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Acquired hemophilia A (AHA) is a rare bleeding disorder that can lead to spontaneous hemorrhage or bleeding induced by invasive procedures or trauma. We describe a patient who presented with multiple hematomas and a relapse of bullous pemphigoid shortly after his first dose of Vaxzevria ChAdOx1‐S COVID‐19 vaccination. We reviewed literature for cases of AHA following COVID‐19 vaccination. Can COVID‐19 vaccines induce (a recurrence of) AHA? The diagnosis of AHA with a relapse of bullous pemphigoid was made. The patient was treated with recombinant activated factor VII, emicizumab, rituximab, and methylprednisolone. There were no further bleeding events. However, the patient deteriorated because of sepsis and died on the fifteenth day of admission. Vaccines may trigger autoimmune events such as AHA. However, proof of causality is not possible and in this case the relapse of bullous pemphigoid before vaccination challenges this even more.

Objectives We review the evidence for tranexamic acid (TXA) for the treatment and prevention of bleeding caused by surgery, trauma and bleeding disorders. We highlight therapeutic areas where evidence is lacking and discuss safety issues, particularly the concern regarding thrombotic complications. Methods An electronic search was performed in PubMed and the Cochrane Library to identify clinical trials, safety reports and review articles. Findings TXA reduces bleeding in patients with menorrhagia, and in patients undergoing caesarian section, myomectomy, hysterectomy, orthopedic surgery, cardiac surgery, orthognathic surgery, rhinoplasty, and prostate surgery. For dental extractions in patients with bleeding disorders or taking antithrombotic drugs, as well as in cases of idiopathic epistaxis, tonsillectomy, liver transplantation and resection, nephrolithotomy, skin cancer surgery, burn wounds and skin grafting, there is moderate evidence that TXA is effective for reducing bleeding. TXA was not effective in reducing bleeding in traumatic brain injury and upper and lower gastrointestinal bleeding. TXA reduces mortality in patients suffering from trauma and postpartum hemorrhage. For many of these indications, there is no consensus about the optimal TXA dose. With certain dosages and with certain indications TXA can cause harm, such as an increased risk of seizures after high TXA doses with brain injury and cardiac surgery, and an increased mortality after delayed administration of TXA for trauma events or postpartum hemorrhage. Whereas most trials did not signal an increased risk for thrombotic events, some trials reported an increased rate of thrombotic complications with the use of TXA for gastro-intestinal bleeding and trauma. Conclusions TXA has well-documented beneficial effects in many clinical indications. Identifying these indications and the optimal dose and timing to minimize risk of seizures or thromboembolic events is work in progress.

Increasing age and renal impairment are risk factors for venous thrombosis but also for anticoagulant-induced bleeding. In large-scale phase III trials, non-VKA oral anticoagulants (NOACs) were at least as effective and safe for the treatment of acute venous thromboembolism as warfarin. Here, we review the efficacy and safety of dabigatran, rivaroxaban, apixaban and edoxaban in the subgroups of elderly patients (≥75 years) and patients with impaired renal function (creatinine clearance ≤50 ml/min). In all phase III trials, the efficacy of NOACs in the prevention of recurrent VTE was conserved both in the elderly subgroup and in the subgroup with impaired renal function. In a meta-analysis of the pooled results, NOACs reduced VTE recurrence compared with warfarin in elderly patients. In elderly patients and patients with impaired renal function, the safety of NOACs was in line with the results of the overall study. NOACs may offer an effective, safer and more convenient alternative for VKAs also in the elderly. However, the efficacy/safety profile of NOACs in the aged population needs to be confirmed in real-life.

