Life-threatening Bleeding Research Articles

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors

BackgroundDirect oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. ObjectivesThe ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. MethodsHuman FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. ResultsF174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. ConclusionThese human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

Clinical characteristics, radiological features and outcomes in pulmonary involvement of cryoglobulinemia

BackgroundCryoglobulinemia with pulmonary involvement is rare, and its characteristics, radiological findings, and outcomes are still poorly understood.MethodsTen patients with pulmonary involvement of 491 cryoglobulinemia patients at Peking Union Medical College Hospital were enrolled in this retrospective study. We analyzed the characteristics, radiological features and management of pulmonary involvement patients, and compared with those of non-pulmonary involvement with cryoglobulinemia.ResultsThe 10 patients with pulmonary involvement (2 males; median age, 53 years) included three patients with type I cryoglobulinemia and seven patients with mixed cryoglobulinemia. All of 10 patients were IgM isotype cryoglobulinemia. All type I patients were secondary to B-cell non-Hodgkin lymphoma. Four mixed patients were essential, and the remaining patients were secondary to infections (n = 2) and systemic lupus erythematosus (n = 1), respectively. Six patients had additional affected organs, including skin (60%), kidney (50%), peripheral nerves (30%), joints (20%), and heart (20%). The pulmonary symptoms included dyspnea (50%), dry cough (30%), chest tightness (30%), and hemoptysis (10%). Chest computed tomography (CT) showed diffuse ground-glass opacity (80%), nodules (40%), pleural effusions (30%), and reticulation (20%). Two patients experienced life-threatening diffuse alveolar hemorrhage. Five patients received corticosteroid-based regimens, and four received rituximab-based regimens. All patients on rituximab-based regimens achieved clinical remission. The estimated two-year overall survival (OS) was 40%. Patients with pulmonary involvement had significantly worse OS and progression-free survival than non-pulmonary involvement patients of cryoglobulinemia (P < 0.0001).ConclusionsA diagnosis of pulmonary involvement should be highly suspected for patients with cryoglobulinemia and chest CT-indicated infiltrates without other explanations. Patients with pulmonary involvement had a poor prognosis. Rituximab-based treatment may improve the outcome.

Inflammatory Responses of the Remote Organs After Tourniquet-Induced Ischemia-Reperfusion in Mouse Hindlimb

Tourniquet use is the most effective tool for controlling life-threatening extremity hemorrhage before other treatments and for creating bloodless operating fields in surgical procedures. However, tourniquet-induced ischemia-reperfusion (IR) also causes skeletal muscle injury and associated secondary end-organ damage. Our previous studies have demonstrated that there are involvements of inflammatory cytokines in tourniquet-induced skeletal muscle IR injuries. The objective of this study is to investigate the inflammatory responses of end-organs after tourniquet-induced mouse hindlimb IR. We hypothesized that tourniquet use would result in an inflammatory response in the remote organs. The unilateral hindlimbs of mice were subjected to 3 hours of tourniquet application by placing a rubber band at the hip joint. Then the rubber bands were released for reperfusion over different periods of time (1, 3, 7, and 14 days). The mRNA levels of IL-1β and TNFα (two inflammatory cytokines) in the lungs, liver, kidneys, and heart were measured using real-time RT-PCR analysis. In the lungs, the levels of IL-1β and TNFα mRNA were significantly elevated at day 1 after tourniquet-induced IR, then decreased at days 3 and 7, and returned to a high level at day 14. In the liver, the levels of IL-1β and TNFα mRNA were increased at day 1 and remained at a high level until day 14. However, tourniquet-induced hindlimb IR did not change the levels of IL-1β or TNFα mRNA in the kidneys or heart during the whole period of tourniquet-induced IR. In conclusion, these results suggest that the inflammatory response to tourniquet-induced hindlimb IR is different among distant organs, which will help to develop therapeutic strategies for different end-organs after tourniquet-induced hindlimb IR. NIH/NIGMS 1R01GM145736 to Y-LL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Safety and Feasibility Single-Arm Study of a Novel Catheter Thrombectomy Device for the Treatment of Pulmonary Embolism (ENGULF)

