Infective endocarditis is a life‐threatening and enigmatic disease with a mortality of 30% and a pathophysiology that is poorly understood. However, at its core, an endocarditis lesion is mainly a ...fibrin and platelet blood clot infested with bacteria, clinging at the cardiac valves. Infective endocarditis therefore serves as a paradigm of immunothrombosis gone wrong. Immunothrombosis refers to the entanglement of the coagulation system with innate immunity and the role of coagulation in the isolation and clearance of invading pathogens. However, in the case of infective endocarditis, instead of containing the infection, immunothrombosis inadvertently creates the optimal shelter from the immune system and allows some bacteria to grow almost unimpeded. In every step of the disease, the coagulation system is heavily involved. It mediates the initial adhesion of bacteria to the leaflets, fuels the growth and maturation of a vegetation, and facilitates complications such as embolization and valve destruction. In addition, the number one cause of infective endocarditis, Staphylococcus aureus, has proven to be a true manipulator of immunothrombosis and thrives in the fibrin rich environment of an endocarditis vegetation. Considering its central role in infective endocarditis, the coagulation system is an attractive therapeutic target for this deadly disease. There is, however, a very delicate balance at play and the use of antithrombotic drugs in patients with endocarditis is often accompanied with a high bleeding risk.
Abstract
Aims
The pathogenesis of endocarditis is not well understood resulting in unsuccessful attempts at prevention. Clinical observations suggest that Staphylococcus aureus infects either damaged ...or inflamed heart valves. Using a newly developed endocarditis mouse model, we therefore studied the initial adhesion of S. aureus in both risk states.
Methods and results
Using 3D confocal microscopy, we examined the adhesion of fluorescent S. aureus to murine aortic valves. To mimic different risk states we either damaged the valves with a surgically placed catheter or simulated valve inflammation by local endothelium activation. We used von Willebrand factor (VWF) gene-deficient mice, induced platelet and fibrinogen depletion and used several S. aureus mutant strains to investigate the contribution of both host and bacterial factors in early bacterial adhesion. Both cardiac valve damage and inflammation predisposed to endocarditis, but by distinct mechanisms. Following valve damage, S. aureus adhered directly to VWF and fibrin, deposited on the damaged valve. This was mediated by Sortase A-dependent adhesins such as VWF-binding protein and Clumping factor A. Platelets did not contribute. In contrast, upon cardiac valve inflammation, widespread endothelial activation led to endothelial cell-bound VWF release. This recruited large amounts of platelets, capturing S. aureus to the valve surface. Here, neither fibrinogen, nor Sortase A were essential.
Conclusion
Cardiac valve damage and inflammation predispose to S. aureus endocarditis via distinct mechanisms. These findings may have important implications for the development of new preventive strategies, as some interventions might be effective in one risk state, but not in the other.
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.
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.
Adhesion of Staphylococcus aureus to blood vessels under shear stress requires von Willebrand factor (VWF). Several bacterial factors have been proposed to interact with VWF, including VWF-binding ...protein (vWbp), a secreted coagulase that activates the host's prothrombin to generate fibrin. We measured the adhesion of S aureus Newman and a vWbp-deficient mutant (vwb) to VWF, collagen, and activated endothelial cells in a microparallel flow chamber. In vivo adhesion of S aureus was evaluated in the mesenteric circulation of wild-type (WT) and VWF-deficient mice. We found a shear-dependent increase in adhesion of S aureus to the (sub)endothelium that was dependent on interactions between vWbp and the A1-domain of VWF. Adhesion was further enhanced by coagulase-mediated fibrin formation that clustered bacteria and recruited platelets into bacterial microthrombi. In vivo, deficiency of vWbp or VWF as well as inhibition of coagulase activity reduced S aureus adhesion. We conclude that vWbp contributes to vascular adhesion of S aureus through 2 independent mechanisms: shear-mediated binding to VWF and activation of prothrombin to form S aureus–fibrin–platelet aggregates.
•vWbp mediates adhesion of S aureus under flow to activated endothelial cells and the subendothelium via VWF.•vWbp activates prothrombin and triggers the formation of bacteria–fibrin–platelet aggregates, which enhance adhesion to vessels under flow.
Summary
Anticoagulants are effective at preventing and treating thrombosis, but can cause bleeding. For decades, vitamin K antagonists (VKAs) have been the only available oral anticoagulants. The ...development of non-VKA oral anticoagulants (NOACs), which inhibit either factor Xa or thrombin stoichiometrically, has provided alternatives to VKAs for several indications. The results of recent large-scale randomised controlled trials comparing NOACs with VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) have produced some unexpected results. As a group, NOACs showed similar efficacy as warfarin, but a reduced risk of major bleeding. The reduction in bleeding with NOACs was greatest with intracranial hemorrhage. In contrast, the relative risk of gastro-intestinal bleeding was increased with some NOACs. In this review, we explore the potential mechanisms as well as the implications of these organ-specific bleeding patterns.
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.
An electronic search was performed in PubMed and the Cochrane Library to identify clinical trials, safety reports and review articles.
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.
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.
Psoriasis is a chronic inflammatory skin disease associated with numerous comorbidities. Psoriasis has been linked to an increased risk of metabolic syndrome and atherosclerotic arterial disease. ...Inflammatory conditions are known to increase the risk of venous thromboembolism (VTE), a frequent cause of morbidity and mortality. However, the relationship between psoriasis and VTE has received little attention and existing studies have shown conflicting results.
This systematic review aims to perform a meta-analysis on VTE in psoriasis patients.
We conducted a systematic electronic search of the incidence of VTE (pulmonary embolism PE, deep venous thrombosis DVT and/or retinal vein occlusion RVO) in psoriasis patients on PubMed, Web of Science, Embase and Cochrane (specifics: see
Appendix 1 in Supporting information
). Only English literature and full manuscripts were included; abstracts were excluded. Pooled risk ratio and 95% confidence interval were calculated using Review Manager.
Seven articles were included. Each study separately indicated a correlation between psoriasis and VTE after adjustment for several clinical parameters. The confounders included in the adjustment differed between studies, but all included adjustment for age, gender and comorbidities. A meta-analysis of the unadjusted data of the five studies that reported raw data on number of VTE events and patient follow-up (person-years) showed a pooled risk ratio for VTE and psoriasis of 1.29 (95% CI: 0.92-1.81). The statistical heterogeneity was high with I
2
of 97%.
Published data adjusted for key confounders demonstrate in general a significantly increased prevalence of VTE in psoriasis patients. Both psoriasis severity and number of confounders assessed seem to have an impact on this correlation. In this review, we pooled unadjusted data of the studies and we found a non-significant increased risk for VTE in psoriasis patients compared to healthy controls. This discrepancy suggests that psoriasis severity, age, gender or comorbidities may influence the risk of VTE in subgroups of the psoriasis population. Future research to identify subgroups at risk for VTE is warranted.
Key messages
The included studies reported an increased risk of VTE, DVT, PE and RVO in psoriasis patients.
A meta-analysis was performed on five studies that reported raw data and showed that the pooled risk ratio for VTE in psoriasis patients overall was increased, however not significantly, compared to healthy controls.
Further research to pinpoint psoriasis subgroups at risk (e.g. severe psoriasis patients, younger age, associated comorbidities) of developing VTE is warranted.
Abstract
Background
The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure ...is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol.
Methods
PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group.
Conclusion
The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.
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