Oral bleeding after dental extraction in patients on non-vitamin K oral anticoagulants (NOACs) is a frequent problem. We investigated whether 10% tranexamic acid (TXA) mouthwash decreases post-extraction bleeding in patients treated with NOACs. The EXTRACT-NOAC study is a randomized, double-blind, placebo-controlled, multicenter, clinical trial. Patients were randomly assigned to 10% TXA or placebo mouthwash and were instructed to use the mouthwash once prior to dental extraction, and thereafter for 3 times a day for 3 days. The primary outcome was the number of patients with any post-extraction oral bleeding up to day 7. Secondary outcomes included periprocedural, early, and delayed bleeding, and the safety outcomes included all thrombotic events. The first patient was randomized on February 9, 2018 and the last patient on March 12, 2020. Of 222 randomized patients, 218 patients were included in the full analysis set, of which 106 patients were assigned to TXA (74.8 (±8.8) years; 81 men) and 112 to placebo (72.7 (±10.7) years; 64 men). Post-extraction bleeding occurred in 28 (26.4%) patients in the TXA group and in 32 (28.6%) patients in the placebo group (relative risk, 0.92; 95% confidence interval [CI], 0.60 to 1.42; P = 0.72). There were 46 bleeds in the TXA group and 85 bleeds in the placebo group (rate ratio, 0.57; 95% CI, 0.31 to 1.05; P = 0.07). TXA did not reduce the rate of periprocedural bleeding (bleeding score 4 ± 1.78 versus 4 ± 1.82, P = 0.80) and early bleeding (rate ratio, 0.76; 95% CI, 0.42 to 1.37). Delayed bleeding (rate ratio, 0.32; 95% CI, 0.12 to 0.89) and bleeding after multiple extractions (rate ratio, 0.40; 95% CI, 0.20 to 0.78) were lower in the TXA group. One patient in the placebo group had a transient ischemic attack while interrupting the NOAC therapy in preparation for the dental extraction. Two of the study limitations were the premature interruption of the trial following a futility analysis and the assessment of the patients' compliance that was based on self-reported information during follow-up. In patients on NOACs undergoing dental extraction, TXA does not seem to reduce the rate of periprocedural or early postoperative oral bleeding compared to placebo. TXA appears to reduce delayed bleeds and postoperative oral bleeding if multiple teeth are extracted. ClinicalTrials.gov NCT03413891 EudraCT; EudraCT number:2017-001426-17; EudraCT Public website: eudract.ema.europa.eu.

Many patients suffer from venous thromboembolism (VTE) and its consequences. Despite substantial advancements with the introduction of direct oral anticoagulants (DOACs), patients and clinicians still encounter challenges in the acute and long‐term management of VTE, such as recurrent events, anticoagulant‐related bleeding complications, and post‐thrombotic symptoms. Additionally, certain patient populations, including those with advanced kidney failure and liver cirrhosis and elderly individuals, were excluded from phase 3 clinical DOAC trials. Therefore, the call for innovative anticoagulants in the acute and long‐term management of VTE resonates, not only to mitigate long‐term recurrences and post‐thrombotic symptoms but also to maintain the delicate harmony of hemostasis. Novel targets within the coagulation and fibrinolytic system, as well as mechanisms governing adherence to the vessel wall, are currently being explored to address these unmet needs. First, factor XI inhibitors have shown promise in preclinical and phase 2 clinical studies to tackle thrombosis while preserving hemostasis, although phase 3 trials are required for confirmation. Next, there is interest to boost the endogenous fibrinolytic system, with α2‐antiplasmin, thrombin‐activatable fibrinolysis inhibitor, and plasminogen activator inhibitor‐1 emerging as potential attractive targets. Finally, strategies to inhibit the interaction between leucocytes and the vessel wall are also under exploration. This review provides an overview of the latest clinical advancements in the pharmacological management of VTE.

Objectives The aim of this study was to validate a standardized pragmatic approach to manage new oral anticoagulants (NOACs) in patients who undergo dental extractions. Materials and methods This prospective case-control study in patients undergoing dental extraction included 26 patients (mean age 76 years, 57% male) treated with dabigatran, rivaroxaban, or apixaban and 26 matched controls. Regardless of timing of extraction, drug regimen, or renal function, patients were instructed to skip only the dose on the morning of the procedure. A procedural bleeding score was recorded and early and delayed bleeding was assessed at day 1 and day 7. Bleeding events were compared with a prospectively matched control group not taking any antithrombotic drug. Results There was no difference in the procedural bleeding score or in early bleeding events (5 in both groups). However, delayed bleeding occurred more frequently in anticoagulated compared to non-anticoagulated patients (7 versus none, p  = 0.01). Conclusions Skipping the morning dose of NOACs avoids excess bleeding during and early after the procedure. However, anticoagulated patients had an increased risk of delayed bleedings. Further study is needed to determine the optimal post-procedural management. Clinical relevance This is the first prospective study for the management of patients on NOACs undergoing dental extraction. Our pragmatic approach, omitting only a single morning dose, can guide clinical practice. Both patients and physicians should be aware of the increased delayed bleeding risk.

