BACKGROUND:Large language models (LLMs) have demonstrated remarkable capabilities in various medical fields, yet their performance in thrombosis and hemostasis, particularly in patient education and complex clinical decision making, is unexplored. OBJECTIVES:We aimed to compare the quality of responses from LLMs vs thrombosis experts and assess clinician's ability to distinguish between them. METHODS:Three experts on thrombosis and hemostasis and 3 LLMs (Le Chat Pixtral Large, DeepSeek-R1, and ChatGPT-4.5) answered 3 patient education and 3 clinical decision-making queries. Thirty-seven physicians rated responses for adequacy (1 = very poor; 10 = excellent) and estimated their origin (1 = certainly LLM; 10 = certainly human). Mean differences were assessed via t-tests, medians via Wilcoxon tests, and correlations via Spearman test. All P values were adjusted with Bonferroni correction. RESULTS:LLMs provided significantly better patient education responses than experts. Mean adequacy score differences were as follows: Le Chat Pixtral Large +1.6 (95% CI, 1.3-2.0; P < .01), DeepSeek-R1 +1.7 (95% CI, 1.3-2.1; P < .001), and ChatGPT-4.5 +1.9 (95% CI, 1.6-2.3; P < .001). In clinical decision-making, DeepSeek-R1 outperformed experts (+1.4; 95% CI, 1.1-1.8; P < .001), whereas Le Chat Pixtral Large (-0.3; 95% CI, -0.8-0.1; P = .96) and ChatGPT-4.5 (+0.5; 95% CI, 0.0-0.9; P = .18), performed comparably with experts. Evaluators could not distinguish between expert (median, 6.0; IQR, 3.0-8.0) and LLM-generated responses (median, 6.0; IQR, 4.0-8.0). CONCLUSION:LLMs outperform experts in venous thromboembolism-related patient education and match or exceed them in clinical decision making, providing responses indistinguishable from experts. Although major barriers need to be addressed, LLMs have strong potential to support clinical management and patient education in the field of thrombosis and hemostasis.

Die vorliegende aktualisierte Leitlinie soll einen praxisnahen Leitfaden für die Diagnostik und Therapie von Personen mit Hämophilie (Persons with Haemophilia, PwH) in Österreich darstellen. In der Hämophilie-Therapie gibt es wenige vergleichende Interventionsstudien, daher haben die Empfehlungen einen meist niedrigen Evidenzgrad und beruhen auf einem Expertenkonsensus. Als wesentliche Grundlage dieser Leitlinie dienen die internationalen Guidelines der „World Federation of Hemophilia (WFH)“ aus dem Jahr 2020. Diese wurden den nationalen Gegebenheiten und Erfahrungen angepasst. Behandelt werden Diagnostik und Verlaufskontrollen, medikamentöse sowie begleitende Therapieoptionen und Prophylaxe, weiters spezielle Aspekte bei Kindern und Erwachsenen mit schwerer Hämophilie, Messung von Outcomes, die Vorgehensweise bei Traumen, speziellen Blutungen und Eingriffen einschließlich Zahnextraktionen, das Thema Hemmkörper sowie mögliche Probleme bei Konduktorinnen und psychosoziale Aspekte bei Hämophilie.

This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects.

