Search

Objective We aim to evaluate 3-year effects of ocrelizumab (humanized anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS)) on lymphocytes, neutrophils and immunoglobulins: (1) when compared with pre-infusion assessment; (2) over the course of treatment; and (3) possible clinical correlates of the observed immunological modifications. Methods This real-world observational cohort study has been conducted on prospectively collected data from 78 MS patients (mean age 47.8 ± 10.5 years; females 48.7%) commencing on ocrelizumab from 2018, with mean follow-up of 36.5 ± 6.8 months. Clinical data and blood samples were collected every three months. Total lymphocyte count and subpopulations were assessed on peripheral blood using flow cytometry. Serum immunoglobulins were evaluated with nephelometry. Results When compared with pre-infusion values, we observed reduction of total, CD19 and CD20 lymphocyte counts; however, after the first infusion, their levels remained substantially stable. Over time we observed a progressive reduction of CD8 lymphocytes, while no changes were observed for CD4, CD27, CD3CD27, and CD19CD27. After the first infusion, we observed reduction in IgG, which further decreased during the follow-up. Higher probability of EDSS progression was associated with reduced modulation of CD8 lymphocytes. Interpretation Ocrelizumab affects both humoral and cellular immune responses. Disability progression over the follow-up was associated with lower CD8 cytotoxic T-lymphocyte reduction. Changes in humoral response are immediate and sustained, while modulation of cellular immunity occurs progressively through regular re-treatment, and is related to clinical stability.

Background Patients with multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) that can expose them to reactivation of potential occult hepatitis B virus (HBV) infection (pOBI). We aimed to evaluate the MS Centers behavior regarding HBV screening and prophylaxis in a large cohort of MS patients receiving anti-CD20 or cladribine. Methods Retrospective, multicentric study recruiting Italian MS patients treated with rituximab, ocrelizumab and cladribine. Results We included 931 MS patients from 15 centers. All but 38 patients performed a complete HBV screening. Patients’ age > 50 years was significantly associated with no history of vaccination and HBsAb titres p p = 0.5), pre-or post-therapy vaccination (p = 0.2) and number of previous DMTs (p = 0.2). Among pOBI patients (n = 53), 21 received antiviral prophylaxis, while only 13 had HBV DNA monitoring and 19 patients neither monitored HBV DNA nor received prophylaxis. Conclusions Baseline HBV screening in patients receiving anti-CD20 and cladribine is a consolidated practice. Nonetheless, HBV vaccination coverage is still lacking in such population and age is a significant factor associated with low HBV protection. Rituximab, ocrelizumab and cladribine did not impair HBV vaccine response. Almost 35% of pOBI patients fail to receive HBVr prevention. Management of HBV prophylaxis could be improved in MS patients and further prospective studies are needed to assess the effectiveness of prophylactic strategies in such patients.

Background: To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). Case: We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. Conclusions: Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.

Background It is still unknown whether COVID-19 vaccines induce a prothrombotic state or increase the hypercoagulable condition in subjects with a predisposition to thrombosis. Objectives We evaluated the coagulation profile in a series of healthy subjects who received the first dose of the BNT162b2 or the ChAdOx1 vaccines and assessed whether hypercoagulability developed. Patients/methods Volunteers among the staff of the University of Padua or health care professionals in the Padua University Hospital who had received either the ChAdOx1 or BNT162b2 vaccine in the previous 10 ± 2 days were eligible. A cohort of unvaccinated volunteers among family members of the University staff acted as control group. Global coagulation monitoring was assessed by whole blood rotational thromboelastometry, whole blood impedance aggregometry and thrombin generation. Platelet count was also obtained. Results One hundred and ninety subjects were enrolled: 101 (53.2%) received the ChAdOx1 vaccine and 89 (46.8%) the BNT162b2 vaccine. Twenty-eight non-vaccinated subjects acted as controls. Thromboelastometry parameters were all comparable among groups. Thrombin receptor activating peptide (TRAP)-, ADP- and ASPI-induced platelet aggregation were similar among groups, as well as platelet count. Endogenous thrombin potential (ETP) was comparable among groups. The results were confirmed after controlling for age, gender and hormonal. Considering women taking combined oral contraceptives or thrombophilia carriers, no differences were detected in thromboelastometry or thrombin generation parameters between subjects who received ChAdOx1 vs. BNT162b2 vaccines. Conclusions No significant activation of fibrinogen-driven coagulation, plasma thrombin generation or clinically meaningful platelet aggregation after ChAdOx1 or BNT162b2 vaccination was observed.

