.

Pain Ther 2022 Jan 12. Epub 2022 Jan 12.

Università degli Studi di Milano, Dipartimento di Fisiopatologia e Medicina dei Trapianti, Via Pace, 9, 20122, Milan, Italy.

Introduction: Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint.

Methods: We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management.

Results: In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients.

Conclusions: The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.
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http://dx.doi.org/10.1007/s40122-021-00345-xDOI Listing
January 2022

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study.

J Clin Med 2021 Dec 18;10(24). Epub 2021 Dec 18.

BioMarin Pharmaceutical Inc., Novato, CA 94949, USA.

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0-86.0) and 1.85 (0-37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5-13541.7) and 3708.0 (1311.0-14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0-364.0) and 122.4 (38.0-363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4-100.0) ( = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.
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http://dx.doi.org/10.3390/jcm10245959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705574PMC
December 2021

Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.

PLoS One 2021 18;16(10):e0258675. Epub 2021 Oct 18.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Background: We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers.

Aims: To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants.

Methods: ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted.

Results: We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5).

Conclusions: ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523043PMC
November 2021

Consumption of complement in a 26-year-old woman with severe thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.

J Autoimmun 2021 11 27;124:102728. Epub 2021 Sep 27.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi, Hemophilia and Thrombosis Center, and Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.

Extremely rare reactions characterized by thrombosis and thrombocytopenia have been described in subjects that received ChAdOx1 nCoV-19 vaccination 5-16 days earlier. Although patients with vaccine-induced thrombotic thrombocytopenia (VITT) have high levels of antibodies to platelet factor 4 (PF4)-polyanion complexes, the exact mechanism of the development of thrombosis is still unknown. Here we reported serum studies as well as proteomics and genomics analyses demonstrating a massive complement activation potentially linked to the presence of anti-PF4 antibodies in a patient with severe VITT. At admission, complement activity of the classical and lectin pathways were absent (0% for both) with normal levels of the alternative pathway (73%) in association with elevated levels of the complement activation marker sC5b-9 (630 ng/mL [n.v. 139-462 ng/mL]) and anti-PF4 IgG (1.918 OD [n.v. 0.136-0.300 OD]). The immunoblotting analysis of C2 showed the complete disappearance of its normal band at 110 kDa. Intravenous immunoglobulin treatment allowed to recover complement activity of the classical pathway (91%) and lectin pathway (115%), to reduce levels of sC5b-9 (135 ng/mL) and anti-PF4 IgG (0.681 OD) and to normalize the C2 pattern at immunoblotting. Proteomics and genomics analyses in addition to serum studies showed that the absence of complement activity during VITT was not linked to alterations of the C2 gene but rather to a strong complement activation leading to C2 consumption. Our data in a single patient suggest monitoring complement parameters in other VITT patients considering also the possibility to target complement activation with specific drugs.
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http://dx.doi.org/10.1016/j.jaut.2021.102728DOI Listing
November 2021

Increased Risk of Urticaria/Angioedema after BNT162b2 mRNA COVID-19 Vaccine in Health Care Workers Taking ACE Inhibitors.

Vaccines (Basel) 2021 Sep 11;9(9). Epub 2021 Sep 11.