BackgroundDespite advances in therapy options, pulmonary embolism (PE) continues to carry a high risk of mortality and morbidity. Currently, therapeutic options are limited with only 2 US Food and Drug Administration-cleared catheter-based embolectomy devices approved for the treatment of intermediate-risk PE. The novel Hēlo PE thrombectomy catheter (Endovascular Engineering, Inc) has a flexible and collapsible funnel with an internal agitator for a dual mechanism of treatment for acute PE. We sought to investigate the safety and feasibility of the novel Hēlo PE thrombectomy catheter in intermediate-risk PE. MethodsA prospective, single-arm feasibility study evaluating the Hēlo PE catheter was performed in patients presenting with intermediate-risk PE. Patients underwent preprocedural and postprocedural computed tomography angiography. Primary efficacy was the difference in preprocedural to postprocedural right ventricle/left ventricle (RV/LV) ratio. Primary and secondary safety outcomes were all-cause mortality, major life-threatening bleeding, device-related serious adverse events, pulmonary or cardiac injury, and clinical decompensation at 48 hours postprocedure and at 30 days. ResultsA total of 25 patients from 8 centers were consented and included in the analysis. Preprocedural computed tomography angiography revealed an RV/LV ratio of 1.53 ± 0.27. All patients underwent a successful thrombectomy procedure. Postprocedure, the RV/LV ratio was reduced to 1.15 ± 0.18, translating into a 23.2 ± 12.81% decrease from baseline. No patients underwent adjunctive thrombolysis. Two patients had adjunctive catheter-directed embolectomy with an alternative device. Two patients had postprocedural anemia requiring transfusion but did not meet criteria for major life-threatening bleeding by VARC-2 criteria. There were no major adverse events including no deaths, major bleeding, pulmonary injury, or vascular complications at 48 hours or 30 days post procedure. ConclusionsIn this multicenter first-in-human study, use of the Hēlo PE thrombectomy catheter was feasible and safe for the treatment of acute PE.

Triple Action of Lignosulfonic Acid Sodium: Anti-protease, Antioxidant, and Anti-inflammatory Effects of a Polymeric Heparin Mimetic.

Heparins are sulfated glycosaminoglycans that are used as anticoagulants to treat thrombosis. Heparins exhibit other potential therapeutic effects, such as anti-inflammatory, anti-viral, and anti-malarial effects. However, the strong anticoagulant activity of heparins poses a risk of life-threatening bleeding, limiting their therapeutic use for other diseases beyond thrombosis. To exploit the other effects of heparins and eliminate the bleeding risk, we explored an alternative polymer called lignosulfonic acid sodium (LSAS), which acts as a sulfonated heparin mimetic. LSAS targets factor XIa to exert an anticoagulant effect, and thus, unlike heparins, it is unlikely to cause bleeding. This study investigated the multiple effects of LSAS to identify potential leads for complex pathologies treatment. A series of chromogenic substrate hydrolysis assays were used to evaluate the inhibition of three inflammation-related proteases by LSAS. Its chemical antioxidant activity against the system of ABTS/hydrogen peroxide/metmyoglobin was also determined. Lastly, the effect of LSAS on TNFα-induced activation of the NF-κB pathway in HEK-293 cells was also tested to determine its cellular anti-inflammatory activity. The results showed that LSAS effectively inhibited human neutrophil elastase, cathepsin G, and plasmin, with IC50 values ranging from 0.73 to 212.5 μg/mL. Additionally, LSAS demonstrated a significant chemical antioxidant effect, with an IC50 value of 44.1 μg/mL. Furthermore, at a concentration of approximately 530 μg/mL, LSAS inhibited the TNFα-induced activation of the NF-κB pathway in HEK-293 cells, indicating a substantial anti-inflammatory effect. An essential advantage of LSAS is its high water solubility and virtual non-toxicity, making it a safe and readily available polymer. Based on these findings, LSAS is put forward as a polymeric heparin mimetic with multiple functions, serving as a potential platform for developing novel therapeutics to treat complex pathologies.