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.

Background Microvesicles (MVs) play a role in inflammation, coagulation, and vascular homeostasis in liver disease. Aim To characterize circulating plasma MVs profile in patients with decompensated cirrhosis and acute kidney injury (AKI). Methods We measured the levels of total, endothelial, platelet, tissue factor (TF)+, leukocyte and hepatocyte MVs by new generation flow-cytometry in a prospective cohort of patients with decompensated cirrhosis with and without AKI. Results Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Patients with cirrhosis with AKI had significantly higher calcein+ (total), endothelial, and platelet-MVs. Conversely, TF+, leukocyte, and hepatocyte-MVs were comparable between groups. Resolution of AKI was associated with significantly decreased total and endothelial-MVs that became comparable with those in patients without AKI. Platelet MVs significantly decreased but remained higher compared to patients without AKI. TF+MVs significantly decreased and became lower than patients without AKI. Leukocyte and hepatocyte-MVs remained unchanged. Creatinine (OR 4.3 [95%CI 1.8–10.7]), MELD (OR 1.13 [95%CI 1.02–1.27]), any bleeding (OR 9.07 [95%CI 2.02–40.6]), and hepatocyte-MVs (OR 1.04 [95%CI 1.02–1.07]) were independently associated with 30-day mortality. Conclusion AKI worsened vascular and cellular homeostasis in patients with cirrhosis, particularly by inducing endothelial dysfunction and platelet activation. AKI did not worsen systemic inflammation and hepatocytes activation.

High coagulation factor VIII (FVIII) levels comprise a common risk factor for venous thromboembolism (VTE), but the underlying genetic determinants are largely unknown. We investigated the molecular bases of high FVIII levels in 2 Italian families with severe thrombophilia. The proband of the first family had a history of recurrent VTE before age 50 years, with extremely and persistently elevated FVIII antigen and activity levels (>400%) as the only thrombophilic defects. Genetic analysis revealed a 23.4-kb tandem duplication of the proximal portion of the F8 gene (promoter, exon 1, and a large part of intron 1), which cosegregated with high FVIII levels in the family and was absent in 103 normal controls. Targeted screening of 50 unrelated VTE patients with FVIII levels ≥250% identified a second thrombophilic family with the same F8 rearrangement on the same genetic background, suggesting a founder effect. Carriers of the duplication from both families showed a twofold or greater upregulation of F8 messenger RNA, consistent with the presence of open chromatin signatures and enhancer elements within the duplicated region. Testing of these sequences in a luciferase reporter assay pinpointed a 927-bp region of F8 intron 1 associated with >45-fold increased reporter activity in endothelial cells, potentially mediating the F8 transcriptional enhancement observed in carriers of the duplication. In summary, we report the first thrombophilic defect in the F8 gene (designated FVIII Padua) associated with markedly elevated FVIII levels and severe thrombophilia in 2 Italian families.

Glucocorticoids are potent anti-inflammatory agents that are widely used for the treatment of many inflammatory, autoimmune, and neoplastic disorders. However, their beneficial effect is associated with several side effects, including an increased risk of cardiovascular complications, such as myocardial infarction and stroke. Whether their use also contributes to a procoagulant state, and therefore increases the risk of venous thromboembolism (VTE), is still a matter of debate. As an increased risk of venous thrombotic events is described in patients with Cushing's syndrome, which is characterized by endogenous hypercortisolism, it is reasonable to speculate that the chronic administration of glucocorticoids may induce a hypercoagulable state. However, it seems virtually impossible to separate the role of the drug from the underlying condition, which itself predisposes to the development of VTE. Actually, some evidence suggests that the use of exogenous glucocorticoids for the treatment of underlying disease and its exacerbations may further amplify the risk of VTE. Moreover, a procoagulant state has also been reported in healthy participants receiving oral glucocorticoids versus placebo. We have performed a concise narrative review on available data on the influence of exogenous glucocorticoids on hemostasis and their clinical impact on the risk of VTE.