Infectious Diseases Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Urticarial eruptions and angioedema are the most common cutaneous reactions in patients undergoing mRNA COVID-19 vaccinations. The vasoactive peptide bradykinin has long been known to be involved in angioedema and recently also in urticaria. Bradykinin is mainly catabolized by angiotensin-converting enzyme (ACE), which is inhibited by ACE inhibitors, a commonly employed class of antihypertensive drugs. We evaluated the risk of developing urticaria/angioedema after inoculation with the BNT162b2 mRNA COVID-19 vaccine in a population of 3586 health care workers. The influences of ACE inhibitors and selected potential confounding variables (sex, age, previous SARS-CoV-2 infection, and allergy history) were evaluated by fitting univariate and multivariable Poisson regression models. The overall cumulative incidence of urticaria/angioedema was 1.8% (65 out of 3586; 95% CI: 1.4-2.3%). Symptoms were mild, and no subject consulted a physician. Subjects taking ACE inhibitors had an adjusted three-fold increased risk of urticaria/angioedema (RR 2.98, 95% CI: 1.12-7.96). When we restricted the analysis to those aged 50 years or more, the adjusted RR was 3.98 (95% CI: 1.44-11.0). In conclusion, our data indicate that subjects taking ACE inhibitors have an increased risk of urticaria/angioedema after vaccination with the BNT162b2 mRNA COVID-19 vaccine. Symptoms are mild and self-limited; however, they should be considered to adequately advise subjects undergoing vaccination.
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http://dx.doi.org/10.3390/vaccines9091011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473401PMC
September 2021

Delivery of AAV-based gene therapy through haemophilia centres-A need for re-evaluation of infrastructure and comprehensive care: A Joint publication of EAHAD and EHC.

Haemophilia 2021 Nov 22;27(6):967-973. Epub 2021 Sep 22.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre and Fondazione Luigi Villa, Milan, Italy.

Introduction: Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET).

Aim And Methods: This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres.

Results: The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable 'hub-and-spoke' model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance.

Conclusion: We propose a modifiable, networked 'hub and spoke' model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.
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http://dx.doi.org/10.1111/hae.14420DOI Listing
November 2021

The EHA Research Roadmap: Blood Coagulation and Hemostatic Disorders.

Hemasphere 2021 Oct 10;5(10):e643. Epub 2021 Sep 10.

Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy.

n 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.
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http://dx.doi.org/10.1097/HS9.0000000000000643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432639PMC
October 2021

Distinct Metabolic Profile Associated with a Fatal Outcome in COVID-19 Patients during the Early Epidemic in Italy.

Microbiol Spectr 2021 10 1;9(2):e0054921. Epub 2021 Sep 1.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutegrid.4714.6, Stockholm, Sweden.

In one year of the coronavirus disease 2019 (COVID-19) pandemic, many studies have described the different metabolic changes occurring in COVID-19 patients, linking these alterations to the disease severity. However, a complete metabolic signature of the most severe cases, especially those with a fatal outcome, is still missing. Our study retrospectively analyzes the metabolome profiles of 75 COVID-19 patients with moderate and severe symptoms admitted to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Lombardy Region, Italy) following SARS-CoV-2 infection between March and April 2020. Italy was the first Western country to experience COVID-19, and the Lombardy Region was the epicenter of the Italian COVID-19 pandemic. This cohort shows a higher mortality rate compared to others; therefore, it represents a unique opportunity to investigate the underlying metabolic profiles of the first COVID-19 patients in Italy and to identify the potential biomarkers related to the disease prognosis and fatal outcome. Understanding the metabolic alterations occurring during an infection is a key element for identifying potential indicators of the disease prognosis, which are fundamental for developing efficient diagnostic tools and offering the best therapeutic treatment to the patient. Here, exploiting high-throughput metabolomics data, we identified the first metabolic profile associated with a fatal outcome, not correlated with preexisting clinical conditions or the oxygen demand at the moment of diagnosis. Overall, our results contribute to a better understanding of COVID-19-related metabolic disruption and may represent a useful starting point for the identification of independent prognostic factors to be employed in therapeutic practice.
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http://dx.doi.org/10.1128/Spectrum.00549-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565516PMC
October 2021

Comparison of adverse drug reactions among four COVID-19 vaccines in Europe using the EudraVigilance database: Thrombosis at unusual sites.

J Thromb Haemost 2021 10 25;19(10):2554-2558. Epub 2021 Aug 25.

Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, UOC Medicina Generale, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Background: Real-world experience with adenoviral vector vaccines against COVID-19 raised some safety concerns. Cases of cerebral vein thrombosis (CVT) associated with thrombocytopenia have been observed after the first dose of the adenoviral vector vaccines CHADOX1 NCOV-19 and AD26.COV2.S.