Abstract 123: Hemostatic Fibrin Knob Triggered Microgel To Promote Clotting With Reduced Thrombotic Risks In Neonates

Introduction: Effective neonatal hemostatic therapies are vital for complex surgery-related life-threatening bleeding [1]. Neonatal hemostatic systems differ significantly from adults [2, 3]; however, current treatments for bleeding include adult blood products (ABP). Neonatal ABP use poses an elevated thrombotic risk [4, 5], necessitating alternative approaches. We propose hemostatic therapies leveraging age-dependent clotting differences. In adults, clot formation relies on fibrin(ogen) A:a knob-hole binding, while B:b binding dominates in neonates. Targeting B:b interactions with synthetic Bknob conjugated platelet-like particles (BK-PLP) could crosslink neonatal fibrinogen, catalyze clot formation, and enhance clot strength with lower thrombotic risk than ABP. To test this, we synthesized pNIPAm microgels and conjugated them to B-knob (AHRPYAAK), A-knob (GPRPFPAK), and non-binding control peptides (GPSPFPAK) to prepare BK-PLP, AK-PLP, and NB-PLP. Materials and Methods: We prepared BK-PLP, AK-PLP, and NB-PLP by conjugating microgels with mimetic peptides using EDC-Sulfo-NHS chemistry (Fig. 1A); Fibrin clot polymerization, stability, density, and stiffness, were analyzed via plate-based assays, confocal microscopy, and AFM. Results and Discussion: BK-PLPs significantly increased clot stability compared to AK-PLP, NB-PLP, or fibrin-only clots (Fig. 1B). Fiber density also increased with BK-PLPs, indicating a role in promoting denser fibrin clot structures (Fig. 1C). Clot mechanical properties assessment suggested that AKnob and NB-PLPs may disrupt clot networks, decreasing stiffness (Fig. 1D). Conclusion: Our study explored the effects of peptide conjugate particles on neonatal fibrin clots. BK-PLP incorporation increased clot stability, while AK-PLP and NB-PLP decreased clot stiffness, supporting further BK-PLP development for neonatal hemostasis.

Memorial Regional Hospital Placenta Accreta Spectrum Program: Quality Evaluation of Outcomes [ID 2683637

INTRODUCTION: Placenta accreta spectrum (PAS) affects 1/272 deliveries with a mortality rate of 7%, which is often related to life-threatening hemorrhage. Morbidity related to PAS is often due to complications such as hemorrhage requiring blood transfusion, intensive care unit (ICU) admission, and prolonged hospital stay. The American College of Obstetricians and Gynecologists supports a multidisciplinary approach to management of pregnancies complicated by PAS, and as such our protocol for management of PAS was started in 2016. Our approach to the management of PAS includes a high-risk navigation team, monthly multidisciplinary team meetings, early admission for surgical planning, a dedicated team with 24-hour coverage, blood bank specialist involvement at the time of surgery, the availability of backup surgeons, and coordination with other surgical subspecialties. METHODS: This project is a quality review of outcomes of 216 females between 2016 and 2023. Using linear regression analysis, we evaluated four primary outcomes: quantitative blood loss (QBL), blood products transfusion (BPT), length of stay (LOS), and ICU admissions. RESULTS: Linear regression outcomes showed that our QBL, BPT, and LOS among non-ICU patients is lower than the national average and within national average among those admitted to the ICU, with the exception of BPT. Finally, placenta pathology and location may not be a major factor negatively affecting surgical outcomes among PAS patients in a structured program and should be a factor considered when developing PAS centers. CONCLUSION: Our findings from our quality review support the use of a multidisciplinary and surgically structured approach for managing patients with PAS.

Prophylactic occlusion balloons of both internal iliac arteries in caesarean hysterectomy for placenta accreta spectrum disorder reduces blood loss: A retrospective comparative study

