HEMOSTATIC ACTIVATION MARKERS AND SEROLOGICAL RESPONSE IN SUBJECTS RECEIVING ANTICOVID- 19 VACCINATION

Background: SARS-COV2 infection is associated with inflammation, hypercoagulability and endothelial damage. Anti-SARS-COV2 vaccines have radically changed the course of the pandemic, however, reports on rare thrombotic events raise concern in the scientific community and the general population. Aims: In a prospectively enrolled cohort of adult subjects undergoing mRNA or adenovirus vector vaccination, we wanted to longitudinally evaluate the changes in levels of hemostatic biomarkers (i.e. activation of blood coagulation and perturbance of endothelium and fibrinolysis), together with the serological response, and occurrence of manifest thrombotic complications. Methods: Peripheral venous blood samples were collected at enrollment (day 0, D0) before the 1st vaccine dose, and on 15 (D15), 60 (D60), 90 (D90) and 180 (D180) days after the 1st dose. At each time point, hemostatic markers (i.e., fibrinogen, D-dimer, FVIII, von Willebrand Factor [vWF] antigen and activity, F1+2, thrombomodulin, protein C, protein S, FXIII, tPA, and PAI-1), and anti-Spike receptor-binding-domain protein (anti-S/RBD) IgG were measured. Follow up is currently continuing. Results: Fifty-three subjects (57% males) with a median age of 50 years (range 23-86) were enrolled into the study and followed-up for 6 months: 36 (68%) received BNT162b2, 6 (11%) mRNA-1273, and 8 (15%) ChAdOx1 nCoV-19 vaccines, in 2 doses over 21, 30 and 77 days, respectively;while 3 (6%) subjects received Ad26.COV2.S as single shot. Twenty individuals (38%) reported previous history of COVID-19, with a mean time from infection to vaccination of 10 months (4-18);only 1 required Hospitalization. Nine subjects presented cardiovascular risk factors and 4 a prior, non-active, cancer;3 were on anticoagulation for atrial fibrillation. The evaluation of the hemostatic biomarkers at the different time points showed variations in some of the parameters evaluated, with median values remaining within normal range levels. Specifically, compared to baseline, we observed a significant increase in thrombomodulin at D90 (p=0.001) and D180 (p=0.03), in parallel to a significant decrease in fibrinogen (D60), vWFAg (D60 and D180), FVIII (D60, D90 and D180), and TPA (D60 and D90) levels. The reduction of these biomarkers was particularly evident in individuals with a history of COVID-19. Of interest, this group of subjects was also characterized by significantly lower levels of PAI-1 both at baseline (7.18 ng/mL vs 17.53 ng/mL;p<0.0001), and at other time points (p<0.0001), and by an increase in F1+2 at D90 (p=0.02). The association between lower baseline PAI-1 levels with history of COVID-19 was confirmed by linear regression analysis (B= -10.351, p=0.013), and was independent by the time of infection resolution. Notably, no differences were observed in the hemostatic biomarkers according to vaccine types. All subjects positively responded to vaccination with a significant increase in anti-S/RBD IgG from baseline (D0) to each time point, especially COVID-19 subjects (D15, D60, and D90:p<0.0001;D180:p=0.031). No thrombotic or cardiovascular complications occurred during follow-up. Summary/Conclusion: No hypercoagulable state elicited by COVID-19 vaccination was observed, contrarily we detected an overall persistent reduction of coagulation activation over time. Subjects with previous SARS-COV2 infection had persistently low levels of PAI-1, supporting enhanced fibrinolysis activation. Compared with recent studies, our results provide a longer observation follow-up with all vaccine types and reassure on the safety of anti- SARS-COV2 vaccination.