Background: There are known complications for fetuses after infection with SARS-CoV-2 during pregnancy. However, previous studies of SARS-CoV-2 in pregnancy have largely been limited to histopathologic studies of placentas and prenatal studies on the effects of different SARS-CoV-2 variants are scarce to date. To investigate the effects of SARS-CoV-2 variants on the placenta and fetus, we aimed to investigate fetal and extra-fetal structures using prenatal MRI.Methods: For this prospective case-control study, two obstetric centers consecutively referred pregnant women for prenatal MRI after confirmed SARS-CoV-2 infection.Forty-three prenatal MRI examinations were included after confirmed infection with SARS-CoV-2 and matched 1:1 with 43 control cases with respect to sex, MRI field strength, and gestational age (average deviation 1·7 ± 1·6 days).Where available, the pathohistological examination of the placenta was included in the analysis.In prenatal MRI, the shape and thickness of the placenta, possible lobulation, and vascular lesions were quantified. Fetuses were scanned for organ or brain abnormalities.Findings: Of the 43 included cases after SARS-CoV-2 infection, 25 (58%) were infected with pre-Omicron variants and 18 (42%) with Omicron. Prenatal MRIs were performed on an average of 144 ± 70·7 days after the first positive PCR test.Both pre-Omicron (P=·002) and Omicron (P=·016) groups showed abnormalities in form of a globular placenta compared to control cases. In addition, placentas in the pre-Omicron group were significantly thickened (Mean Diff. 7·32mm, 95% CI 2·05 to 12·59, P=·009), and showed significantly more frequent lobules (P=·031), and hemorrhages (P=·003).Fetal growth restriction (FGR) was observed in 28% (P=·004) in the pre-Omicron group.Interpretation: SARS-CoV-2 infections in pregnancy can lead to placental lesions based on vascular events, which can be well visualized on prenatal MRI. Pre-Omicron variants cause greater damage than Omicron sub-lineages in this regard.Funding Information: Vienna Science and Technology Fund.Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The institutional review board of the Medical University of Vienna approved this prospective study (Ethics Committee number 2306/2020). Written informed consent was obtained before study inclusion.

Abstract Aims Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. Methods and results We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT–qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT–qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. Conclusion Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.

Objectives Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. Methods We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex- and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EVs) and citrullinated histone H3 levels were determined in plasma upon inclusion by flow cytometry and immunoassay. Results In total, 20 patients had severe and 21 nonsevere disease. The number of EV (median [25th, 75th percentile]) was significantly higher in patients compared with controls (658.8 [353.2, 876.6] vs. 435.5 [332.5, 585.3], geometric mean ratio [95% confidence intervals]: 2.6 [1.9, 3.6]; p <0.001). Patients exhibited significantly higher numbers of EVs derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EVs from alveolar-macrophages and alveolar-epithelial cells were detectable in plasma and were significantly higher in patients. Intercellular adhesion molecule-1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin-converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and nonsevere COVID-19. Citrullinated histone H3 levels (ng/mL, median [25th, 75th percentile]) were higher in patients than in controls (1.42 [0.6, 3.4] vs. 0.31 [0.1, 0.6], geometric mean ratio: 4.44 [2.6, 7.7]; p <0.001), and were significantly lower in patients with nonsevere disease compared with those with severe disease. Conclusion EV and citrullinated histone H3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) was reported after adenovector-based COVID-19 vaccination with ChAdOx1 and Ad26.COV2·S as a rare, but very severe complication [1Greinacher A. Selleng K. Palankar R. Wesche J. Handtke S. Wolff M. et al.Insights in Chadox1 Ncov-19 vaccine-induced immune thrombotic thrombocytopenia.Blood. 