Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

Rare bleeding disorders: Advances in management.

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

[Angiology and hemostasis: what's new in 2023]. / Angiologie et hémostase: ce qui a changé en 2023.

We discuss four topics among the angiology and hemostasis studies of importance in 2023. The BASIL-2 study provides new data for the management of chronic limb-threatening ischemia by comparing surgical and endovascular treatment. The new classification of antiphospholipid antibody (aPL) syndrome integrates new clinical elements and gives a different weight among the isotype and titer of aPL. Concizumab, an antibody targeting the tissue factor pathway inhibitor, broadens the therapeutic arsenal for hemophilia A and B as evidenced by the results of the EXPLORER 7 study. The PREVENT-CLOT and CASTING study focus on the prevention of thrombosis after trauma, by testing the role of aspirin or the lack of thromboprophylaxis, respectively.

Parmi les sujets d'angiologie et d'hémostase qui ont marqué l'année 2023, quatre ont retenu notre attention. L'étude BASIL-2 apporte de nouvelles données pour la prise en charge de l'ischémie critique des membres inférieurs en comparant les traitements chirurgical et endovasculaire. La nouvelle classification du syndrome des anticorps antiphospholipides (aPL) intègre de nouveaux items cliniques et donne un poids différent aux isotypes et titres des aPL. Le concizumab, un anticorps ciblant l'inhibiteur de la voie du facteur tissulaire, vient élargir l'arsenal thérapeutique pour les hémophilies A et B comme en témoignent les résultats de l'étude EXPLORER 7. Les études PREVENT-CLOT et CASTING s'intéressent à la prévention de la thrombose après traumatisme, en testant la place de l'aspirine ou l'absence de thromboprophylaxie.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

How I treat dysfibrinogenemia.

Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.

Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia.

Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities, and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n = 72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n = 37) received ≥1 injection per week, and 16.6% (n = 34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients, and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa, and a previous thrombotic event were statistically correlated with a worse HRQoL. In summary, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined. This trial was registered at www.clinicaltrials.gov as #NCT03484065.

Physiological correction of hereditary mild hypofibrinogenemia during pregnancy.

INTRODUCTION: Hereditary hypofibrinogenemia is a rare fibrinogen disorder characterised by decreased levels of fibrinogen. Pregnant women with hypofibrinogenemia are at risk of adverse obstetrical outcomes, depending on the fibrinogen level. AIM: We investigated how the physiological changes of hemostasis throughout the pregnancy impact the hemostatic balance in a woman with hereditary mild hypofibrinogenemia. METHODS: Fibrin clot properties were analyzed by turbidimetry and scanning electron microscopy, clot weight and red blood cells retention were measured by whole clot contraction, and in vitro thrombin generation was assessed by calibrated automated thrombogram and ex vivo by TAT. RESULTS: Throughout the pregnancy, the fibrinogen levels increased reaching normal values in the third trimester (activity 3.1 g/L, antigen 3.2 g/L). In parallel, the fibrin polymerisation increased, the fibrinolysis decreased, the fibrin clot network became denser with thicker fibrin fibers, and the fibrin clot weight and red blood cells retention increased, reaching control's value at the third trimester. Similarly, in vitro and ex vitro thrombin generation increased, reaching maximum values at the delivery. CONCLUSION: In this case of hereditary mild hypofibrinogenemia we observed a physiological increase of fibrinogen and thrombin generation. Future studies should focus on moderate and severe hypofibrinogenemia, to assess fibrinogen variation and the overall impact of increased TG on the hemostasis balance.

Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders.

INTRODUCTION: The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described. AIM: Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.

Clinicians' adherence to guidelines for the preoperative management of direct oral anticoagulants in a tertiary hospital: a retrospective study.