PRIOR EXPOSURE TO IMMUNOSUPPRESSIVE AGENTS AND COMORBIDITIES ARE ASSOCIATED WITH WORSE OUTCOMES OF SARS-COV2 INFECTION IN PH-NEG CHRONIC MYELOPROLIFERATIVE NEOPLASMS: RESULTS OF EPICOVIDEHA SURVEY

Background: Philadelphia-negatie chronic myeloproliferatie neoplasms (MPN) typically incur high rates of thrombosis and infections and cytoreductie drugs may modulate such risks. Aims: The present analysis aims at assessing the seerity and outcomes of MPN facing coronairus disease 2019 (COVID-19). Hence, we aimed to assess the impact of immunosuppressie agents and comorbidity burden in COVID- 19 outcome. Methods: The EPICOVIDEHA registry is an online surey (www.clinicalsureys.net) that has collected since April 2020 until January 2022 5,445 cases of COVID-19 in indiiduals with baseline haematological malignancies (Salmanton-García et al, 2021 Hemasphere) The surey is promoted by the European Hematology Association - Infectious Diseases Working Party (EHA-IDWP) and has been approed centrally by the Institutional Reiew Board and Ethics Committee of Fondazione Policlinico Uniersitario A. Gemelli - IRCCS - Uniersità Cattolica del Sacro Cuore, Rome, Italy (Study ID: 3226). Results: Oerall, 308 patients (5.6%) with MPN were obsered for a median of 102 days (IQR: 21-223, range 22-97) after COVID-19 diagnosis. Median age at infection was 69 years (IQR: 58-77, range 22-97) and at least one comorbidity was reported from most of the indiiduals (62.6%, n = 193). A large portion of patients had a history of cardiopathy (n=109, 35.4%), diabetes (n=40, 15.9%), or chronic pulmonary disease (n=44, 14.3%). Myelofibrosis (MF) (n=140, 45.4%) was the most prealent baseline malignancy, with 18 MF patients (12.9%) reporting 3 or more comorbidities. Out of the whole cohort, 72 patients (42.8% of MF) receied immunosuppressige therapies including steroids, immunomodulatory drugs (IMiDs) or JAK-inhibitors. Hospitalization and consecutie admission to intensie care unit was required for 187 (60.7%) and 45 (24%) patients, respectiely. At multiariate logistic regression, Hospital admission was predicted by age >70 years (OR 2.809;95% CI 1.651-4.779), exposure to immunosuppressie therapies (OR 2.802;95% CI 1.5380-5.103) and comorbidity burden. During the study follow-up (median 101 days;range 21-222) 84 patients deceased after a median time of 14 days (IQR: 8-49, range 0-457) since COVID-19 diagnosis. The fatality rate (FR) decreased from 40.3% (50 out of 124) in the first two quarters of year 2020 to 15.8% (3 out of 19) in the first two quarters of year 2021 (p<0.05). Death was principally attributable to COVID-19 in 58 patients (69.0%) and contributable by COVID-19 in 15 (17.9%). FR was particularly high (54 out of 140, 38.6%) in MF patients and in patients receiing immunosuppressie agents (32 out of 86, 37%). Moreoer, FR increased from 13.0% in indiiduals with no comorbidity to 36.0% and 62.1% in those with >2 or >3 comorbidities, respectiely. More specifically, three comorbidities independently increased the FR: chronic cardiopathy (HR 1.653;95%CI 1.017-2.687), chronic pulmonary disease (HR 1.847;95% CI 1.097-3.109), and diabetes mellitus (HR 1.712;95% CI 1.006-2.914). A heay comorbidity burden, namely 3 or more comorbidities (HR 2.956;95% CI 1.403-6.227), adanced age, namely >70 years (HR .809;95% CI 1.651-4.779), myelofibrosis (HR 2.501;95% CI 1.384-4.519), and ICU admission (HR 2.669;95% CI 1.641-4.342) independently predicted FR. (MF) (n=140, 45.4%) was the most prealent baseline malignancy, with 18 MF patients (12.9%) reporting 3 or more comorbidities. Out of the whole cohort, 72 patients (42.8% of MF) receied immunosuppressige therapies including steroids, immunomodulatory drugs (IMiDs) or JAK-inhibitors. Hospitalization and consecutie admission to intensie care unit was required for 187 (60.7%) and 45 (24%) patients, respectiely. At multiariate logistic regression, Hospital admission was predicted by age >70 years (OR 2.809;95% CI 1.651-4.779), exposure to immunosuppressie therapies (OR 2.802;95% CI 1.5380-5.103) and comorbidity burden. During the study follow-up (median 101 days;range 21-222) 84 patients deceased after a median time of 14 days (IQR: 8-49, range 0-457) since COVID-19 diagnosis. The fatality rate (FR) dec eased from 40.3% (50 out of 124) in the first two quarters of year 2020 to 15.8% (3 out of 19) in the first two quarters of year 2021 (p<0.05). Death was principally attributable to COVID-19 in 58 patients (69.0%) and contributable by COVID-19 in 15 (17.9%). FR was particularly high (54 out of 140, 38.6%) in MF patients and in patients receiing immunosuppressie agents (32 out of 86, 37%). Moreoer, FR increased from 13.0% in indiiduals with no comorbidity to 36.0% and 62.1% in those with >2 or >3 comorbidities, respectiely. More specifically, three comorbidities independently increased the FR: chronic cardiopathy (HR 1.653;95%CI 1.017-2.687), chronic pulmonary disease (HR 1.847;95% CI 1.097-3.109), and diabetes mellitus (HR 1.712;95% CI 1.006-2.914). A heay comorbidity burden, namely 3 or more comorbidities (HR 2.956;95% CI 1.403-6.227), adanced age, namely >70 years (HR .809;95% CI 1.651-4.779), myelofibrosis (HR 2.501;95% CI 1.384-4.519), and ICU admission (HR 2.669;95% CI 1.641-4.342) independently predicted FR. Summary/Conclusion: COVID-19 infection led to a particularly dismal outcome in patients exposed to immunosuppressie agents and in those with chronic heart or pulmonary diseases, or diabetes. These data allow to tailor future strategies for preenting seere COVID-19 in MPN patients. (Table Presented).

