[Treatment of haemophilia in Austria]. / Hämophilie-Behandlung in Österreich.

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.

The Vienna Prediction Model for identifying patients at low risk of recurrent venous thromboembolism: a prospective cohort study.

BACKGROUND AND AIMS: Patients with unprovoked venous thromboembolism (VTE) have a high recurrence risk, and guidelines suggest extended-phase anticoagulation. Many patients never experience recurrence but are exposed to bleeding. The aim of this study was to assess the performance of the Vienna Prediction Model (VPM) and to evaluate if the VPM accurately identifies these patients. METHODS: In patients with unprovoked VTE, the VPM was performed 3 weeks after anticoagulation withdrawal. Those with a predicted 1-year recurrence risk of ≤5.5% were prospectively followed. Study endpoint was recurrent VTE over 2 years. RESULTS: A total of 818 patients received anticoagulation for a median of 3.9 months. 520 patients (65%) had a predicted annual recurrence risk of ≤5.5%. During a median time of 23.9 months, 52 patients had non-fatal recurrence. The recurrence risk was 5.2% [95% confidence interval (CI) 3.2-7.2] at 1 year and 11.2% (95% CI 8.3-14) at 2 years. Model calibration was adequate after 1 year. The VPM underestimated the recurrence risk of patients with a 2-year recurrence rate of >5%. In a post-hoc analysis, the VPM's baseline hazard was recalibrated. Bootstrap validation confirmed an ideal ratio of observed and expected recurrence events. The recurrence risk was highest in men with proximal deep-vein thrombosis or pulmonary embolism and lower in women regardless of the site of incident VTE. CONCLUSIONS: In this prospective evaluation of the performance of the VPM, the 1-year rate of recurrence in patients with unprovoked VTE was 5.2%. Recalibration improved identification of patients at low recurrence risk and stratification into distinct low-risk categories.

SARS-CoV-2 variant-related abnormalities detected by prenatal MRI: a prospective case-control study.

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 examine the effects of SARS-CoV-2 variants on the placenta and fetus, we investigated 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. Thirty-eight prenatal MRI examinations were included after confirmed infection with SARS-CoV-2 and matched 1:1 with 38 control cases with respect to sex, MRI field strength, and gestational age (average deviation 1.76 ± 1.65, median 1.5 days). Where available, the pathohistological examination and vaccination status 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 38 included cases after SARS-CoV-2 infection, 20/38 (52.6%) were infected with pre-Omicron variants and 18/38 (47.4%) with Omicron. Prenatal MRIs were performed on an average of 83 days (±42.9, median 80) days after the first positive PCR test. Both pre-Omicron (P = .008) 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 (6.35, 95% CI .02-12.65, P = .048), and showed significantly more frequent lobules (P = .046), and hemorrhages (P = .002). Fetal growth restriction (FGR) was observed in 25% (n = 5/20, P = .017) 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: Vienna Science and Technology Fund.

Plasma levels of platelet-enriched microRNAs change during antiplatelet therapy in healthy subjects.

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.

Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy.

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.

Extracellular Vesicles and Citrullinated Histone H3 in Coronavirus Disease 2019 Patients.

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.

Association of cardiometabolic microRNAs with COVID-19 severity and mortality.

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.

Long-Term Survival After Venous Thromboembolism: A Prospective Cohort Study.

Background: Little is known about long-term survival after the initial treatment of venous thromboembolism (VTE). In a prospective cohort study, we aimed to assess the long-term mortality and key predictor variables relating to disease severity, treatment intensity, and comorbidities. Materials and Methods: Between 1988 and 2018, 6,243 consecutive patients with VTE from a University outpatient unit were prospectively included and followed until December 2019; clinical characteristics, measures of disease severity, and treatment details were recorded. Dates of death were retrieved from the Swiss Central Compensation Office. Results: Overall, 254 deaths occurred over an observation period of 57,212 patient-years. Compared to the Swiss population, the standardized mortality ratio was 1.30 (95% CI: 1.14, 1.47; overall mortality rate: 4.44 per 1,000 patient-years). The following predictors were associated with increased mortality: Unprovoked VTE (hazard ratio [HR]: 5.06; 95% CI: 3.29, 7.77), transient triggering risk factors (HR: 3.46; 95% CI: 2.18, 5.48), previous VTE (HR: 2.05; 95% CI: 1.60, 2.62), pulmonary embolism (HR: 1.45, 95% CI: 1.10, 1.89), permanent anticoagulant treatment (HR: 3.14; 95% CI: 2.40, 4.12), prolonged anticoagulant treatment (7-24 months; HR: 1.70; 95% CI: 1.16, 2.48), and cardiovascular comorbidities. Unprovoked VTE, previous VTE, permanent and prolonged anticoagulation remain independent risk factors after adjustment for age, sex, and comorbidities. Conclusion: Survival after VTE was significantly reduced compared to the Swiss general population, especially in patients with more severe disease, cardiovascular comorbidities, and longer anticoagulant treatment.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

The EHA Research Roadmap: Blood Coagulation and Hemostatic Disorders.