INTRODUCTION: Despite clear, relatively easy-to-use guidance, many clinicians find the preoperative management of direct oral anticoagulants (DOACs) challenging. Inappropriate management can delay procedures and lead to haemorrhagic or thromboembolic complications. We aimed to describe preoperative management practices regarding DOACs in a tertiary hospital and clinicians' adherence to in-house recommendations. METHOD: We included all patients being treated with DOACs who underwent elective surgery in 2019 and 2020 (n = 337). In-house recommendations for perioperative management were largely comparable to the 2022 American College of Chest Physicians guidelines. RESULTS: Typical patients were older adults with multiple comorbidities and high thrombotic risk stratification scores, and 65.6% (n = 221) had not undergone recommended preoperative anticoagulation management protocols. Patients operated on using local anaesthesia (adjusted OR = 0.30, 95%CI 0.14-0.66; p < 0.01) were less likely to have been treated following institutional recommendations, but no association between their procedure's bleeding risk and adherence was found. Clinicians' failures to adhere to recommendations mostly involved late or non-indicated interruptions of anticoagulation treatment (n = 89, 26.4%) or inappropriate heparin bridging (n = 54, 16.0%). Forty-five (13.3%) procedures had to be postponed. Incorrect preoperative anticoagulation management was directly responsible for 12/45 postponements (26.7% of postponements). CONCLUSION: This study highlights clinicians' low adherence rates to institutional recommendations for patients treated with DOACs scheduled for elective surgery in a tertiary hospital centre. To the best of our knowledge, this is the first clinical study addressing the issue of clinicians' adherence to guidelines for the preoperative management of DOACs. Going beyond the issue of whether clinicians are knowledgeable about guidelines or have them available, this study questions how generalisable guidelines are in a tertiary hospital managing many highly polymorbid patients. Further studies should identify the causes of poor adherence.

[Angiology and hemostasis : what's new in 2022]. / Angiologie et hémostase : ce qui a changé en 2022.

In this article, we have selected four topics that particularly caught our attention during the year 2022, and which are related to anticoagulation, its bleeding complications, and hemophilia. Thus, we discuss the issue of the treatment with rivaroxaban of atrial fibrillation associated with rheumatic valvulopathy, which has been studied in a randomized trial, the intensity of thromboprophylaxis in COVID outpatients and inpatients, and the bleeding risk of anticoagulation in patients with cerebral tumors. Finally, recent data on gene therapy in severe hemophilia A, an upcoming treatment, are discussed.

Dans cet article, nous avons sélectionné 4 sujets qui ont particulièrement retenu notre attention durant l'année 2022, en lien avec l'anticoagulation, ses complications hémorragiques et l'hémophilie. Ainsi, nous abordons le traitement par rivaroxaban de la fibrillation atriale associée à une valvulopathie rhumatismale qui a fait l'objet d'une étude randomisée, l'intensité de la thromboprophylaxie chez les patients hospitalisés ou traités en ambulatoire avec un Covid dont les données se sont bien étoffées, le risque associé à l'anticoagulation chez les patients avec une néoplasie cérébrale et, finalement, la thérapie génique dans l'hémophilie A sévère qui devrait apparaître sur le marché très prochainement.

One Hundred Years of Congenital Fibrinogen Disorders.

Congenital fibrinogen disorders encompass a broad range of fibrinogen defects characterized by a wide molecular and clinical spectrum. From the first clinical description of afibrinogenemia in 1920, many major achievements have contributed to a better understanding of these complex disorders. The finding of causative mutations in all three fibrinogen genes has contributed to reveal the molecular mechanisms involved in biosynthesis of the fibrinogen molecule and to clarify the basic processes of fibrin polymerization and fibrinolysis. The compilation of abundant cases with detailed genetic, biological, and clinical features has enabled the classification of congenital fibrinogen disorders into several types and subtypes. Thus, the recent classification of congenital fibrinogen disorder is based not only on the clottable and antigenic fibrinogen levels but also on the patient's clinical phenotype and genotype. Fibrinogen supplementation is the cornerstone of bleeding management in fibrinogen disorders. Since the discovery of blood fractionation, the method of production of fibrinogen concentrate has been progressively modified to significantly improve purity and safety. Nevertheless, the availability of such products is still limited to a few countries and the optimal threshold of fibrinogen to target is still not established. In this review, we describe the major advances that have characterized 100 years of congenital fibrinogen disorders, focusing on afibrinogenemia and dysfibrinogenemia.

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

Congenital afibrinogenemia is the most severe congenital fibrinogen disorder, characterized 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 polymerase chain reaction (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 mRNA 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.