Psychological well-being and lockdown: a study on an Italian sample during the first COVID-19 wave

In February and March 2020, the Italian government decided to provide guidelines in order to counter the spreading of Coronavirus disease (COVID-19). Several studies have shown that the first Lockdown deeply affected the psychological well-being of the individuals, but the role of possible protective variables is currently not known. In the present study we aimed to investigate the impact of several psychological variables on individuals' mental states and emotions experienced during the first Lockdown in Italy. Participants were 172 Italian adults and they were asked to answer several questions regarding the intensity of mental states and emotions experienced, the perceived usefulness of lockdown, the feeling of living a normal life, and the coping strategies implemented to face the pandemic. Results showed that, during the first wave of COVID-19 in Italy, only the perceived usefulness of lockdown positively affected people's emotions. This result suggests that a better communication of the experimental findings supporting the political decisions made, and behavioral measures shaped to increase people's commitment to the proposed rules are crucial in order to enhance people's wellbeing. While this result is limited to the first wave and the first lockdown, future research should assess the role of rule acceptance and coping strategies in subsequent waves of COVID-19, and consequent partial or total lockdowns. © 2022 Sapienza Universita Editrice. All Rights Reserved.

Post-covid-19 hemostatic characteristics of convalescent patients: The bergamo experience

Introduction: Severe COVID-19 patients present with a hypercoagulable state, complement activation and endothelial perturbation, which result from an excessive inflammatory response. Thromboinflammation is one important mechanism underlying the COVID-19-associated coagulopathy and the increased risk of thrombosis. Bergamo city is one of the first and most affected area by SARS-CoV-2 infection in the world. For this reason, since the beginning we were actively involved in recruiting convalescent COVID-19 patients, in a program of selection of candidates for convalescent plasma donation. In a large cohort of convalescent COVID-19 patients, we aimed to characterize markers of coagulation activation and endothelial perturbation, in order to explore whether the COVID-19-related hemostasis activation might persist afterwards and evaluate its possible association with the degree of severity of the previous infection, and/or with demographic characteristics, or anti-SARS-CoV-2 antibody levels. Methods: In 392 convalescent COVID-19 patients (216M/176F, median age: 46 years) plasma levels of fibrinogen, protein C, protein S, factor V, factor VIII, factor XIII, D-dimer, von Willebrand factor (vWF), prothrombin fragment F1+2 were measured at the recruitment, i.e. 1-5 months from recovery. Samples were tested for the anti-SARS-CoV-2 antibodies, including anti-S IgG (Anti-S Ab) and anti-N IgG (Anti-N Ab) antibodies at enrollment and at each scheduled subsequent visits. Results: Levels of fibrinogen, D-dimer, von Willebrand factor, protein S and protein C were significantly higher (p<0.05) in patients who were hospitalized for severe COVID-19 as compared to patients who were treated at home. There was no correlation between levels of coagulation biomarkers and days from end of symptoms. Male gender, age > 40 years, and severe form of COVID-19 were identified as independent predictors of high levels of both anti-S and anti-N Ab (p<0.001). Among hemostatic biomarkers, fibrinogen (p<0.01) and vWF (p<0.05) independently predict high levels of anti-S Ab. In particular, vWF levels positively correlated with anti-S Ab levels (vWFantigen r=0.188;vWF-activity r=0.241 and vWF-RiC of r=0.223, p<0.01). Evaluation of anti-SARS-CoV2 antibody levels at different time points during follow up revealed that 30% of patients displayed high levels of anti-S Ab until more than 8 months from the end of symptoms. Conclusions: Convalescent patients, with a history of severe COVID-19 had a persistent endothelium activation, despite of disease clinical remission even after 9 months from end of symptoms. Furthermore, fibrinogen and vWF levels predicted high levels of Anti-S Ab. Among demographic characteristics, gender, age and severe disease can be predictors of increased antibody response. These findings suggest that inflammation, coagulation and endothelial dysfunction may persist after recovery and may explain the findings of persistent clinical symptoms reported in these patients after healing from COVID-19.