BackgroundThe placenta accreta spectrum is a complex disorder characterized by abnormal invasion of the placenta into the uterine wall, posing a significant risk of life-threatening haemorrhage for patients. Its incidence is on the rise, largely attributed to the increasing rates of caesarean sections. Management of this spectrum involves a multidisciplinary approach, although standardized protocols are not yet established. While caesarean hysterectomy remains the standard Gold, several adjunctive treatments have emerged in recent years to mitigate bleeding risk and associated morbidity. Among these, prophylactic occlusion balloons placed in the internal iliac arteries have shown promise. The aim of our study is to demonstrate the effect of prophylactic occlusion balloons in both uterine iliac arteries in the management of placental accreta spectrum disorders. MethodsA retrospective monocentric cohort study was conducted in the Department "C" of Gynaecology and Obstetrics at the Maternity Center of Tunis. The study spanned three years, from January 2nd, 2020, to December 31st, 2022. The study population consisted of two groups: Control Group (CG) comprised patients who underwent caesarean hysterectomy without internal-iliac prophylactic occlusion balloons, and Occlusion balloons of both internal iliac arteries Group (OBIIAG) included patients who underwent caesarean hysterectomy with internal-iliac prophylactic occlusion balloons. ResultsA total of 38 patients were included in the study, all of whom exhibited similar epidemiological characteristics and comparable personal and obstetric histories. The most prevalent risk factor among the patients was a history of caesarean section (92%). On average, patients were diagnosed at 30 weeks of gestation, with third-trimester bleeding being the most common presentation (71% of cases). The median gestational age at delivery was between 36 and 37 weeks. We observed a significant difference in blood loss between the two groups (2888 ml in the control group and 1828 ml in the group with internal-iliac prophylactic occlusion balloons, p < 0.05). Implementation of this technique resulted in a reduced need for massive transfusions (p < 0.01) and shorter operating times (126 min for the control group and 92 min for the group with internal-iliac prophylactic occlusion balloons; p = 0.04). There were no significant differences in morbidity between the two groups. ConclusionThe intra-iliac prophylactic occlusion balloons can help reduce the risk of hemorrhage and the morbidities that come with the placenta accreta spectrum disorder.

Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

Hemophilia A (HA) is a genetic disorder of hemostasis associated with a deficiency or reduced activity of clotting factor VIII (FVIII). This disorder remains unacceptably underdiagnosed in India. Early diagnosis and appropriate management of HA can substantially prevent morbidity and mortality. Currently, HA is managed with regular replacement therapy using standard or extended half-life FVIII concentrates or non-factor drug products. The challenges associated with FVIII concentrates include plateauing of drug effect, issues with its administration and adherence to treatment, breakthrough bleeds, and the development of inhibiting antibodies against administered clotting factors. Emicizumab is a bispecific antibody, launched in India in April 2019, for managing patients with HA. To investigate the role of emicizumab in Indian patients with HA, opinions were sought from 13 eminent hematologists and experts from India on the effectiveness of emicizumab in preventing all bleeds, spontaneous bleeds, perioperative bleeds, and intracranial hemorrhage; resolving target joints; and reducing the rate of hospitalizations and fatality associated with HA in children and adults, with or without inhibitors. The benefits of emicizumab over traditional FVIII concentrates include the subcutaneous route of delivery, less frequent dosing, and a lack of inhibitor development, in addition to providing sustained hemostasis without in-depth monitoring. It is a safe and effective management option for all HA patients, especially for patients with certain archetypes, such as those with inhibitors, those with high annualized bleed rates, those living far away from hemophilia care centers, pediatric patients and infants with intravenous access challenges, and those with a history of life-threatening bleeding events.

Coagulation Tests and Reversal Agents in Patients Treated with Oral Anticoagulants: The Challenging Scenarios of Life-Threatening Bleeding and Unplanned Invasive Procedures.

In clinical practice, the number of patients treated with direct oral anticoagulants (DOACs) has consistently increased over the years. Since anticoagulant therapy has been associated with an annual incidence of major bleeding (MB) events of approximately 2% to 3.5%, it is of paramount importance to understand how to manage anticoagulated patients with major or life-threatening bleeding. A considerable number of these patients' conditions necessitate hospitalization, and the administration of reversal agents may be imperative to manage and control bleeding episodes effectively. Importantly, effective strategies for reversing the anticoagulant effects of DOACs have been well recognized. Specifically, idarucizumab has obtained regulatory approval for the reversal of dabigatran, and andexanet alfa has recently been approved for reversing the effects of apixaban or rivaroxaban in patients experiencing life-threatening or uncontrolled bleeding events. Moreover, continuous endeavors are being made to develop supplementary reversal agents. In emergency scenarios where specific reversal agents might not be accessible, non-specific hemostatic agents such as prothrombin complex concentrate can be utilized to neutralize the anticoagulant effects of DOACs. However, it is paramount to emphasize that specific reversal agents, characterized by their efficacy and safety, should be the preferred choice when suitable. Moreover, it is worth noting that adherence to the guidelines for the reversal agents is poor, and there is a notable gap between international recommendations and actual clinical practices in this regard. This narrative review aims to provide physicians with a practical approach to managing specific reversal agents.