2021; 138: 2256-2268https://doi.org/10.1182/blood.2021013231Crossref PubMed Scopus (145) Google Scholar, 2Greinacher A. Thiele T. Warkentin T.E. Weisser K. Kyrle P.A. Eichinger S. Thrombotic thrombocytopenia after Chadox1 Ncov-19 vaccination.N. Engl. J. Med. 2021; 384: 2092-2101https://doi.org/10.1056/NEJMoa2104840Crossref PubMed Scopus (1394) Google Scholar]. Thrombosis/hypercoagulation has been reported also as a common complication of (severe) COVID-19 and is probably multifactorial due to endothelial dysfunction caused either by direct viral infection or by hyperinflammation, which also leads to activation of platelets and the clotting cascade as well as due to alteration of the blood flow, as explained by the Virchow's triad [[3]Ahmed S. Zimba O. Gasparyan A.Y. Thrombosis in coronavirus disease 2019 (Covid-19) through the prism of Virchow's triad.Clin. Rheumatol. 2020; 39: 2529-2543https://doi.org/10.1007/s10067-020-05275-1Crossref PubMed Scopus (147) Google Scholar]. In VITT, the hypothesis states that platelet activation, aggregation, thrombocytopenia and thrombotic events could occur either due to boosting of preexisting anti-platelet factor 4 (PF4) antibodies or due to de-novo induction of these antibodies by the vaccine since thrombotic events and PF4 antibodies have been detected during severe SARS-CoV-2 infection [4Dakay K. Cooper J. Bloomfield J. Overby P. Mayer S.A. Nuoman R. et al.Cerebral venous sinus thrombosis in Covid-19 infection: a case series and review of the literature.J. Stroke Cerebrovasc. Dis. 2021; 30105434https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105434Abstract Full Text Full Text PDF Scopus (75) Google Scholar, 5Brodard J. Kremer Hovinga J.A. Fontana P. Studt J.D. Gruel Y. Greinacher A. Covid-19 patients often show high-titer non-platelet-activating anti-Pf4/Heparin igg antibodies.J. Thromb. Haemost. 2021; 19: 1294-1298https://doi.org/10.1111/jth.15262Crossref PubMed Scopus (52) Google Scholar]. It is assumed that auto-antibodies against platelet factor 4 (PF4) may lead to VITT similar as in heparin-induced thrombocytopenia that shares clinical and immunological similarities with VITT [[1]Greinacher A. Selleng K. Palankar R. Wesche J. Handtke S. Wolff M. et al.Insights in Chadox1 Ncov-19 vaccine-induced immune thrombotic thrombocytopenia.Blood. 2021; 138: 2256-2268https://doi.org/10.1182/blood.2021013231Crossref PubMed Scopus (145) Google Scholar]. However, despite one study reporting binding of anti-PF4 antibodies to the receptor binding domain (RBD) of the spike protein with possible formation of complexes, it has been demonstrated that anti-PF4 antibodies do not cross-react with SARS-CoV-2 spike protein [[6]Pai M. Epidemiology of vitt.Semin. Hematol. 2022; https://doi.org/10.1053/j.seminhematol.2022.02.002Crossref PubMed Scopus (14) Google Scholar]. Moreover, revaccination of VITT patients did not lead to VITT for a second time and PF4 levels decreased within months, thus arguing for VITT being an antigen-unrelated event [[7]Schonborn L. Thiele T. Kaderali L. Gunther A. Hoffmann T. Seck S.E. et al.Most anti-Pf4 antibodies in vaccine-induced immune thrombotic thrombocytopenia are transient.Blood. 2022; https://doi.org/10.1182/blood.2021014214Crossref PubMed Scopus (23) Google Scholar]. In contrast to the full clinical feature of VITT, oligosymptomatic courses have been described [[8]Salih F. Schonborn L. Kohler S. Franke C. Mockel M. Dorner T. et al.Vaccine-induced thrombocytopenia with severe headache.N. Engl. J. Med. 2021; 385: 2103-2105https://doi.org/10.1056/NEJMc2112974Crossref PubMed Scopus (54) Google Scholar], which responded quickly to treatment without development of thromboembolic events. It might even be the case that anti-PF4 antibodies occur without the typical clinical feature of VITT. Data on pre- and post-vaccination anti-PF4 antibodies in a large cohort vaccinated with ChAdOx1 are not yet available. In this retrospective analysis, we investigated in a cohort of 400 health care workers (HCW) the prevalence of anti-PF4 antibodies prior to the first dose of ChAdOx1and three to four weeks after vaccination. Blood samples were obtained for anti-SARS-CoV-2 antibody testing upon personal choice from HCW immediately prior to and 3 to 4 weeks after the first dose of ChAdOx1 (Vaxzevria, Astra Zeneca) during the University's vaccination campaign between March and June 2021 (n = 1255). From these vaccinees, a random sample of 400 participants was drawn, in whom pre- and post-vaccination samples intended for SARS-CoV-2 antibody testing were available, and tested for anti-PF4 antibodies. Age at vaccination and sex were recorded. The study was approved by the Ethic Committee of the Medical University of Vienna (EK: 2274/2021). Anti-PF4/heparin IgG was tested by using the Zymutest HIA IgG immunoassay (Hyphen Biomed, Neuville-sur-Oise, France) according to the manufacturer's instructions. Cut-off for positivity was an optical density (OD) value above 0.5. Intra-assay and inter-assay reproducibility are reported with 3.07 % and 7.11 % respectively by the manufacturer. SARS-CoV-2-specific IgG antibodies against the subunit 1 (S1) of the spike protein were measured by ELISA (Quantivac®, Euroimmun) in