Objectives: To assess the reporting rate of CVT as adverse drug reaction (ADR) for the COVID-19 vaccines authorized in Europe.

Patients And Methods: This observational study assessed the CVT reporting rate attributed to four COVID-19 vaccines authorized in Europe, namely Tozinameran (Pfizer-Biontech), CX-024414 (Moderna), CHADOX1 NCOV-19 (AstraZeneca), and AD26.COV2.S (Janssen). Data on thrombotic ADRs reported on EudraVigilance database between January 1, 2021 and July 30, 2021, were collected. ADRs referring to CVT were identified. The reporting rate of CVT was expressed as 1 million individual vaccinated-days with 95% confidence interval. Finally, an observed-to-expected (OE) analysis was performed.

Results: The reporting rate of CVT per 1 million person vaccinated-days was 1.92 (95% confidence interval [CI], 1.71-2.12) for Tozinameran, 5.63 (95% CI, 4.74-6.64) for CX-024414, 21.60 (95% CI, 20.16-23.11) for CHADOX1 NCOV-19, and 11.48 (95% CI, 9.57-13.67) for AD26.COV2.S. CVT occurred alongside thrombocytopenia for the four vaccines. The OE ratio was greater than one for all four vaccines, both with the lowest and the highest CVT background incidence.

Conclusions: This report on EudraVigilance data strengthens anecdotal findings on CVT following COVID-19 vaccinations. Although the European Medicines Agency released an alert only for CHADOX1 NCOV-19 and AD26.COV2.S, Tozinameran and CX-024414 also are complicated by CVT, albeit to lesser extent.
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http://dx.doi.org/10.1111/jth.15493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420446PMC
October 2021

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

Blood Adv 2021 08;5(15):2987-3001

Centre Régional de Traitement de l'Hémophilie-Laboratoire d'Hématologie, Nantes, France.

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361454PMC
August 2021

Clinical risk scores for the early prediction of severe outocomes in patients hospitalized for COVID-19: comment.

Intern Emerg Med 2021 Aug 3. Epub 2021 Aug 3.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-021-02807-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329608PMC
August 2021

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH.

J Thromb Haemost 2021 08;19(8):1883-1887

Aflac Cancer and Blood Disorders, Emory University, Decatur, Georgia, USA.

Hemophilia A and B predominantly attracts clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01-0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research.
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http://dx.doi.org/10.1111/jth.15397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361713PMC
August 2021

Subclinical myopathic changes in COVID-19.

Neurol Sci 2021 Oct 25;42(10):3973-3979. Epub 2021 Jul 25.

U.O. Neurofisiopatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy.

Introduction: Coronavirus disease 2019 (COVID-19) is associated to neuromuscular symptoms in up to 10.7% of hospitalized patients. Nevertheless, the extent of muscular involvement in infected subjects with no signs of myopathy has never been assessed with neurophysiological investigations.

Methods: Over a 3-week period - from April 30 through May 20, 2020 - a total of 70 patients were hospitalized in the Internal Medicine Ward of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy. After excluding patients who underwent invasive ventilation and steroid treatment, 12 patients were evaluated. Nerve conduction studies (NCS) included the analysis of conduction velocity, amplitude, and latency for bilateral motor tibial, ulnar nerves, and sensory sural and radial nerves. Unilateral concentric-needle electromyography (EMG) was performed evaluating at least 4 areas of 8 selected muscles. For each muscle, spontaneous activity at rest, morphology, and recruitment of motor unit action potentials (MUAPs) were evaluated.

Results: While nerve conduction studies were unremarkable, needle electromyography showed myopathic changes in 6 out of 12 subjects. All patients were asymptomatic for muscular involvement. Clinical features and laboratory findings did not show relevant differences between patients with and without myopathic changes.