This study investigates longitudinal changes in health-related quality of life (HRQoL) in early-onset multiple sclerosis (MS) patients and explores the impact of disease activity (relapses) on such changes. People with MS (PwMS) onset between 12 and 25 years of age were followed longitudinally. At baseline and at year 4, patients were asked to fill the Paediatric Quality of life inventory (PedsQL). Demographic and clinical features were collected at both time points. Longitudinal within-group comparison of HRQoL total score and sub-scores was performed via paired samples t-test. The effect of relapses on the HRQoL changes over time was explored via linear mixed-effects analysis. No longitudinal changes were observed in the overall PedsQL score, nor in the physical, school and psychological functioning. An increase in the social functioning subscale (p < 0.001) and a decrease in the emotional subscale (p = 0.006) were observed. The change in social functioning, but not the one in the emotional subscale, was affected by the occurrence of relapses (p = 0.044). In conclusion, stimulating the patients to accept their emotional responses to health-related limitations, while preserving their social and relational resources seems key to the preservation of an adequate QoL over time in juvenile-onset MS.

The typical symptoms of COVID-19 mimic those of the common season flu. In addition, several changes in the coagulation processes have been observed. To date, it's not fully clear how COVID-19 may affect patients with hereditary bleeding disorders. Anticoagulation in patients with haemophilia is still debated, but in this case could be needed. We are reporting a case of an elderly patient with mild haemophilia A hospitalized for Sars-Cov-2. On the 15th day of hospitalization, we observed an increase of all coagulation parameters. An antithrombotic prophylaxis at low dosage was immediately started, then increased at prophylactic dosage. Even if much more data are needed to ascertain the real thrombotic risk of haemophilia A in COVID-19 patients, it's clear that the FVIII and vWF should be strictly monitored in order to promptly establish an adequate treatment and avoid the onset of thromboembolic events, even fatal, causing many deaths in COVID-19 patients.

Background Hypocoagulability and impaired platelet function have been associated with a high risk of death in sepsis. The aim of this cohort study was to determine whether sepsis-induced hypocoagulability and platelet dysfunction (assessed by ROTEM® and MULTIPLATE®, respectively) are increased in sepsis patients who died within 28 days after diagnosis compared with patients who died between 29 and 90 days after diagnosis. Methods Consecutive patients admitted to the intensive care unit of Padova University Hospital from March 2015 to March 2018 for severe sepsis were considered. We collected blood samples from all patients to determine ROTEM® and MULTIPLATE® parameters. Each enrolled patient underwent a 90-day follow-up and the mortality rate was recorded. Results Of 120 patients, 36 (30%) died within 28 days post-diagnosis (Group A), 23 (19%) died between days 29 and 90 post-diagnosis (Group B), and 61 (51%) were alive after 90 days (survivors). The clotting time in the ROTEM® test and clot formation time in the EXTEM test were significantly more prolonged in Group A than in B. Both groups showed a significantly higher hypocoagulability than survivors in the EXTEM test. MULTIPLATE® platelet function analysis showed that platelet function was significantly lower in Group A than in Group B. Conclusions The present study showed that the combination of thromboelastometry and impedance aggregometry may help identifying sepsis patients at high risk of short-term death. Larger studies are warranted to corroborate our results.

Patients with pancreatic cancer have a very high risk of both venous and arterial thrombosis compared with other cancers, caused by a tumour-driven hypercoagulable state. Better understanding of pancreatic cancer-associated prothrombotic and proinflammatory mechanisms opens the door to controlling prothrombotic states, ideally, without affecting the overall haemostasis. This narrative review brings together currently available evidence on epidemiology and pathogenesis of thrombotic complications in pancreatic adenocarcinoma. We describe risk factors for thrombosis and established and novel mechanisms of hypercoagulability. Among novel pathways of hypercoagulability, the release of neutrophils extracellular traps (NETs) by activated neutrophils and the crucial role of extracellular vesicles (EV) in participating in platelet and coagulation activation were described. We also reported recent evidence on EV role in thrombin generation amplification through the activation of the intrinsic pathway, discussing potential molecules implicated in this process.