diluted sera (1:101) according to the manufacturer's instructions. Results are expressed in binding antibody units/ml (BAU/ml) with values above 35.2 BAU/ml considered positive. Only descriptive, graphical methods with scatterplots and case-profile line plots were applied. Sample size was determined on the following assumptions: The study should have an 80 % power to detect an odds-ratio of at least 2 for anti-PF4 positivity after vaccination to before vaccination at a (two-sided) significance level of 5 % assuming 18 % discordant pairs. Among the 400 participants, (61.7 % females) the median age was 37.0 years (± 9.9 standard deviation (SD)). No thrombosis, thrombocytopenia or clinical VITT were reported from the participants until the second dose of ChAdOx1. In total, six of 400 participants (1.5 %) tested positive for anti-PF4 antibodies before the first dose (Fig. 1A ). Five of the six samples were considered low to moderately reactive with OD < 1. Only one sample was highly reactive with an OD of 1.5. The median age of the anti-PF4 antibody positive participants was 47.3 (± 12.1 SD) years that is non-significantly higher than in the anti-PF4 antibody negatives (37.0 years ±12.0 SD). Four of the six positive individuals were females (Table 1). Comparison of positive anti-PF4 levels before and after vaccination revealed no change (mean change in OD was 0.997-fold) and levels remained stable (Fig. 1A). In none of the participants de novo positivity occurred. None of the six participants, positive for anti-PF4 antibodies displayed serological evidence of past SARS-CoV-2 infection since all had negative SARS-CoV-2 spike-specific IgG at baseline (Fig. 1B). In addition, the 12 individuals in this study identified as recovered from COVID-19 by SARS-CoV-2 IgG seropositivity prior to vaccination did not show anti-PF4 antibodies before (mean 0.084 ± 0.098) or after (mean 0.078 ± 0.079) the first dose of ChAdOx1. Furthermore, there was no correlation of the anti-PF4-antibody levels and the immunological responses to the first dose of ChAdOx1 in our study cohort measured by anti-SARS-CoV2 IgG antibody levels before and after the first dose for titers neither below nor above the cut-off of 35.2 BAU/ml (Fig. 1B).Table 1Demographic characteristics of anti-PF4 positive individuals.SubjectSexAgeAnti-PF4 antibody OD before/afterComorbidities1m250.58/0.56Information not available2f341.45/1.49None3f390.55/0.53Information not available4m550.85/0.84Seasonal allergy5f560.54/0.62Seasonal allergy6f560.86/0.84Type 1 diabetes Open table in a new tab Anti-PF4 antibodies are considered a hallmark of VITT and testing for anti-PF4 antibodies is indicated upon clinically suspected VITT in recently SARS-CoV-2-vaccinated patients with new onset of thrombosis, thrombocytopenia and elevated D-Dimer [[9]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N. Engl. J. Med. 2021; 385: 1680-1689https://doi.org/10.1056/NEJMoa2109908Crossref PubMed Scopus (295) Google Scholar]. Here, we demonstrate within a large cohort of 400 HCW that anti-PF4 antibodies were already prevalent albeit at a low frequency of 1.5 % before vaccination. Furthermore, no new PF4 antibody formation was detected after vaccination. The prevalence of anti-PF4 antibodies in our study appears to be lower than the 6.6 % detected in the pre-pandemic era in a cohort of blood donors representing a preselected healthy study population. However, the discrepancy in prevalence might be explained by the lower cut-off at OD 0.4 used in the former study compared to 0.5 in our analysis. Using this lower cut-off would increase prevalence in our study to 2 %. These data indicate that anti-PF4 antibodies are not solely specific for VITT and can be also detected at low frequency in healthy individuals. With regard to anti-PF4 antibody levels measured after vaccination with ChAdOx1 a previous study featuring a comparable cohort of HCW showed a prevalence of 1.2 %, all with OD < 1.5 and no onset of VITT [[10]Sorvoll I.H. Horvei K.D. Ernstsen S.L. Laegreid I.J. Lund S. Gronli R.H. et al.An observational study to identify the prevalence of thrombocytopenia and anti-Pf4/Polyanion antibodies in norwegian health care workers after Covid-19 vaccination.J. Thromb. Haemost. 