Conclusion: Our data show that in SARS-CoV-2 infection muscular involvement can occur despite the absence of clinical signs or symptoms and should be considered part of the disease spectrum. The application of muscle biopsy to unravel the mechanisms of myofiber damage on tissue specimens could help to clarify the pathogenesis and the treatment response of coronavirus-mediated injury.
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http://dx.doi.org/10.1007/s10072-021-05469-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310558PMC
October 2021

Massive cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

Haematologica 2021 Nov 1;106(11):3021-3024. Epub 2021 Nov 1.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and Fondazione Luigi Villa, Milan, Italy; University of Milan, Department of Pathophysiology and Transplantation, Milan.

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http://dx.doi.org/10.3324/haematol.2021.279246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561270PMC
November 2021

Hemophilic arthropathy: Current knowledge and future perspectives.

J Thromb Haemost 2021 09 27;19(9):2112-2121. Epub 2021 Jul 27.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

Hemophilia A and B are rare X-linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. Unless appropriately managed, even subclinical hemarthrosis can lead to the development of hemophilic arthropathy, a disabling condition characterized by joint remodelling, chronic pain, and a reduced quality of life, and eventually requires joint replacement. Given the lack of specific treatments to reduce blood-induced synovitis, the prevention of bleeding is pivotal to the maintenance of joint health. Prophylactic coagulation factor replacement therapy using extended half-life recombinant drugs has significantly improved patients' quality of life by reducing the burden of intravenous injections, and the more recent introduction of nonreplacement therapies such as subcutaneous emicizumab injections has improved treatment adherence and led to the greater protection of patients with hemophilia A. However, despite these advances, chronic arthropathy is still a significant problem. The introduction of point-of-care ultrasound imaging has improved the diagnosis of acute hemarthrosis and early hemophilic arthropathy, and allowed the better monitoring of progressive joint damage, but further research into the underlying mechanisms of the disease is required to allow the development of more targeted treatment. In the meantime, patient management should be based on the risk factors for the onset and progression of arthropathy of each individual patient, and all patients should be collaboratively cared for by multidisciplinary teams of hematologists, rheumatologists, orthopedic surgeons, and physiotherapists at comprehensive hemophilia treatment centers.
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http://dx.doi.org/10.1111/jth.15444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456897PMC
September 2021

A homozygous duplication of the exon 8-intron 8 junction causes congenital afibrinogenemia. Lessons learned from the study of a large consanguineous Turkish family.

Haematologica 2021 Jul 1. Epub 2021 Jul 1.

Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Congenital afibrinogenemia is the most severe congenital fibrinogen disorder, characterised by undetectable fibrinogen in circulation. Causative mutations can be divided into two main classes: null mutations with no protein production at all and missense mutations producing abnormal protein chains that are retained inside the cell. The vast majority of cases are due to single base pair mutations or small insertions or deletions in the coding regions or intron-exon junctions of FGB, FGA and FGG. Only a few large rearrangements have been described, all deletions involving FGA. Here we report the characterization of a 403 bp duplication of the FGG exon 8-intron 8 junction accounting for congenital afibrinogenemia in a large consanguineous family from Turkey. This mutation, which had escaped detection by Sanger sequencing of short PCR amplicons of coding sequences and splice sites, was identified by studying multiple alignments of reads obtained from Whole Exome Sequencing of a heterozygous individual followed by PCR amplification and sequencing of a larger portion of FGG. Because the mutation duplicates the donor splice site of intron 8, we predicted that the impact of the mutation would be on FGG transcript splicing. Analysis of mRNAs produced by cells transiently transfected with normal or mutant minigene constructs showed that the duplication causes production of several aberrant FGG transcripts generating premature truncating codons.
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http://dx.doi.org/10.3324/haematol.2021.278945DOI Listing
July 2021

Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge.

Clin Chem Lab Med 2021 Sep 1;59(10):1699-1708. Epub 2021 Jul 1.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan and Fondazione Luigi Villa, Milan, Italy.

Objectives: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP.

Methods: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved.

Results: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved.