[Direct oral anticoagulant for venous thrombosis in unusual sites]. / Place des anticoagulants oraux directs dans le traitement des thromboses veineuses de localisation inhabituelle.

Thrombosis in unusual sites account for approximately 4% of venous thromboembolic events. The safety of direct oral anticoagulants (DOACs) has led to the widespread use of these treatments. However, they have mainly been studied in deep vein thrombosis of the lower limbs and in pulmonary embolism. This review of the literature assesses the current knowledge of the use of DOACs for venous thrombosis in unusual sites (splanchnic, cerebral, ovarian, upper-extremity deep vein thrombosis). Numerous case reports or observational studies have been published, but very few randomized trials. Nevertheless, experts-based guidelines suggest that these anticoagulants may be considered in specific cases.

La maladie thromboembolique veineuse de localisation atypique (MTEV-LA) représente environ 4 % des événements thromboemboliques veineux. Les anticoagulants oraux directs (ACOD), faciles d'utilisation et sécuritaires, ont essentiellement été étudiés dans la MTEV classique (thrombose veineuse profonde des membres inférieurs et embolie pulmonaire). Dans cette revue de la littérature, nous dressons un état des lieux sur les connaissances actuelles concernant l'utilisation des ACOD dans la MTEV-LA, notamment les thromboses splanchnique, cérébrale, ovarienne et des membres supérieurs. De nombreuses descriptions de cas et études observationnelles ont été publiées mais très peu d'essais randomisés l'ont été. Malgré cela, plusieurs sociétés savantes proposent la prescription d'ACOD dans certains cas spécifiques de MTEV-LA.

[Bleeding of unknown cause: diagnostic and therapeutic approach]. / Saignements d'origine indéterminée : approche diagnostique et thérapeutique.

A bleeding tendency is a frequent cause of hematological consultation. However, despite extensive biological investigations, no hemostasis abnormality is identified in the majority of patients, leading to the diagnosis of bleeding of unknown cause (BUC). Overall, the pathogenesis of BUC is most likely of multifactorial etiology and the accumulation of minor alterations in fibrin clot structure, fibrinolysis, platelet function and thrombin generation can tip the balance of hemostasis towards the bleeding side. In recent years, unconventional biological explorations have found new hemorrhagic abnormalities. Therapeutic options are limited but are usually effective to prevent bleeding.

Une tendance hémorragique est une cause fréquente de consultation hématologique. Toutefois, malgré des investigations biologiques étendues, aucune anomalie de l'hémostase n'est identifiée dans la majorité des cas. Il s'agit donc de saignements d'origine indéterminée. Dans l'ensemble, ceux-ci sont le plus vraisemblablement d'étiologie multifactorielle, et l'accumulation d'altérations mineures au niveau de la structure du caillot de fibrine, de la fibrinolyse, de la fonction plaquettaire et de la génération de thrombine peut faire basculer l'équilibre de l'hémostase du côté hémorragique. Ces dernières années, des explorations biologiques non conventionnelles ont permis de mettre en évidence de nouvelles anomalies hémorragipares. Les possibilités thérapeutiques sont peu nombreuses mais s'avèrent efficaces.

[Selected highlights in angiology and haemostasis for the year 2021]. / Angiologie-hémostase - Année 2021 : morceaux choisis.

Several topics among those that marked the year 2021 are discussed in this article. Factor XI represents an original target for new anticoagulants, and the first results of a phase 2 study of prophylaxis after knee replacement surgery are very promising. A real-life study confirms that the pulmonary embolism exclusion strategy using an age-adjusted D-dimer cut-off is safe and increases the diagnostic yield. Several studies of tranexamic acid provide further insight into the indications for its use and highlight some potential risks. Finally, the concerns regarding a potential risk of increased mortality related to paclitaxel-eluting technology used in lower limb revascularisation are questioned by the results of the latest trials.