2021; 19: 1813-1818https://doi.org/10.1111/jth.15352Crossref PubMed Scopus (66) Google Scholar]. Importantly, we could show that the levels of anti-PF4 antibodies before and after vaccination with ChAdOx1 did not change/increase and remained below OD 1.5 in all individuals. The OD value is important because an OD below 1.5 seem to be unrelated to VITT since patients with confirmed VITT displayed an OD above 2 [[2]Greinacher A. Thiele T. Warkentin T.E. Weisser K. Kyrle P.A. Eichinger S. Thrombotic thrombocytopenia after Chadox1 Ncov-19 vaccination.N. Engl. J. Med. 2021; 384: 2092-2101https://doi.org/10.1056/NEJMoa2104840Crossref PubMed Scopus (1394) Google Scholar]. Additionally, not all anti-PF4 antibodies seem to be able to activate platelets, which is a prerequisite for the pathogenesis of VITT. We did not test for platelet activation capacity in anti-PF4 positive sera but considering that all participants remained healthy, capacity of platelet activation of the detected antibodies must have been limited. So far, data are limited on whether anti-PF4 antibodies arise from SARS-CoV-2 vaccination or are already preexisting and expand upon antigen contact. Since anti-PF4 antibody detection is described to be transient [[7]Schonborn L. Thiele T. Kaderali L. Gunther A. Hoffmann T. Seck S.E. et al.Most anti-Pf4 antibodies in vaccine-induced immune thrombotic thrombocytopenia are transient.Blood. 2022; https://doi.org/10.1182/blood.2021014214Crossref PubMed Scopus (23) Google Scholar], comparison of pre- to post-vaccination anti-PF4 levels in close temporal proximity to vaccination seems essential. We did not find de-novo induction of anti-PF4 antibodies upon application of the first dose of the COVID-19 vector vaccine ChAdOx1 within the 400 participants. This is in line with a previous study [[11]Thiele T. Ulm L. Holtfreter S. Schonborn L. Kuhn S.O. Scheer C. et al.Frequency of positive anti-Pf4/Polyanion antibody tests after Covid-19 vaccination with Chadox1 Ncov-19 and Bnt162b2.Blood. 2021; 138: 299-303https://doi.org/10.1182/blood.2021012217Crossref PubMed Scopus (100) Google Scholar] reporting preexisting low-level anti-PF4 antibodies (OD < 1) at the day of the first dose of ChAdOx1 that remained within the same OD range until two weeks after vaccination in one individual, however, the sample size of this subgroup was very small (n = 7). Taken together these data support the notion that the de-novo induction of high-level anti-PF4 antibodies associated with VITT in the context of the SARS-CoV-2 vector vaccines are rare events [[9]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N. Engl. J. Med. 2021; 385: 1680-1689https://doi.org/10.1056/NEJMoa2109908Crossref PubMed Scopus (295) Google Scholar]. Since vector-based vaccines are a major part of the global COVID-19 vaccine supply, it would be helpful to define markers to predict and to identify vaccinees at risk for developing VITT. However, anti-PF4 antibodies, at least in low concentration, seem not an appropriate prediction marker, since pre-vaccination anti-PF4 antibodies are not associated with development of VITT. Incidence of VITT ranges from 1 case per 26,500 to 127,300 first doses of ChAdOx1 administered according a recent publication [[6]Pai M. Epidemiology of vitt.Semin. Hematol. 2022; https://doi.org/10.1053/j.seminhematol.2022.02.002Crossref PubMed Scopus (14) Google Scholar]. Compared to one anti-PF4 positive case per 67 prior to vaccination, incidence of VITT is at least two orders of magnitude less frequent suggesting additional conditions underlying pathogenesis of VITT. Since pre-vaccination anti-PF4 antibody levels are rarely known, detection of post-vaccination anti-PF4 antibodies has to be interpreted with caution and testing should only be done in patients with clinical suspicion of VITT. That includes new onset thrombocytopenia, with or without thrombosis five to 30 days after vaccination and elevated D-Dimer [[9]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N. Engl. J. Med. 2021; 385: 1680-1689https://doi.org/10.1056/NEJMoa2109908Crossref PubMed Scopus (295) Google Scholar]. Limitations of this study are the restriction to HCW, mainly younger than 60 years of age that may represent different immunological profiles as compared to the general population of vaccinees and the reliance on clinical symptoms for thrombosis, without performing platelet counts and coagulation assays. However, since VITT mainly occurred in females below age of 60 [[9]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N. Engl. J. Med. 2021; 385: 1680-1689https://doi.org/10.1056/NEJMoa2109908Crossref PubMed Scopus (295) Google Scholar] our study cohort is indeed representative for the population at risk to develop VITT. In addition, we determined anti-PF4 antibodies by ELISA to measure heparin-dependent antibodies of the IgG isotype since the polyanion responsible for VITT has not been identified yet. Furthermore, we are aware that the analyzed anti-PF4 antibodies are only one possible marker involved in the pathomechanism of VITT. In conclusion, pre-existing anti-PF4 antibodies do not seem to be relevant for VITT induction, as they did not expand after vaccination and occurrence of new anti-PF4 antibodies were not detected in our cohort. No funding was received for this retrospective study.