Second versus first wave of covid-19 in patients with mpn

Introduction. MPN-COVID is a European LeukemiaNet cohort study, launched in March 2020 in patients with myeloproliferative neoplasms (MPN) with COVID-19. The first cohort of 175 cases was analyzed at the end of first wave (July 2020) and results provided estimates and risk factors of overall mortality (Barbui T. Leukemia, 2021), thrombosis incidence (Barbui T. Blood Cancer J, 2021), and post-COVID outcomes (Barbui T. Blood Cancer J, 2021). In the second wave of pandemic (June 2020 to June 2021), case-fatality risk in the general population has been found variable across different countries, and no information is available in MPN patients with COVID-19 diagnosed during the second wave in comparison with those of the first wave. Methods. In an electronic case report form, we registered a total of 479 cases of ET (n=161, 34%), PV (n=135, 28%), pre-PMF (n=49, 10%) and overt MF (n=134, 28%), from 39 European hematology units (Italy, Spain, Germany, France, UK, Poland, Croatia). Of these, 304 were diagnosed COVID-19 during the second wave. Results. Patients in the second wave were significantly different from those in the first wave, including parameters such as age (median: 63 vs. 71 years, p<.001), sex (females: 52% vs. 42%, p=0.037), MPN category (MF 24% vs. 34%, p=0.020), comorbidity (at least one comorbidity 63% vs. 74%, p=0.012), disposition (home: 68% vs. 23%, regular ward: 29% vs. 66%, ICU: 3% vs. 11%, p<.001), need of respiratory support (28% vs. 59%, p<.001) and degree of systemic inflammation (C-Reactive Protein: 51% vs. 74%, p=0.008;Neutrophil to Lymphocyte Ratio: 4.1 vs. 5.4, p=0.038). In regard to COVID-19-directed therapy, in the second wave steroids were more frequently prescribed (28% vs. 40%, p=0.007), while the use of antibiotics, antivirals, hydroxychloroquine and experimental therapies was significantly less frequent (p<.001 for all the differences). Interestingly, only 4 out of 46 patients (8.7%) discontinued Ruxolitinib during second-wave acute COVID (all MF admitted to regular ward). In the two waves, distribution probability of COVID-19 incidence by Kernel method showed a substantially similar shape, whereas the two incidence peaks were associated with very different mortality, as reported in Fig. 1A. The difference between the probability of death was highly significant during the first (n=175) vs. second (n=304): 31% vs. 9% at 60 days from COVID-19 diagnosis, respectively (p<.001) (Fig. 1B). Of note, among 26 deaths, 4 (15%) occurred at home, 19 (73%) on regular wards and 3 (12%) in the ICU, and death more frequently afflicted patients with (n=17, 65%) than ET (n=5, 19%) and PV (n=4. 15%) (p<.001). Independent risk factors for death in a multivariate Cox regression model fitted on the whole cohort and adjusted for the wave to which patients belonged, were age over 70 years (HR=5.2, 95% CI 1.8-15.1, p=0.002), male sex (HR=1.9, 95% CI 1.1-3.1, p=0.016), COVID-19 severity revealed by the need for respiratory support (HR=4.5, 95% CI 1.9-10.7, p=0.001), and Ruxolitinib discontinuation (HR=3.0, 95% CI 1.3-6.9, p=0.011). Conversely, in patients who continued this drug, no risk was documented (HR=1.21, p=0.566). Taking into account death as competing event, the second outcome of interest was the incidence of thrombosis, wich occurred in a significantly lower proportion of patients in the second wave compared to the first one (n=5 [1.6%] vs. n=14 [8.0%] at +60 days, respectively, SHR=0.20, p=0.002) (Fig. 1C). All the events, but one (n=4/5) were venous and were reported in patients with ET (SHR=4.4, 95% CI 1.8-10.7, p=0.001). Conclusions. This is the largest series of MPN patients who incurred COVID-19 from June 2020 onward, namely during the 'second COVID-19 wave'. Compared to the first wave, the second one recorded a lower overall COVID-19 severity, but Ruxolitinib discontinuation still remained a risk factor for a dismal outcome. Greater vulnerability of ET than PV in developing venous thrombosis was confirmed also during the second wave. This finding suggests that ET warrants a specific antithrombo ic prophylaxis in addition to heparin.