Sonographic Features of Uterine Arteriovenous Malformation: A Case Series.

Uterine arteriovenous malformation (AVM) is very rare but potentially life-threatening. Early and accurate diagnosis is the cornerstone of its management. The objective of this study is to encourage sonographers to become familiar with a variety of grayscale sonographic features, facilitating rapid recognition of the patterns and prompting them to apply color flow Doppler for a diagnosis of uterine AVM and possible further investigations or interventions. We present six cases of uterine AVM presenting with abnormal uterine bleeding at varying degrees of severity, from abnormal menstruation to life-threatening bleeding following curettage. All initially provided some clues of uterine AVM upon grayscale ultrasound, leading to the application of color Doppler flow to support a diagnosis, with confirmation using abdominal computer tomography angiography (CTA) in most cases, resulting in definitive treatment using uterine artery embolization or other interventions. Most importantly, this study provides various sonographic features of uterine AVM, such as appearances of small tubular structures, spongy patterns, a conceptive-product-like appearance, and spaghetti-like patterns. Hopefully, familiarity with these sonographic features can facilitate practitioners to make an early diagnosis, leading to proper further investigation and intervention, and to prevent serious complications from potentially being caused by this subtle but very serious disorder.

Massive Transfusion in Pediatric Patients on Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Massive Transfusion in Children (MATIC) Study.

Few data describe pediatric patients who receive massive transfusion for life-threatening hemorrhage (LTH) while on extracorporeal membrane oxygenation (ECMO). We present a retrospective secondary analysis of a multicenter prospective observational study to describe resource utilization and mortality in pediatric patients with LTH while on ECMO. Children who were on ECMO during an LTH were compared to children with LTH who were not on ECMO. Primary outcomes were volumes of blood products administered and 28 day mortality. Comparisons were assessed by two-sided Fisher's exact test or Wilcoxon rank sum test. A total of 449 children, including 36 on ECMO, were included. Compared to those not on ECMO, children on ECMO received a higher volume of blood products (110 [50-223] vs . 59 [28-113]) ml/kg, p = 0.002) and were more likely to receive antifibrinolytic therapy (39% vs . 10%, p < 0.001). Blood product ratios were similar. Extracorporeal membrane oxygenation patients had higher 28 day mortality (64% vs. 35%, p = 0.001), although 24 hour mortality was similar (17% vs . 23%, p = 0.5). In conclusion, children on ECMO with LTH experience high resource utilization and 28 day mortality. Studies are needed to identify children at risk for LTH and to evaluate ECMO-specific treatment strategies.

The Challenge for a Correct Diagnosis of Refractory Thrombocytopenia: ITP or MDS with Isolated Thrombocytopenia?

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The aim of this review is to summarize the conditions associated with isolated thrombocytopenia and highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases of persistent thrombocytopenia a detailed diagnostic work-up is applied-including evaluation of peripheral-blood smear, bone marrow examination and cytogenetic testing-to avoid unnecessary therapy delay.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Evaluation of modified fixed dose four-factor prothrombin complex concentrate for warfarin reversal.

Non-activated four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred reversal strategy for patients on warfarin with life-threatening bleeding. Current dosing recommendations for 4F-PCC require pre-treatment international normalized ratio (INR) and bodyweight values, resulting in ordering and administration delays. Studies have shown that alternative dosing regimens are safe and efficacious. This retrospective, single-center, pre- and post-protocol analysis was conducted to assess the efficacy of a pharmacist driven modified fixed-dose 4F-PCC regimen versus package insert weight- and INR-based dosing regimen for warfarin reversal. The primary outcome was achievement of INR less than two. Secondary outcomes included dose and cost of 4F-PCC, a time analysis, incidence of concomitant vitamin K administration, and incidence of thrombosis within seven days of 4F-PCC. There were 195 patients included in the analysis, with 74 in the pre-cohort and 121 in the post-cohort. Baseline characteristics were similar between cohorts with the most common indication for warfarin use being atrial fibrillation (48.6% versus 47.1%) and reversal being intracerebral hemorrhage (68.9% versus 43.0%). Achievement of the primary endpoint occurred in 92% versus 95% (p = 0.097) of patients. A statistically significant difference was seen between cohorts regarding median dose and cost of 4F-PCC administered (p < 0.001). Eleven thromboembolic events occurred with three events in the pre-cohort and eight events in the post-cohort (p = 0.453). A fixed-dose of 1500IU of 4F-PCC was effective in reversing INR to less than two in most patients regardless of reversal indication with minimal thrombotic risks.

