Search

Venous thromboembolism (VTE) disease is the second leading cause of mortality in cancer patients. In the general population, the annual incidence of a thromboembolic event is about 117 cases per 100,000 persons, but cancer increases this risk about fourfold, while in patients receiving chemotherapy and surgical treatment, it is about sevenfold. Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer and represents a multistep process in which environmental factors and genetic alterations are implicated. Thrombotic risk is considered empirically low in OSCC patients, although few data are available. Having limited information available may result in poor awareness of VTE prevention in OSCC, risking jeopardising the oncologic treatment and increasing the morbidity and mortality among these patients. In this paper, the topic of OSCC-associated thrombosis will be discussed.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy >= 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC >= 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8-12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagul

Background. Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half‐life (EHL) CFCs and the non‐replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden. Methods. To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate‐Talk‐Estimate (ETE) method (“mini‐Delphi”), in this way reaching consensus. Results. Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real‐world experience, particularly in some clinical settings, and the lack of evidence on long‐term safety and efficacy of non‐replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection. Conclusions. The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long‐term clinical and laboratory follow‐up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed.

Not available

Oncologists continue to prefer traditional low molecular weight heparins over direct oral anticoagulants (DOAC) for the treatment of venous thromboembolism (VTE) cancer-related. Recently published studies supporting the use DOACs in this patient setting confirm the safety and efficacy of the treatment, but this still does not seem to be enough. The major obstacles to their use are interaction with chemotherapeutic agents, fear of haemorrhage, poor habit of using DOACs for VTE prophylaxis. But what if the haemostasis and thrombosis laboratory reassured oncologists? In this short report we talk about this topic in order to stimulate a fruitful discussion between expert.

N/A

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 (Formula presented.) 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.

Background: Patients hospitalized with COVID-19 experienced an increased risk of venous thromboembolism. Aims: To evaluate the effect of chronic oral anticoagulation (OAC) therapy, both with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), on prognosis of COVID-19 older patients. Methods: Single-center prospective study conducted in the Emergency Department (ED) of a teaching hospital, referral center for COVID-19 in central Italy. We evaluated all the patients ≥ 65 years, consecutively admitted to our ED for confirmed COVID-19. We compared the clinical outcome of those who were on chronic OAC at ED admission with those who did not, using a propensity score matched paired cohort of controls. The primary study endpoint was all-cause in-hospital death. Patients were matched for age, sex, clinical comorbidities, and clinical severity at presentation (based on NEWS ≥ 6). Study parameters were assessed for association to all-cause in-hospital death by a multivariate Cox regression analysis to identify independent risk factor for survival. Results: Although overall mortality was slightly higher for anticoagulated patients compared to controls (63.3% vs 43.5%, p = 0.012), the multivariate adjusted hazard ratio (HR) for death was not significant (HR = 1.56 [0.78–3.12]; p = 0.208). Both DOACs (HR 1.46 [0.73–2.92]; p = 0.283) and VKAs (HR 1.14 [0.48–2.73]; p = 0.761) alone did not affect overall survival in our cohort. Conclusions: Among older patients hospitalized for COVID-19, chronic OAC therapy was not associated with a reduced risk of in-hospital death. Moreover, our data suggest similar outcome both for patients on VKAs or in patients on DOACs.

We concisely review clinical, autopsy, experimental and molecular data of 2019 coronavirus disease (COVID-19). Angiotensin-converting enzyme 2 disruption and thromboinflammatory microangiopathy emerge as distinctive features. Briefly, entry of the virus into microvessels can profoundly disrupt the local renin-angiotensin system, cause endothelial injury, activate the complement cascade and induce powerful thromboinflammatory reactions, involving, in particular, von Willebrand factor, that, if widespread, may lead to microvascular plugging, ischemia and, ultimately, organ failure. We believe the current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disease.

AIMS: The ORal anticoagulants In fraGile patients with percutAneous endoscopic gastrostoMy and atrIal fibrillation (ORIGAMI) study investigates the safety and efficacy of Edoxaban administered via PEG in patients with atrial fibrillation and a clinical indication for a long-term anticoagulation. DESIGN: In this prospective, single-centre observational study, 12 PEG-treated patients with indication to anticoagulation will receive edoxaban via PEG and will be followed up to 6 months. Plasma antifactor Xa activity and edoxaban concentrations will be assessed. Thromboembolic (ischaemic stroke, systemic embolism, venous thromboembolism) and bleeding events (Bleeding Academic Research Consortium and Thrombolysis in Myocardial Infarction) will be recorded at 1 and 6 months. PRELIMINARY RESULTS: A retrospective analysis of five atrial fibrillation cases undergoing PEG implantation at our Institution who received edoxaban via PEG showed plasma anti-FXa levels at a steady state of 146 ± 15 ng/ml, without major adverse event at a mean follow-up of 6 months. CONCLUSION: ORIGAMI prospectively investigates PEG-administration of edoxaban in PEG-treated patients requiring long-term anticoagulation. Our preliminary retrospective data support this route of DOAC administration. CLINICALTRIALSGOV IDENTIFIER: NCT04271293.