Plusieurs sujets parmi ceux qui ont marqué l'année 2021 sont abordés dans cet article. Le facteur XI représente une cible originale pour de nouveaux anticoagulants et les premiers résultats d'une étude de phase 2 dans la prophylaxie après chirurgie du genou sont très prometteurs. Une étude de vie réelle confirme que la stratégie d'exclusion de l'embolie pulmonaire en utilisant un seuil de D-dimères adapté à l'âge est sûre et augmente le rendement diagnostique. Plusieurs études concernant l'acide tranexamique permettent de mieux cerner les indications de son utilisation et soulignent quelques risques potentiels. Finalement, les données récentes remettent en cause le risque de surmortalité liée à la technologie à élution au paclitaxel utilisée dans les interventions endovasculaires des membres inférieurs rapporté précédemment.

A Unique Case of Acquired Hemophilia A Presenting with Transient Ischemic Attack.

Acquired hemophilia A (AHA) is a rare but serious condition, usually associated with significant spontaneous or traumatic bleeding and a high mortality rate. In this report, we describe the case of an elderly patient presenting a transient ischemic attack concurrently with AHA. A thrombotic event in AHA is occasionally associated with the use of bypassing agents for treatment, but a spontaneous thrombotic event has not ever been described.

Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders.

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia® with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bß chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among FGG and FGA mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure-function relationship of fibrin to support hemostasis.

Fibrin(ogen) in human disease: both friend and foe.

Fibrinogen is an abundant protein synthesized in the liver, present in human blood plasma at concentrations ranging from 1.5-4 g/L in healthy individuals with a normal half-life of 3-5 days. With fibrin, produced by thrombin-mediated cleavage, fibrinogen plays important roles in many physiological processes. Indeed, the formation of a stable blood clot, containing polymerized and cross-linked fibrin, is crucial to prevent blood loss and drive wound healing upon vascular injury. A balance between clotting, notably the conversion of fibrinogen to fibrin, and fibrinolysis, the proteolytic degradation of the fibrin mesh, is essential. Disruption of this equilibrium can cause disease in distinct manners. While some pathological conditions are the consequence of altered levels of fibrinogen, others are related to structural properties of the molecule. The source of fibrinogen expression and the localization of fibrin(ogen) protein also have clinical implications. Low levels of fibrinogen expression have been detected in extra-hepatic tissues, including carcinomas, potentially contributing to disease. Fibrin(ogen) deposits at aberrant sites including the central nervous system or kidney, can also be pathological. In this review, we discuss disorders in which fibrinogen and fibrin are implicated, highlighting mechanisms that may contribute to disease.

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future.

Hereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding. Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

Influence of a 3-month low-calorie Mediterranean diet compared to the vegetarian diet on human gut microbiota and SCFA: the CARDIVEG Study.

PURPOSE: We evaluated the effect of low-calorie mediterranean (MD) and vegetarian (VD) diets on gut microbiome (GM) composition and short-chain-fatty acids (SCFA) production. METHODS: We performed next generation sequencing (NGS) of 16S rRNA and SCFA analysis on fecal samples of 23 overweight omnivores (16 F; 7 M) with low-to-moderate cardiovascular risk. They were randomly assigned to a VD or MD, each lasting 3 months, with a crossover study design. RESULTS: Dietary interventions did not produce significant diversity in the GM composition at higher ranks (family and above), neither between nor within MD and VD, but they did it at genus level. MD significantly changed the abundance of Enterorhabdus, Lachnoclostridium and Parabacteroides, while VD significantly affected the abundance of Anaerostipes, Streptococcus, Clostridium sensu stricto, and Odoribacter. Comparison of the mean variation of each SCFA between MD and VD showed an opposite and statistically significant trend for propionic acid (+ 10% vs - 28%, respectively, p = 0.034). In addition, variations of SCFA were negatively correlated with changes of some inflammatory cytokines such as VEGF, MCP-1, IL-17, IP-10 and IL-12, only after MD. Finally, correlation analyses showed a potential relationship-modulated by the two diets-between changes of genera and changes of clinical and biochemical parameters. CONCLUSIONS: A short-term dietary intervention with MD or VD does not induce major change in the GM, suggesting that a diet should last longer than 3 months for scratching the microbial resilience. Changes in SCFA production support their role in modulating the inflammatory response, thus mediating the anti-inflammatory and protective properties of MD.