One wave or another in the pandemic: psychological well-being during the third COVID-19 wave

BACKGROUND After a year from the emergence of COVID-19 in February 2020, between March and May 2021 Italy faced its third wave of infections. Previous studies have shown that in the first phases of the pandemic certain factors had a protective effect against distress. However, little is known regarding the role of possible protective variables after prolonged pandemic situations. PARTICIPANTS AND PROCEDURE 454 Italian adults were asked questions regarding the intensity of mental states and emotions experienced, the perceived usefulness of lockdown, the feeling of living a normal life, and the coping strategies implemented to face the pandemic. RESULTS Our findings indicate that the presence of acceptance attitudes toward restrictive measures and the implementation of recreational activities helped participants face a prolonged pandemic with positive emotions. CONCLUSIONS These results extend previous findings about the impact of several behavioral variables on individuals' mental states and emotions experienced during the COVID-19 pandemic in Italy.

Interview With A Sample Of Occupational Health Physicians About Their Role During The Covid-19 Pandemic

Introduction. The COVID-19 pandemic legislation integrated the legislation already present in the workplace. The presence of the Occupational Health Physician (OHP) was essential in the company. The OHP, according to the D. Lgs. No 81/2008, is a physician with professional qualifications and requirements, who collaborates in the risk assessment and carries out health surveillance, to protect the health and safety of workers. During the pandemic his work has been incessant and has led to professional enrichment. Reflecting on his actions is essential to create innovative paths. Material and method. A semi-structured interview to a sample of OHP operating in the Lazio region was administered through videoconference system. All have received and have conseted the information on the processing of data, as established by the privacy legislation. The interview, lasting about 1 hour according to the focused conversation method. The data were analyzed using statistical text analysis software. Results and Conclusion. The interviews revealed a growth in both inter-professional (colleagues) and intra-professional (safety officers, employer, workers) relationship. In terms of increasing skills and knowledge, the need to update and keep employers updated was a positive element. On the psychological level, job satisfaction, the perception of one's role, awareness of new job requests and the resources activated was detected. In terms of utility and sense of accomplishment, the pandemic has clearly brought out the importance of prevention aspects, beyond current legislation and established routines. This study is still in progress.

Social inequalities and nutritional disparities: the link between obesity and COVID-19.