Purpose: Cerebral venous thrombosis (CVT) is a rare disease in children, characterized by partial or total occlusion of blood flow in the cerebral venous system. The aim of this study is to describe clinical presentation, neuroimaging features, therapeutic management, and outcome of children with CVT. Methods: We retrospectively analyzed the data, including clinical manifestations, laboratory data, neurological findings, and treatment of children with radiologically confirmed CVT, admitted between January 2010 and March 2020 to our hospital. Cases of CVT complicating brain surgery were excluded. Results: We enrolled 24 children with CVT. Infection was the main etiology (58.3%), followed by trauma in 16.7% of cases. In the remaining 25% of cases, the cause was identified only in one patient presenting a thrombophilic factor. The most frequent site of thrombosis was the superficial venous system (86.8%), with multiple localizations disclosed in 79% of patients. All children received anticoagulant therapy with low molecular weight heparin (LMWH). One patient died for systemic complications of an underlying disease. No patient developed hemorrhagic events during the therapy, lasting from 35 to 360 days (mean 86 days). In all but one surviving patients (22 out of 24), recanalization of the sinus was observed at AngioMRI performed during follow-up. No neurological complications of CVT were recorded (mean follow-up: 1.5 year). Conclusions: CVT may present with subtle and unspecific clinical manifestations in children. High level of suspicion should be kept in trauma and sinusitis. Anticoagulation treatment is safe and effective and should be promptly started to improve outcome.

Not available

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 D9D3 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.

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.

Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for extensive conformational transitions in the VWF multimers that change their structure from a globular form to a stretched linear conformation. This feature makes this protein particularly prone to be investigated by mechanochemistry, the branch of the biophysical chemistry devoted to investigating the effects of shear forces on protein conformation. This review describes the structural elements of the VWF molecule involved in the biochemical response to shear forces. The stretched VWF conformation favors the interaction with the platelet GpIb and at the same time with ADAMTS-13, the zinc-protease that cleaves VWF in the A2 domain, limiting its prothrombotic capacity. The shear-induced conformational transitions favor also a process of self-aggregation, responsible for the formation of a spider-web like network, particularly efficient in the trapping process of flowing platelets. The investigation of the biophysical effects of shear forces on VWF conformation contributes to unraveling the molecular mechanisms of many types of thrombotic and haemorrhagic syndromes.

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.

Extensive data support the safety of direct oral anticoagulants compared with vitamin K antagonists in patients with non-valvular atrial fibrillation, leading to a significantly increase in the use of these compounds in clinical practice. However, there is no compelling evidence supporting the use of direct oral anticoagulant in individuals who are intubated or have a percutaneous endoscopic gastrostomy (PEG): patients with several co-morbidities are underrepresented in clinical trials, so the best long-term strategy for anticoagulation is difficult to ascertain. The aim of the present report was to evaluate the safety and efficacy of edoxaban administered via PEG in a patient with heart failure and a history of atrial fibrillation affected by amyotrophic lateral sclerosis (ALS). A 71-year-old man with atrial fibrillation, advanced ALS, type II diabetes mellitus, and hypertension presented to the emergency department with dyspnoea and tachycardia. Because vitamin K antagonist and rivaroxaban 15 mg were dropped because of difficult international normalized ratio control (time in therapeutic range <30%) and severe haematuria, respectively, edoxaban 30 mg (crushed pill) daily was administered based on the patient's weight of 58 kg. Mean edoxaban plasma concentration–time profiles were measured, as anti-Xa activity, 2 h before and at 2, 6, and 22 h after drug administration and then compared with the pharmacokinetic profile of edoxaban 30 mg in healthy subjects. An additional testing of steady-state peak plasma concentration of edoxaban after 10 days and a 30 day follow-up were evaluated. The values of the pharmacokinetic parameters, analysed with a non-compartmental analysis by PKSolver module, showed that Cmax and AUC0→t were only slightly higher than those observed in healthy subjects, while the half-life and observed clearance were significantly longer and lower, respectively, than in normal subjects. Steady-state peak plas

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

Background: The optimal duration of anticoagulant treatment after venous thromboembolism (VTE) should be evaluated in relation to bleeding risk. This assessment is particularly difficult with elderly patients, because of their increased risk of both recurrences and hemorrhages. Bleeding risk stratification models have been proposed, but their predictive ability in very elderly patients is unknown. We aimed to assess six bleeding stratification models in this setting, by using information available in our dataset. Patients and methods: Patients aged ≥ 80 years receiving vitamin K antagonists (VKAs) for the secondary prevention of VTE were eligible for this prospective cohort study. All patients were followed at Italian anticoagulation clinics for monitoring of VKA treatment. Risk factors for bleeding were collected, and major bleeding events and mortality were documented during follow-up. The association of bleeding events with the available risk factors was tested by means of Cox regression analysis; the c-statistic was used to quantify the predictive validity of the classification schemes. Results: A total of 1078 patients (37.2% males; mean age, 84 years) were enrolled in the study, for a total observation period of 1981 patient-years. The rate of major bleeding was 2.4 per 100 patient-years (47 events; one was fatal). The mortality rate was 5.2 per 100 patient-years. None of the considered risk factors were significantly associated with bleeding events. The predictive validity of the risk stratification models was low, and the most accurate model was not specifically developed for VTE patients (HEMORR2 HAGES, c-statistic 0.60, 95% confidence interval 0.49-0.70). Conclusions: Bleeding risk stratification models appear to have little accuracy in very elderly VTE patients.

Background: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of alpha-granule secretory proteins, myelofibrosis and splenomegaly. Methods and results: Platelet function studies showed a marked reduction of aggregation and Ca(2+) mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B(2) (TXB(2)) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or alpha-granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet alpha-granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB(2) production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. Conclusions: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of alpha-granule content in GPS.

n/a

In this study, the experimental conditions to perform the electrophoretic analysis of the platelet membrane's glycoproteins are described