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. OBJECTIVES: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE. METHODS: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. RESULTS: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%). CONCLUSIONS: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Can Heparin-Coated ECMO Cannulas Induce Thrombocytopenia in COVID-19 Patients?

Extracorporeal membrane oxygenation (ECMO) is often used in the management of COVID-19-related severe respiratory failure. We report the first case of a patient with COVID-19-related ARDS on ECMO support who developed symptoms of heparin-induced thrombocytopenia (HIT) in the absence of heparin therapy. A low platelet count of 61 G/L was accompanied by the presence of circulating HIT antibodies 12 days after ECMO initiation. Replacement of the ECMO system including cannulas resulted in the normalization of the platelet count. However, the clinical situation did not improve, and the patient died 9 days later. Careful consideration of anticoagulant therapy and ECMO circuit, as well as routine HIT antibody testing, may prevent a fatal course in ECMO-supported COVID-19 patients.

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.

BACKGROUND: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. METHODS: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay. RESULTS: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. CONCLUSIONS: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

MicroRNA Signatures in Plasma of Patients With Venous Thrombosis: A Preliminary Report.

BACKGROUND: Venous thromboembolism (VTE) is a frequent and potentially fatal disease, but its pathophysiology is incompletely understood. microRNAs (miR) dysregulate hemostatic proteins and influence thrombotic pathology by posttranscriptional regulation of gene expression. Consensus in defining VTE-related miR clusters and functionally relevant miR has not been reached. We aimed to generate a miR database in patients at high thrombotic risk of VTE and explored their biological functions by seeking information on their messenger RNA targets. METHODS: By high-throughput screening (Affymetrix miRNA Microarray), we identified 159 miR in venous blood of male patients who had two unprovoked VTE and in age-matched male controls. RESULTS: Of the 159 miR, 41 were significantly higher expressed in patients compared to controls. Six miR (hsa-miR-6798-3p, hsa-miR-6789-5p hsa-miR-4651, hsa-miR-6765-5p, hsa-miR-6816-5p, hsa-miR-4734) were modulated ≥ 5.0-fold higher. Higher expression levels of 4 of these miR (hsa-miR-6789-5p, hsa-miR-4651, hsa-miR-6765-5p, and hsa-miR-6816-5p; primers were unavailable for hsa-miR-6798-3p and hsa-miR-4734) were confirmed by quantitative real-time polymerase chain reaction in 10 independent patients and 10 control samples. Ingenuity Pathway Analysis identified 23 altered miR including hsa-miR-6789-5p, hsa-miR-4651, hsa-miR-6765-5p and hsa-miR-4734 as the main regulators of messenger RNAs involved in the pathology of VTE. Seven messenger RNA targets including thrombomodulin and four targets related to platelet function had a direct relationship to 4 identified miR. CONCLUSIONS: We provide evidence of distinct, independently validated miR signatures in patients with VTE and identified a subset of miR as main regulators of messenger RNA involved in disorders related to pathophysiologic processes in venous thrombosis development.

Inflammatory Bowel Disease and Risk of Major Bleeding During Anticoagulation for Venous Thromboembolism.

BACKGROUND: Little is known about the bleeding risk in patients with inflammatory bowel disease (IBD) and venous thromboembolism (VTE) treated with anticoagulation. Our aim was to elucidate the rate of major bleeding (MB) events in a well-defined cohort of patients with IBD during anticoagulation after VTE. METHODS: This study is a retrospective follow-up analysis of a multicenter cohort study investigating the incidence and recurrence rate of VTE in IBD. Data on MB and IBD- and VTE-related parameters were collected via telephone interview and chart review. The objective of the study was to evaluate the impact of anticoagulation for VTE on the risk of MB by comparing time periods with anticoagulation vs those without anticoagulation. A random-effects Poisson regression model was used. RESULTS: We included 107 patients (52 women, 40 with ulcerative colitis, 64 with Crohn disease, and 3 with unclassified IBD) in the study. The overall observation time was 388 patient-years with and 1445 patient-years without anticoagulation. In total, 23 MB events were registered in 21 patients, among whom 13 MB events occurred without anticoagulation and 10 occurred with anticoagulation. No fatal bleeding during anticoagulation was registered. The incidence rate for MB events was 2.6/100 patient-years during periods exposed to anticoagulation and 0.9/100 patient-years during the unexposed time. Exposure to anticoagulation (adjusted incidence rate ratio, 3.7; 95% confidence interval, 1.5-9.0; P = 0.003) and ulcerative colitis (adjusted incidence rate ratio, 3.5; 95% confidence interval, 1.5-8.1; P = 0.003) were independent risk factors for MB events. CONCLUSION: The risk of major but not fatal bleeding is increased in patients with IBD during anticoagulation. Our findings indicate that this risk may be outweighed by the high VTE recurrence rate in patients with IBD.