Quality of life after immune suppressive therapy in aplastic anemia.

Acquired aplastic anemia (AA) is a rare form of immune-mediated bone marrow failure, which can result in life-threatening infections or bleeding if left untreated. Treatment consists of either immune suppressive therapy (IST) or allogeneic stem cell transplantation (alloHSCT). While considerable research has been published regarding survival, response rate and toxicity of both treatments, knowledge on the impact on quality of life (QoL) is scarce. We used the recently developed AA-specific QoL questionnaire (QLQ-AA/PNH-54) to evaluate QoL in a single center cohort of AA patients who were successfully treated with IST. The 54 questions represent 12 different QoL domains. Results were analyzed for all patients and grouped based on hematologic response (complete response (CR) or partial response (PR)). Thirty-six successfully treated adult patients (15 in CR, 21 in PR) completed the questionnaire (median age 54years, range 21-71; median time since last IST 5years, range 0-41). Fatigue was experienced by 83% of patients. Even though total QoL scores did not significantly differ between patients with PR and CR (105 vs 92, p-value 0,17) there appeared to be a trend towards higher scores in patients with PR, especially in domains concerning psychological wellbeing. This trend was most clear in the domains fear of progression (2,12 in PR patients vs 1,73 in CR patients; p-value 0,08) and role functioning (2,22 vs 1,88; p-value 0,07). In conclusion, patients with AA continue to experience psychological and physical effects despite successful IST.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Outcomes of mitral valve transcatheter edge-to-edge repair for patients with hemodynamic instability: A systematic review and meta-analysis

BackgroundThe outcomes after mitral valve transcatheter edge-to-edge repair (M-TEER) for the patients with severe mitral regurgitation (MR) in hemodynamically unstable conditions, such as cardiogenic shock, still remain unclear. We aimed to integrate previous publications regarding M-TEER indicated for life-threatening conditions and indirectly particularly compared the short-term outcomes thereof, with that of other treatments. MethodsWe systematically searched the PubMed, Cochrane, and MEDLINE databases for studies from inception to June 2023, regarding M-TEER in patients with hemodynamic instability and severe MR. The primary outcomes analyzed included the in-hospital and 30-day mortality rates, and peri-procedural complications. ResultsOf the initial 820 publications, we conducted a meta-analysis of a total of 25 studies. The relative risk of moderate-to-severe or severe MR was 0.13 (95 % confidence interval [CI]: 0.10–0.18, I2 = 45.2 %). The pooled in-hospital and 30-day mortality rates were 11.8 % (95 % CI: 8.7–15.9, I2 = 96.4 %) and 14.1 % (95 % CI: 10.9–18.3, I2 = 35.5 %), respectively. The 30-day mortality rate was statistically significantly correlated with the residual moderate-to-severe or severe MR, as per the meta-regression analysis (coefficient β = 3.48 [95 % CI: 0.99–5.97], p = 0.006). Regarding peri-procedural complications, the pooled rates of a stroke or transient ischemic attack, life-threatening or major bleeding, acute kidney injury, and peri-procedural mitral valve surgery were 2.3 % (95 % CI: 1.9–2.6), 7.6 % (95 % CI: 6.8–8.5), 32.9 % (95 % CI: 31.6–34.3), and 1.0 % (95 % CI: 0.8–1.3), respectively. ConclusionsThis meta-analysis demonstrates that the relatively higher rates of procedural complications were observed, nevertheless, M-TEER can potentially provide favorable short-term outcomes even in hemodynamically unstable patients. PROSPERO registration numberCRD42023468946.

Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.