A large number of daily requests to exclude possible prothrombotic risk factors for coronavirus disease 2019 (COVID-19) vaccines were received. Our aim was to longitudinally evaluate coagulation profiles in a series of healthy subjects who received COVID-19 vaccination and assess hypercoagulability thereafter. Volunteers awaiting a first or second dose of either the ChAdOx1 or BNT162b2 vaccine were enrolled. Venous samples were obtained at baseline (before the vaccine) and longitudinally 3 ± 2 days (T1) and 10 ± 2 days after the vaccine (T2). Global coagulation monitoring was assessed via platelet count, whole blood thromboelastometry and impedance aggregometry, plasma thrombin generation, and anti-platelet factor 4 (PF4)/heparin immunoglobulin G antibodies. One hundred and twenty-two subjects were enrolled (61 [50%] ChAdOx1 and 61 BNT162b2). The ChAdOx1 cohort showed a slight but transient increase in thrombin generation (mainly endogenous thrombin potential [ETP] with thrombomodulin and ETP ratio) at T1, which promptly decreased at T2. In addition, the second dose of either vaccine was associated with increased thrombin peak, ETP with thrombomodulin, and ETP ratio. At baseline, 3.2% of the ChAdOx1 cohort and 1.6% BNT162b2 cohort were positive for PF4/heparin antibodies with a stable titer through T1 and T2. No relevant differences were detected in platelet count and aggregation, or thromboelastometry parameters. No thrombotic or hemorrhagic events occurred. We can confirm that no clinically meaningful hypercoagulability occurred after either vaccine, albeit keeping in mind that thrombin generation may increase in the first days after the second dose of either vaccine and after the first dose of the ChAdOx1 vaccine.

Pivotal trials showed the effectiveness of the monoclonal antibody ocrelizumab in relapsing and progressive multiple sclerosis (MS). However, data on everyday practice in MS patients and markers of treatment effectiveness are scarce. We aimed to collect real-world data from ocrelizumab-treated MS patients, relapsing-remitting (RR) and progressive MS patients (PMS), including active secondary progressive MS (aSPMS) and primary progressive MS (PPMS) patients, and to explore potential prognostic factors of clinical outcome. Patients were enrolled at MS centres in the Campania region, Italy. We collected clinic-demographic features retrospectively one year before ocrelizumab start (T−1), at ocrelizumab start (T0), and after one year from ocrelizumab start (T1). We explored possible clinical markers of treatment effectiveness in those patients receiving ocrelizumab treatment for at least one year using multilevel-mixed models. We included a total of 383 MS patients (89 RRMS and 294 PMS; 205 females, mean age: 45.8 ± 11.2, disease duration: 12.7 ± 11.6 years). Patients had a mean follow-up of 12.4 ± 8.2 months, and 217 patients completed one-year ocrelizumab treatment. Overall, EDSS increased from T−1 to T0 (coeff. = 0.30, 95% coefficient interval [CI] = 0.19–0.41, p < 0.001) without a further change between T0 and T1 (p = 0.61). RRMS patients did not show an EDSS change between T−1 and T0 nor between T0 and T1. Conversely, PMS patients showed EDSS increase from T−1 to T0 (coeff. = 0.34, 95% CI = 0.22–0.45, p < 0.001) without a further change between T0 and T1 (p = 0.21). PMS patients with a time from conversion shorter than 2 years showed increased EDSS from T−1 to T0 (coeff. = 0.63, 95% CI = 0.18–1.08, p = 0.006) without a further change between T0 and T1 (p = 0.94), whereas PMS patients with a time from conversion longer than 2 years showed increased EDSS from T0 to T1 (coeff. = 0.30, 95% CI = 0.11–0.49, p = 0.002). Naïve patients showed an EDSS decrease between T0 and T1 (coeff. = −0.30, 95% CI = −0.50–−0.09, p = 0.004). In conclusion, our study highlighted that early ocrelizumab treatment is effective in modifying the disability accrual in MS patients.

The incidence of post-thrombotic syndrome (PTS) in patients with deep vein thrombosis (DVT) treated with direct oral anticoagulants (DOACs) remains a matter of debate. Hence, our endeavor to investigate a large cohort of patients with a first episode of proximal DVT treated with DOACs to ascertain the incidence and predisposing risk factors for PTS. All consecutive patients referred to the Thrombotic and Haemorrhagic Diseases Unit of Padova University Hospital (Italy) between January 2014 and January 2018 for a first episode of proximal DVT were considered for enrollment. Participants received DOACs for a minimum period of 3 months. PTS was assessed using the Villalta score up to 36 months after DVT diagnosis. Among 769 enrolled patients (M/F 353/416, age range 26–87 years), 152 (19.8%) developed PTS and 30 (3.9%) developed severe PTS. The adjusted hazard ratio was significant for obesity (1.64, 95% CI 1.28–2.39) and DVT site (femoral and/or iliac veins vs popliteal vein) (1.23, 95% CI 1.15–3.00). The incidence of PTS is not negligible in patients with proximal DVT despite the use of DOACs. We identified obesity and iliofemoral DVT as possible risk factors for PTS. Larger prospective studies are needed to confirm our findings and optimize therapeutic strategies.