Summary Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1–3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since. The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.

Thromboembolic events are frequent complications in cancer patients, yet knowledge about their prognostic value in gastroesophageal cancer patients is scarce. We analyzed arterial as well as venous thromboembolic events throughout patient history and associated events at the time of first cancer diagnosis with overall survival (OS) in patients with gastroesophageal cancer, who were treated at the Medical University of Vienna between 1990 and 2020. Survival analyses were performed with log-rank analyses. We analyzed 1574 patients (70% male, mean age 63 (SD 11.8)) with gastroesophageal cancer (13% stage I, 21% stage II, 30% stage III, 36% stage IV; 79% adenocarcinoma). 79% of patients were already dead at the time of this analysis. Thromboembolic events occurred in 477 (30%) patients and 135 (28%) even experienced multiple events throughout patient history. 290 (61%) occurred in the arterial, 163 (34%) in venous and 24 (5%) in both vascular systems. The table shows the thromboembolic events of this cohort. Tumor stage was neither associated with thromboembolic events throughout patient history (p=0.370) nor with venous (p=0.421) or arterial (p=0.693) thromboembolic events at first diagnosis using the Mann-Whitney-U test. Venous thromboembolic events at first cancer diagnosis were not statistically associated with a poorer OS (with event, n=32: median OS 17.9 months (95% CI 0.0-41.3), without event: median OS 20.9 (19.3-22.5), p=0.868), neither were arterial thromboembolic events at first cancer diagnosis (with event, n=48: median OS 20.7 (15.6-25.8), without event: 21.0 (19.3-22.7), p=0.070). We did not find a prognostic effect of venous or arterial thromboembolic events at diagnosis of gastroesophageal cancer. Prospective studies are warranted to further explore this issue and improve patient management.Table: 1242PThromboembolic eventBefore cancer diagnosis n (%)At the time of cancer diagnosis* n (%)After cancer diagnosis n (%)DVT**- leg27 (2%)10 (0.6%)41 (3%)Pulmonary embolism19 (1%)22 (1%)64 (4%)DVT - arm3 (0.2%)1 (0.1%)14 (0.9%)Splenic/portal vein3 (0.2%)1 (0.1%)7 (0.4%)Device associated3 (0.2%)1 (0.1%)2 (0.1%)Sinus vein001 (0.1%)Other venous events4 (0.3%)3 (0.2%)4 (0.3%)Myocardial infarction117 (7%)13 (0.8%)28 (2%)Peripheral artery disease57 (4%)16 (1%)19 (1%)Stroke35 (2%)8 (0.5%)24 (2%)Central artery disease29 (2%)10 (0.6%)16 (1%)Other arterial events6 (0.4%)1 (0.1%)5 (0.3%)*defined as -3 to +1 month from histological cancer diagnosis**deep vein thrombosis Open table in a new tab

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to what extent is unclear. In a retrospective analysis, hospital data were searched for adult patients who underwent gastrectomy for gastroesophageal or pancreatic cancer, and DOAC therapy for VTE or AF after gastrectomy. DOAC blood levels were determined by chromogenic assays before and after administration, and thromboembolic and bleeding complications were recorded. Eleven patients (median age 76 years) received a factor Xa inhibitor (FXaI; apixaban (3), edoxaban (3), rivaroxaban (4)) or the factor IIa inhibitor dabigatran (1) for VTE (7) or AF (4) after gastrectomy. Eight patients on FXaI had anti-Xa (aXa) trough levels within the expected range (ER). In all of them, aXa levels increased upon DOAC administration. Two patients on 30 mg edoxaban had low aXa trough levels. Administration of 20 mg of rivaroxaban resulted in trough levels in the ER in one of them. None of the FXaI patients had thromboembolism, while two experienced bleeding (arterial puncture site, gastrointestinal). One dabigatran AF patient with trough and peak concentrations below the ER had strokes during 110 mg and 150 mg dabigatran administration. While on apixaban, aXa levels were in the ER, and no clinical complications occurred. DOACs, particularly FXaI, were adequately absorbed in cancer patients after gastrectomy. Our observation of recurrent thromboembolic events in a patient treated with dabigatran warrants cautious use in this specific patient population.