Conclusions: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.
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http://dx.doi.org/10.1515/cclm-2021-0538DOI Listing
September 2021

Adoption of emicizumab (Hemlibra®) for hemophilia A in Europe: Data from the 2020 European Association for Haemophilia and Allied Disorders survey.

Haemophilia 2021 Sep 30;27(5):736-743. Epub 2021 Jun 30.

Hemostasis and Thrombosis Unit, Division of Hematology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium.

Background: Emicizumab, a bispecific monoclonal antibody administered subcutaneously, mimicking the action of activated coagulation factor VIII, has been approved in Europe for use in patients with severe hemophilia of all ages.

Aims: To assess availability, acceptance, adverse events, efficacy and laboratory monitoring of emicizumab and the effect of the coronavirus disease 2019 (COVID-19) pandemic on its use.

Methods: Online questionnaire sent to 144 hemophilia treatment centres (November 2020 to January 2021).

Results: Forty-six physicians from 21 countries responded, with a total of 3420 patients with severe HA under their care. Emicizumab was widely available, for 100% of inhibitor patients and 88% of non-inhibitor patients. No major adverse events were reported. Four reported deaths in patients on emicizumab were not thought to be related to emicizumab. An annualized bleeding rate (ABR) of zero was achieved in 73% of inhibitors patients. Haemostasis was satisfactory in the majority of minor (93.7%) and major (90.7%) surgical procedures performed while on emicizumab. Inhibitor titers were monitored in 78.4% of inhibitor patients on emicizumab, but chromogenic FVIII assay was only available in 73% of centres. The COVID-19 pandemic did not have a major impact on the adoption of emicizumab in most centres (64.9%).

Conclusion: Three years after its rollout in Europe, emicizumab is widely available. Clinical efficacy and safety were evaluated to be very good, keeping in mind the inherent limitations of the study. Unmet needs include establishment of treatment guidelines for surgery and breakthrough bleeding, limited expertise, especially in young children, and availability of laboratory assays.
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http://dx.doi.org/10.1111/hae.14372DOI Listing
September 2021

International Society on Thrombosis and Haemostasis: Present and future.

J Thromb Haemost 2021 07;19(7):1599-1601

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1111/jth.15325DOI Listing
July 2021

Impact of a commercially available DOAC absorbent on two integrated procedures for lupus anticoagulant detection.

Thromb Res 2021 08 5;204:32-39. Epub 2021 Jun 5.

Ospedale Maggiore Cremona, Italy.

Background: Lupus anticoagulant (LA)-detection in anticoagulated patients is an unmet need, which becomes even more cogent with the introduction of direct oral anticoagulants (DOAC) that may lead to false-positive results.

Aims: We aimed to investigate the effect of a commercially available DOAC absorbent on residual drug concentrations, and on integrated procedures for LA-detection.

Methods: Blood from patients treated for atrial fibrillation with either dabigatran (n = 39), rivaroxaban (n = 55), apixaban (n = 47) or edoxaban (n = 47) were collected at peak and trough, and centralized for testing with two LA integrated procedures [i.e., the silica clotting time (SCT) and dilute Russel viper venom (dRVVT)] before and after DOAC absorbent exposure.

Results: The commercially available DOAC absorbent investigated in this study proved effective in reducing the concentrations of all the investigated DOAC, although small residual drug was detected after absorption, especially in patients on edoxaban. Results mimicking LA were observed in patients on DOAC before absorbent exposure, especially for rivaroxaban when testing was performed with dRVVT (88% rate at peak and 20% at trough) and much less with SCT (12% at peak and 8% at trough). The correspondent rate of results mimicking LA in patients on rivaroxaban after exposure was reduced [dRVVT (peak 8%, trough 4%); SCT (peak and trough 8%)], but not abolished.

Conclusions: Overall, in vitro DOAC absorbance by active charcoal compounds is a useful laboratory tool for LA-detection in patients on DOAC. Caution should however be exerted when used in daily practice.
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http://dx.doi.org/10.1016/j.thromres.2021.06.001DOI Listing
August 2021

Von Willebrand disease combined with coagulation defects in Iran.