Botulinum toxin (BT) is an effective treatment for spasticity symptoms in multiple sclerosis (MS). Despite its wide use in clinical practices, only few studies have explored long-term persistence. We aim to evaluate the rate of discontinuation of BT treatment and the correlation with MS, spasticity, and injection variables. This retrospective study on 3-year prospectively collected data included 122 MS patients receiving BT injections for spasticity. We collected MS clinical variables (disease durations, Expanded Disability Status Scales [EDSSs], disease-modifying treatments [DMT], and Symbol Digit Modalities Tests [SDMTs]), modified Ashworth scales [MASs], concomitant treatments, and injection variables (formulation, dose, number of injections, and intervals between injections). A total of 14 out of the 122 patients discontinued BT after a mean time of 3.0 ± 1.5 years. In the Cox regression model including the MS clinical variables, the probability of BT discontinuations increased in patients with DMT changes during follow-ups (HR = 6.34; 95%Cl = 2.47, 18.08; p < 0.01) and with impaired SDMTs (HR = 1.20; 95%Cl = 1.04, 1.96; p < 0.01). In the model including the spasticity variables, there were no associations between BT discontinuation and MAS or other spasticity treatments. In the model including the injection variables, the probability of discontinuation decreased by 80% for each cumulative injection (HR = 0.16; 95%Cl = 0.05, 0.45; p < 0.01), but increased by 1% for each additional day over the 3-month interval between injections (HR = 1.27; 95%Cl = 1.07, 1.83; p < 0.01). BT discontinuation was associated with concomitant MS-related issues (e.g., treatment failure and DMT change) and the presence of cognitive impairment, which should be accounted for when planning injections. The interval between injections should be kept as short as possible from regulatory and clinical perspectives to maximize the response across all of the spasticity symptoms and to reduce discontinuation in the long term.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.

Coronavirus disease 2019 (COVID-19) is a systemic inflammatory condition associated with coagulopathy which may result in severe thromboembolic complications. Cardiac injury is not uncommon in hospitalized COVID-19 patients and therefore we aimed to investigate whether it stems from an abnormal coagulative state.We conducted a retrospective cross-sectional study on consecutive patients hospitalized due to COVID-19. Traditional coagulation and whole blood rotational thromboelastometry tests were compared between patients with and without cardiac injury. Cardiac injury was defined by increased levels of high-sensitivity cardiac troponin I (hs-cTnI).The study population consisted of 104 patients (67% males, median age 65 years), of whom 40 (38%) developed cardiac injury. No clinical differences in the traditional coagulation parameters were observed between patients with and without cardiac injury. Thromboelastometry analysis revealed abnormal maximum clot firmness (MCF) levels in FIBTEM assay in 80 (77%) patients. No significant differences in MCF values (p ​= ​0.450) and percentage of abnormal MCF (p ​= ​0.290) were detected between patients with and without cardiac injury. Cardiac injury - not hypercoagulability - was associated with mortality (p ​= ​0.016).No differences in traditional coagulation and rotational thromboelastometry parameters were found among hospitalized COVID-19 patients with and without cardiac injury. Other mechanisms besides hypercoagulability may be a main culprit for cardiac injury in COVID-19 patients.