Platelets are the main effectors of primary hemostasis but also cause thrombosis in pathological conditions. Antiplatelet drugs are the cornerstone for the prevention of adverse cardiovascular events. Monitoring the extent of platelet inhibition is essential. Currently available platelet function tests come with constraints, limiting use in antiplatelet drug development as well as in clinical routine. With this study, we aim to investigate whether plasma miRNAs might be suitable biomarkers for monitoring antiplatelet treatment. Platelet-poor plasma was obtained from a trial including 87 healthy male volunteers that either received ticagrelor (n = 44) or clopidogrel (n = 43). Blood was collected before drug intake and after 2 h, 6 h, and 24 h. We measured a panel of 11 platelet-enriched miRNAs (thrombomiRs) by RT-qPCR and selected four biomarker candidates (i.e., miR-223-3p, miR-150-5p, miR-126-3p, miR-24-3p). To further characterize those miRNAs, we performed correlation analyses with the number of extracellular vesicles and clotting time dependent on procoagulant vesicles (PPL assay). We show that platelet-enriched miRNAs in the circulation are significantly reduced upon P2Y12-mediated platelet inhibition. This effect occurred fast, reaching its peak after 2 h. Additionally, we demonstrate that higher baseline levels of thrombomiRs are linked to a stronger reduction upon antiplatelet therapy. Finally, we show that miRNAs from our panel might be the cargo of platelet-derived and procoagulant vesicles. In conclusion, we provide evidence that thrombomiR levels change within 2 h after pharmacological platelet inhibition and circulate the body within platelet-derived and procoagulant extracellular vesicles, rendering them potential biomarker candidates for the assessment of in vivo platelet function.

Background : Pulmonary thrombus formation is a hallmark of COVID-19. A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. Aims : To evaluate the role of extracellular vesicles (EV) and citrullinated histone H3 (citH3) as markers of coagulopathy and inflammation. Methods : We studied 41 adult COVID-19 patients with a positive result on a reverse-transcriptase polymerase-chain-reaction assay and 37 sex-and age-matched healthy controls. Number and surface characteristics of EV and citH3 levels were determined in plasma upon admission by flowcytometry and immunoassay, respectively. Values are given as median (25 th , 75 th percentile) and differences by geometric mean ratios (GMR [95% CI]) or mean differences (ΔsMean [95% CI]). Results : 20 patients had severe and 21 mild disease. Patients exhibited significantly higher numbers of total EV, and of EV derived from platelets, endothelial cells, leukocytes, or neutrophils than controls (Table 1). EV from alveolar-macrophages and alveolar-epithelial-cells were detectable in plasma and were significantly higher in patients. ICAM-1 positive EV levels were higher in patients while no difference between TF-positive and ACE-positive EV was seen between the two groups. Levels of EV did not differ between patients with severe and mild COVID-19. citH3 levels were higher in patients than in controls [1.42 (0.6, 3.37) vs 0.31 (0.14, 0.6), GMR 4.44 (2.57, 7.66);P < 0.001], and were significantly lower in patients with mild disease compared to those with severe disease. Conclusions : EV and citH3 are associated with COVID-19. They provide information regarding pathophysiology and could be explored as markers of the disease.