OBJECTIVE: Cohort studies, clinical audits of patients with COVID-19 in hospital and routine primary care records provided evidence-based insights on the relationship between excess weigh, obesity and COVID-19. The purpose of this umbrella review is to highlight the relationship between nutritional quality and social inequalities related to CDNCD, obesity and SARS-CoV-2 infection. MATERIALS AND METHODS: Only articles published from 2008 to the present were included in the search to show an updated picture of the topic. The search for published studies was conducted in February 2021 in the scientific databases PubMed (MEDLINE). The terms used for the search were "COVID-19", "Obesity", "Disparities", "Nutritional inequalities", "Chronic degenerative non-communicable diseases" and "review" OR "systematic review" OR "meta-analysis" separated by the Boolean operator AND. RESULTS: 1874 reviews were found, but only 99 met the objective. Obese or dysmetabolic patients are those who had a worse course of disease following COVID-19. This data was observed not only for Chinese and Caucasians, but also and above all among Africans, African Americans, Latinos and indigenous people. Plausible mechanisms to explain the association between obesity and COVID-19 outcomes, included the role of excess adipose tissue on respiratory function, metabolic dysfunction, the cardiovascular system, enhanced inflammatory response and impaired response to infection. CONCLUSIONS: Today, chronic non-communicable degenerative diseases (CDNCDs) are responsible for 70% of public health expenditure, affecting 30% of the population (one or more chronic diseases). Unfortunately, given the health emergency due to SARS-CoV-2, infectious diseases are currently more at the center of attention. However, the spread of infectious communicable diseases and CDNCDs is facilitated in situations of social disparity. In fact, in the poorest countries there are the highest rates of malnutrition and there is a greater risk of contracting viral infections, as well as, paradoxically, a risk of comorbidity, due to access to cheaper food and qualitatively poor, with high caloric density.

Hemostatic Markers, Adamts-13 Profile and Anti-Sars-Cov-2 Antibody Levels in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving BNT162b2 Vaccination

[Formula presented] Introduction: Patients (pts) with immune thrombotic thrombocytopenic purpura (iTTP) are at high risk of severe COVID-19, therefore protection from SARS-CoV-2 by vaccination is particularly relevant in this setting, although concerns may exist on possible adverse reactions or disease relapse after vaccination. In this study, in a group of iTTP pts who received in-hospital COVID-19 vaccination in a special program for ‘fragile patients’, we prospectively evaluated over time the antibody response, the clinical and laboratory disease parameters and hemostatic biomarker levels. Methods: Twelve iTTP pts in clinical remission and regularly followed-up in our Center were enrolled in April 2021, all of them received 2 doses of BNT162b2 vaccine (Pfizer-BioNTech) over 21 days, and were followed-up for clinical and laboratory testing for 60 days. Blood samples were collected at enrollment (day 0, D0) before the 1 st vaccine dose;on day 21 (D21) before the 2 nd dose;and on day 60 (D60) after the 1 st dose. Blood cell counts, anti-Spike receptor-binding-domain protein (anti-S/RBD) IgG, ADAMTS-13 activity, and anti-ADAMTS-13 IgG (chromogenic assay and ELISA), were measured at each time point. Additionally, an extensive study of hemostatic markers (i.e. FVIII, von Willebrand Factor (vWF) antigen and activity, fibrinogen, D-dimer, tPA, PAI, and F1+2) was performed. Follow up is currently continuing. Results: Median age of our cohort was 65 years with M/F ratio of 4/8. Median time since last acute iTTP episode was 40 months, median follow up of the cohort was 71 months (95% CI 30-126). All pts were in clinical remission, except one patient (P1) who had an iTTP relapse after contracting SARS-CoV-2 infection, in Dec 2020, and was on low-dose steroids on D0. One patient (P2) had an ADAMTS-13 relapse in Jan 2021, and received pre-emptive rituximab. No other pts were on immunosuppressive therapy. Concerning the status of ADAMTS-13 activity on D0, 6 pts showed normal levels (>50%), while 5 had a moderate (50-20%) and 1 a complete (<10%) ADAMTS-13 deficiency. This latter patient (P3) had normal ADAMTS-13 activity before the pandemic. All patients were negative for anti-ADAMTS-13 inhibitor. Further, on D0, the anti-S/RBD IgG testing was positive in 3/12 pts (median 704,1 AU/mL), due to symptomatic infection in 1 case (P1), and asymptomatic in 2 (P3 and 1 pt with ADAMTS-13 activity of 54%, P4). The study of hemostatic markers on D0 showed an increase in median levels of FVIII and vWF antigen and activity. These parameters were altered in 7/12, 11/12 and 8/12 pts, respectively. Fibrinogen and D-dimer were increased in 3/12 and 2/12, respectively. Notably, P1, P3 and P4 presented the highest levels of FVIII and vWF antigen, associated with high levels of vWF activity in P1 and P3 (mean 233%);moreover, P3 showed higher levels of D-dimer (708 ng/mL) and tPA (13 ng/ml). After the 2 doses of BNT162b2, no significant clinical side effects were reported, and no changes in platelet counts. ADAMTS-13 activity and inhibitors did not significantly change on D21 and D60. A complete ADAMTS-13 activity deficiency persisted in P3 on D21 and D60, associated with anti-ADAMTS-13 IgG titer >15 U/ml, despite clinical remission. Overall, a significant increase in anti-S/RBD IgG level was observed on D21 (p = 0.0005) and D60 (p = 0.0005). Remarkably, only P2 did not show an increase in anti-S/RBD IgG titer after both doses of BNT162b2. Median levels of FVIII and vWF antigen did not significantly change during follow up, while increased vWF activity was seen on D60 (p = 0.05). Fibrinogen levels were stable, and an increase in D-dimer (>1000 ng/mL both on D21 and D60) was seen in P3. There were no changes in the other hemostatic parameters, and no thromboses were observed. Conclusions: In our cohort of iTTP pts, COVID-19 was associated with 1 clinical and 1 ADAMTS-13 relapse. Our data show that SARS-CoV-2 vaccination was effective in inducing an antibody response in all but one patient who received rituximab within 3 months before vaccinat on, confirming recent findings. Overall, vaccination had no relevant impact on the hemostatic profile of our pts, and did not appear to be a driver of iTTP relapses. However, anti-SARS-CoV-2 antibodies monitoring in iTTP pts may be useful after vaccination, as currently it is unknown how long the antibody titer may persist. Although small, this study is in favor of efficacy and safety of mRNA vaccines in pts with iTTP. Disclosures: Falanga: Bayer: Honoraria;Sanofi: Honoraria;Leo Pharma: Honoraria;Pfizer: Honoraria.