OBJECTIVESThere is no consensus on the risk of thrombotic events following video-assisted thoracoscopic surgery (VATS) versus open thoracotomy (OT), despite multiple studies. In fact, the estimates for the overall thrombotic risk for VATS versus OT are inconclusive. In this systematic review and meta-analysis, we endeavoured to ascertain the best estimate of thrombotic risk in VATS versus OT.METHODSRelevant studies were searched through PubMed and Cochrane Library database. Outcomes of interests were myocardial infarction (MI), pulmonary embolism (PE) and deep vein thrombosis (DVT). Data were pooled using random-effects model. The results were presented as odds ratio (OR) with the corresponding 95% confidence interval (CI).RESULTSNineteen studies were meta-analysed: 17 observational studies and 2 randomized controlled trials. Using propensity-matched data, in comparison with OT, VATS was associated with a statistically significant, postoperative reduction in MI (OR 0.60, 95% CI 0.39–0.91; P = 0.017), DVT/PE (OR 0.52, 95% CI 0.44–0.61; P CONCLUSIONSOverall, the postoperative thrombotic risk following VATS is significantly lower than OT. Further prospective randomized controlled trials with large sample sizes are warranted to corroborate our findings.

Optical Coherence Tomography Angiography (OCTA) abnormalities occur in multiple sclerosis (MS) over the course of the disease. OCTA investigations at early MS stages are lacking. We aimed to investigate vessel density in macular and papillary regions over two years after an initial demyelinating event (IDE). Vessel density was analyzed in superficial, deep, choriocapillaris and radial peripapillary plexus at baseline, and after one and two years. We also evaluated structural OCT parameter changes of the ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). We evaluated 30 eyes from 15 IDE patients (7 females, 8 males, mean age 28.4 ± 9.6 years) and 30 eyes from 15 healthy controls. After 2 years, we reported in the IDE group a reduced vessel density in the superficial capillary plexus, deep capillary plexus and radial peripapillary capillary plexus with respect to the baseline (coeff. β = −2.779, p = 0.013; coeff. β = −4.055, p = 0.018 and coeff. β = −2.687, p ≤ 0.001; respectively), while GCC and RNFL thicknesses did not change. Vessel density reduction was not associated with an expanded disability status scale (EDSS) change, relapse occurrence or magnetic resonance imaging activity. The analysis of healthy controls did not reveal any impairment in OCT and OCTA parameters over 2 years of follow-up. Retinal vascular loss occurs in patients with an IDE independently from clinical and radiological disease activity. Retinal vessel density could represent a novel early biomarker to monitor the MS pathological burden.

Background: Low plasma levels of protein C or protein S are associated with venous thromboembolism rather than myocardial infarction. The high coagulant activity in patients with thrombophilia with a (familial) defect in protein C or S is explained by defective protein C activation, involving thrombomodulin and protein S. This causes increased plasmatic thrombin generation.Objective: Assess the role of platelets in the thrombus- and fibrin-forming potential in patients with familial protein C or protein S deficiency under high-shear flow conditions.Patients/Methods: Whole blood from 23 patients and 15 control subjects was perfused over six glycoprotein VI-dependent microspot surfaces. By real-time multicolor microscopic imaging, kinetics of platelet thrombus and fibrin formation were characterized in 49 parameters.Results and Conclusion: Whole-blood flow perfusion over collagen, collagen-like peptide, and fibrin surfaces with low or high GPVI dependency indicated an unexpected impairment of platelet activation, thrombus phenotype, and fibrin formation but unchanged platelet adhesion, observed in patients with protein C deficiency and to a lesser extent protein S deficiency, when compared to controls. The defect extended from diminished phosphatidylserine exposure and thrombus contraction to delayed and suppressed fibrin formation. The mechanism was thrombomodulin independent, and may involve negative platelet priming by plasma components.

Background Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation. Methods Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca2+]i, aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed. Results Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation. Conclusion Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.

Objective To conduct a comprehensive evaluation of coagulation profiles-via traditional and whole blood thromboelastometry tests-in coronavirus disease 2019 (COVID-19)-positive vs COVID-19-negative patients admitted to medical wards for acute pneumonia. Patients and Methods We enrolled all consecutive patients admitted to internal medicine wards of Padova University Hospital between 7 March and 30 April, 2020, for COVID-19-related pneumonia (cases) vs non-COVID-19 pneumonia (controls). A group of healthy individuals acted as baseline for thromboelastometry parameters. Results Fifty-six cases (mean age, 64±15 years; male/female, 37/19) and 56 controls (mean age, 76±11 years; male/female, 35/21) were enrolled. Cases and controls exhibited markedly hypercoagulable thromboelastometry profiles vs healthy individuals, mainly characterized by a significantly shorter propagation phase of coagulation (clot formation time) and significantly increased maximum clot firmness (P