Blood Transfus 2021 09 28;19(5):428-434. Epub 2021 May 28.

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

Background: Although Von Willebrand disease (VWD) is the most common inherited bleeding disorder, few cases of VWD combined with coagulation defects have been reported. This study sought to determine the clinical and laboratory features of VWD combined with other coagulation defects and to evaluate the prevalence of this combination in Iran.

Material And Methods: A total of 3,120 cases were evaluated to confirm a suspected diagnosis of VWD. Clinical and laboratory phenotypes, including bleeding scores (BS), were also obtained.

Results: A diagnosis of VWD was established for 130 patients. Following their further characterisation, a subgroup of 25 patients with a dual or triple combination of VWD with coagulation defects (FXII, FXI, FIX, FVII, FV, and lupus anticoagulant) was identified. Their laboratory and clinical data were compared with those of healthy controls (n=25) and VWD-only patients (n=25). No differences were observed for VWF-related laboratory measurements between the combined deficient cases and those with VWD only, results being expectedly lower than in healthy controls. The median BS of combined patients was 4, higher than for VWD-only and control groups (median BS 3 and 1; p=0.55 and p<0.001, respectively).

Discussion: The prevalence of combined coagulation defects was 19.2% among all the VWD cases. The co-occurrence of VWD with clotting factor deficiencies may lead to more severe clinical presentations. To ensure adequate treatment, combined defects should be considered in VWD patients presenting with a more severe bleeding phenotype than expected or with a poor response to treatment.
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http://dx.doi.org/10.2450/2021.0078-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486600PMC
September 2021

Pulmonary immuno-thrombosis in COVID-19 ARDS pathogenesis.

Intensive Care Med 2021 08 30;47(8):899-902. Epub 2021 May 30.

Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Ardilaun House, 111 St. Stephen's Green, Dublin 2, Ireland.

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http://dx.doi.org/10.1007/s00134-021-06419-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164686PMC
August 2021

Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency.

Blood Rev 2021 11 27;50:100833. Epub 2021 Apr 27.

Imperial College London, London, UK; Imperial College Healthcare NHS Trust, London, UK. Electronic address:

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders. Here we provide a comprehensive review of the literature on factor X deficiency, focusing on the hereditary form, and discuss the evolution in disease management and the evidence associated with available treatment options. Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity.
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http://dx.doi.org/10.1016/j.blre.2021.100833DOI Listing
November 2021

Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A.

Haemophilia 2021 Jul 14;27(4):e441-e449. Epub 2021 May 14.

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Background: There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies.

Aims: The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors.

Methods: The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling.

Results: Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively.

Conclusion: Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.
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http://dx.doi.org/10.1111/hae.14325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360203PMC
July 2021

Corrigendum to "Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19" [J. Autoimmun. 117C (2020) 102595].

J Autoimmun 2021 Jun 30;120:102646. Epub 2021 Apr 30.

Universita ' degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaut.2021.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086412PMC
June 2021

Relapse of thrombotic thrombocytopenic purpura after COVID-19 vaccine.

Transfus Apher Sci 2021 08 16;60(4):103145. Epub 2021 Apr 16.

Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.transci.2021.103145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051010PMC
August 2021

Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis.

Blood Adv 2021 04;5(8):2137-2141

Medical Affairs, Sanofi, Diegem, Belgium.

The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.
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http://dx.doi.org/10.1182/bloodadvances.2020001834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095153PMC
April 2021

Pulmonary tumour thrombotic microangiopathy in a young man: clinical and immunohistochemical characterisation of a rare complication of gastric signet-ring cell carcinoma.

Blood Transfus 2021 11 15;19(6):506-509. Epub 2021 Apr 15.

General Medicine, "Angelo Bianchi Bonomi" Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore, Policlinico of Milan, Milan, Italy.

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http://dx.doi.org/10.2450/2021.0016-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580786PMC
November 2021
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