A prospective evaluation of COVID-19 associated coagulopathy with acute coronary syndrome (ACS)

Background: Hospitalised COVID-19 pneumonia patients are characterised by the occurrence of a hypercoagulable state associated to a high risk of thromboembolic events. The main laboratory findings of this coagulopathy include D-dimer increase, mild thrombocytopenia, prolonged PT, and increase endothelial activation biomarkers (vWF, thrombomodulin). No data are available about coagulation profile in patients presenting with an acute coronary syndrome (ACS) combined with SARS-CoV-2 infection. Purpose: In this prospective study, we aimed to evaluate the contribute of concomitant SARS-CoV-2 infection to the haemostatic system derangement (i.e., from endothelial cell activation to fibrinolytic phase) observed in patients presenting with ACS. Further, the role of haemostatic biomarkers (HB) for in-hospital mortality risk prediction was also explored. Methods: Consecutive patients admitted to our hospital for ACS at peak intensity of local pandemia were enrolled into this study. At admission, all patients underwent routine blood examinations with blood count, serum biochemical tests and an extensive coagulation profiling. Data from coronary angiography and percutaneous coronary intervention (PCI), when performed, were collected. In-hospital major adverse cardio and cerebrovascular events -MACCEs- (total and cardiovascular death, stroke, systemic or pulmonary embolism, re-MI and bleedings) are reported. Results: A total of 99 (76M/23F) consecutive patients with a median age of 66.7 (±12.1) were enrolled. According to nasal swab, 24 patients were SARS-CoV-2 positive and 75 negative. The two groups, similar in age, sex and cardiovascular risk factors, significantly differed in presenting symptoms (p<.001) and radiological signs of pneumonia (p<.0001). At admission, there were no differences in routine laboratory values between groups. Differently, analysis of the HB showed significantly higher values of D-dimer, vWF antigen, vWF activity and vWF;RiCof, t-PA and PAI-1 and lower levels of ADAMTS-13 in the positive group. Furthermore, among ACS patients, both STEMI and NSTEMI subjects, positive for SARS-CoV-2, had significantly higher plasma values of all the HB compared to the respective negative counterparts, with SARS-CoV-2 positive STEMI subjects displaying the highest values. When performed, PCI finished more frequently with a final TIMI flow <3 (p=.004) in positive patients. The in-hospital rate of MACCEs was 24% (24/99 patients) with a higher (p<.0001) prevalence in SARS-Co-V2 positive group. Cardiovascular mortality accounted for the majority of deaths (8/10;p=.019). At multivariable analysis, we identified dyspnoea at presentation, vWF antigen and leukocyte values as independent risk factors for in-hospital death. Conclusions: In patients presenting with ACS combined with SARS-Cov- 2 infection an additional HB asset derangement with stronger endothelial cell activation occurs which negatively impact the outcome, regardless of the invasive treatment.