Background A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. Methods This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25–30, ≥ 30 kg/m 2 ). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. Results Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7–13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73–6.28] for normal weight, 2.50 [95% CI: 1.34–4.66] for overweight, and 3.42 [95% CI: 1.81–6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36–3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10–1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). Conclusions Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.

ObjectiveThe interruption of antithrombotics prior to tooth removal because of the fear of bleeding or following postoperative bleeding increases the risk of thromboembolic events. The aim of this systematic review was to investigate which local haemostatic measures can effectively prevent postoperative bleeding in patients continuing oral antithrombotics.MethodsA systematic review was conducted by running a search in PubMed, Embase, Web of Science and Cochrane Library. Clinical randomised trials investigating bleeding and haemostatics after tooth removal in patients on antithrombotics were identified.ResultsIn total, 15 articles were included. The investigated haemostatics included gauze pressure, tranexamic acid-soaked gauze, sponges, glue, calcium sulfate, plant extract Ankaferd Blood Stopper, epsilon-aminocaproic acid and tranexamic acid. In patients treated with vitamin K antagonists, tranexamic acid mouthwash significantly reduced bleeding compared to placebo. Further, histoacryl glue was proven better than gelatin sponges. Other studies failed to show significant differences between haemostatics, but bleeding events were low.ConclusionsTranexamic acid seems to effectively reduce bleeding, although its superiority to other haemostatics was not proven. In view of the rapidly changing landscape of antithrombotics and the lack of standardization of bleeding outcome, adequately powered clinical studies are required to optimise postoperative management in patients on antithrombotics.Clinical relevanceIn order to optimise postoperative management, the best haemostatics over different patient groups have to be identified and implemented in guidelines.

Introduction Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. Methods Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] ( n  = 87) and HC ( n  = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined. Results At baseline, psoriasis patients had higher median amplitude and AUC compared with HC ( p  < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude ( p  = 0.0365). Conclusion This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.

Annually, 10% of patients with atrial fibrillation (AF) or venous thromboembolism (VTE) treated with non-vitamin K oral anticoagulants undergo diagnostic or therapeutic procedures. This subanalysis of the multicenter, prospective, observational Edoxaban Management in Diagnostic and Therapeutic Procedures real-world registry included patients in Europe and Asia with AF or VTE who underwent transcatheter cardiovascular (CV) procedures. Edoxaban interruption and clinical outcomes were assessed for all arterial or venous access procedures and stratified by bleeding risk. Overall, 2695 procedures were reported; 755 (28.0%) were transcatheter CV procedures, of which 373 (49.4%) were arterial access and 382 (50.6%) were venous access procedures. Patients with arterial versus venous access procedures had significantly higher bleeding and stroke and thromboembolism risk scores (P < 0.0001 for both) and underwent procedures that were more frequently classified as having a higher European Heart Rhythm Association bleeding risk. Edoxaban was interrupted in 59.5% (222) arterial versus 42.4% (162) venous access procedures, mostly either only preprocedurally or both pre- and postprocedurally. The combined incidence of clinically relevant ischemic or bleeding event rates and deaths was low (0.8 events/100 procedures). This subanalysis showed that while edoxaban was interrupted in approximately half of all interventions, ischemic events and major bleeding were low, suggesting transcatheter CV procedures can be performed safely in high-risk patients with AF or VTE. Patient and procedural factors should be considered to personalize the decision of edoxaban management around the time of a transcatheter CV procedure. Clinical trial registration number: NCT02950168, NCT02951039