Hemostatic profile of COVID-19 convalescent plasma (CCP) donors from Bergamo Area

Background: Hypercoagulability, complement activation and endothelial perturbation characterize sever COVID-19. After disease remission, a proportion of convalescent subjects still experience post-COVID-19 symptoms. No information is available on persistence of hemostatic alterations in this setting. Bergamo city, represents one of the first and most affected area by SARS-CoV-2 infection in the world. For this reason, since the beginning we were actively involved in recruiting CCP donors. Aims: In a large cohort of CCP donors, we aimed to characterize biomarkers of hypercoagulability and of endothelial perturbation in order to find associations with disease severity, demographic characteristics, and anti-SARS-CoV-2 antibody levels. Methods : Candidate CCP donors were tested for the anti-SARSCoV-2 antibodies, including anti-S IgG antibodies (Anti-S Ab) and anti-N IgG antibodies (Anti-N Ab). In addition, the following plasma biomarkers were assessed: fibrinogen, protein C, protein S, factor V, factor VIII, factor XIII, D-dimer, and von Willebrand factor (vWF). Results: 425 CCP candidates (275M/150F, age range 19-67 years) were admitted to donation. Male gender, age > 40 years, and severe form of COVID-19 were identified as independent predictors of high levels of both anti-S and anti-N Ab ( p <0.001). Among hemostatic parameters, levels of vWF antigen, vWF activity and protein C were significantly higher in CCP donors who had severe COVID-19 compared to donors who had non-severe COVID-19 ( p <0.001). Furthermore, vWF levels positively correlated with anti-S Ab levels (vWF-antigen r=0.216 vWF-activity r=0.257 and vWFRiCof r=0.226, p <0.01). Conclusions: Our data show that gender, age and severe disease can be predictors of an increased immunological response. Furthermore, convalescent subjects show a persistently high vWF levels, suggesting a persistence of the endothelial activation, despite of clinical disease remission.

Role of endothelium activation biomarkers in prediction COVID-19 related intra-Hospital Mortality

Background : Endothelial damage and hypercoagulability are major players behind the hemostatic derangement in SARS-CoV-2 infection. Aims : In this prospective cohort study of COVID-19 patients, we aimed to assess the role of circulating endothelial activation/damage biomarkers in predicting in-hospital mortality. Methods : Clinical data of COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were analyzed. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, CRP and procalcitonin were assessed. Results : Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of Ddimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). Patients with a moderate and severe ARDS (i.e. PaO2/FiO2 ≤200%) have considerably higher vWF and sTM levels, and lower t-PA/PAI-1 values compared to patients in the mild ARDS group (i.e. PaO2/FiO2 >200%). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/ FiO2 were significantly associated with death. Using these variables, we generated a linear score with 3-risk groups (AUC 0.903) that provided a cumulative incidence of death of 0 % in the low-, 32% in the intermediate-, and 78% in the high-risk group ( P < 0.001). Conclusions : In conclusion, our study provides an extensive overview of the endothelial damage induced by SARSCoV-2 infection in hospitalized patients with virus-induced pneumonia and different degrees of disease severity. In addition, despite the small sample size and the need for the external validation, we could generate an accurate score based on circulating vWF to predicting mortality in severe COVID-19 patients.