Respiratory syncytial virus (RSV) is the most common cause of small airways inflammation in the lungs (bronchiolitis) in neonates and immunocompromised adults. The deregulation of cellular and plasma components leads to increased morbidity and mortality. The activation of the clotting cascade plays a key role in the progression of disease severity during viral infection. The current investigation studied the effect of bivalirudin (BR) on the progression and cellular effects of RSV-induced infection in the neonatal mice model. Mice (5-7 days old) were inoculated intranasally with RSV with or without BR administration (2 mg kg-1 day-1, i.v.) for 2 weeks. Tissue histopathology, inflammatory signalling genes such as TLR, and cytokines were analyzed. The results showed pneumocytes exhibiting nuclear pyknosis, cellular infiltration in lung tissue and increased lung titers in RSV-infected mice compared to the control. Furthermore, RSV-infected mice demonstrated altered clotting parameters such as D-dimer, soluble thrombomodulin, and increased inflammatory cytokines IL-5, 6, IFN-γ, IL-13, and CXCL1. Additionally, the mRNA expression analysis displayed increased levels of IL-33, TLR3, and TLR7 genes in RSV-infected lung tissue. Further, to delineate the role of micro RNAs, the qRT-PCR analysis was done, and the results displayed an increase in miR-136, miR-30b, and let-7i. At the same time, the down-regulated expression of miR-221 in RSV-infected mice compared to the control. BR treatment reduced the cellular infiltration with reduced inflammatory cytokines and normalized clotting indices. Thus, the study shows that RSV infection induces specific changes in lung tissue and the clotting related signalling mechanism. Additionally, BR treatment significantly reduces bronchiolitis and prevents the severity of the infections suggesting that BR can possibly be used to reduce the viral-mediated infections in neonates.

Background The effectiveness of vascular closure devices (VCDs) to reduce bleeding after transfemoral percutaneous coronary intervention remains unsettled. Methods and Results Participants in the REGULATE-PCI (Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention) trial who underwent transfemoral percutaneous coronary intervention with VCD implantation were compared with those who underwent manual compression. The primary effectiveness end point was type 2, 3, or 5 Bleeding Academic Research Consortium access site bleeding at day 3. Univariate and multivariate analyses were adjusted by the inverse probability weighting method using propensity score. Time to hemostasis and time to ambulation were compared between groups. Of the 1580 patients who underwent transfemoral percutaneous coronary intervention, 1004 (63.5%) underwent VCD implantation and 576 (36.5%) had manual compression. The primary effectiveness end point occurred in 64 (6.4%) participants in the VCD group and in 38 (6.6%) participants in the manual compression group (inverse probability weighting-adjusted odds ratio, 1.02 [95% CI, 0.77-1.36]; P=0.89). There were statistically significant 2-way interactions between VCD use and female sex, chronic kidney disease, and use of high-potency P2Y12 inhibition (ticagrelor or prasugrel) (P<0.05 for all) with less bleeding with VCD use in these high-risk subgroups. Median time to hemostasis and time to ambulation were shorter in the VCD versus the manual compression group (P<0.01 for both). Conclusions Following transfemoral percutaneous coronary intervention, VCD use is associated with a shorter time to hemostasis and time to ambulation but not less bleeding. Further study of patients with high-bleeding risk is required, including women, patients with chronic kidney disease, and those using high-potency P2Y12 inhibitors. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01848106; Unique identifier: NCT01848106.

Extracorporeal membrane oxygenation (ECMO) has been established as a life-saving technique for patients with the most severe forms of respiratory or cardiac failure. It can, however, be associated with severe complications. Anticoagulation therapy is required to prevent ECMO circuit thrombosis. It is, however, associated with an increased risk of hemocoagulation disorders. Thus, safe anticoagulation is a cornerstone of ECMO therapy. The most frequently used anticoagulant is unfractionated heparin, which can, however, cause significant adverse effects. Novel drugs (e.g., argatroban and bivalirudin) may be superior to heparin in the better predictability of their effects, functioning independently of antithrombin, inhibiting thrombin bound to fibrin, and eliminating heparin-induced thrombocytopenia. It is also necessary to keep in mind that hemocoagulation tests are not specific, and their results, used for setting up the dosage, can be biased by many factors. The knowledge of the advantages and disadvantages of particular drugs, limitations of particular tests, and individualization are cornerstones of prevention against critical events, such as life-threatening bleeding or acute oxygenator failure followed by life-threatening hypoxemia and hemodynamic deterioration. This paper describes the effects of anticoagulant drugs used in ECMO and their monitoring, highlighting specific conditions and factors that might influence coagulation and anticoagulation measurements.

Abdominal compartment syndrome (ACS) is a rare complication of extracorporeal membrane oxygenation (ECMO) and is associated with high morbidity and mortality. Despite being the treatment of choice for ACS, decompressive laparotomy (DL) has been a matter of debate in children supported with ECMO due to high bleeding risk and presumed futility. We report the first neonatal DL for ACS while on ECMO following congenital diaphragmatic hernia (CDH) repair. Given its excellent outcomes, our case challenges current literature and supports prompt bedside laparotomy to treat ACS on neonatal ECMO.

VA-ECMO is commonly used for patients in cardiogenic shock (CS) or refractory cardiac arrest (CA) undergoing PCI for ACS. In this setting at high risk of both thrombotic and hemorrhagic complications, optimal anti-thrombotic therapy remains ill-defined. We hypothesized that an anti-thrombotic therapy comprising a parenteral anticoagulant (bivalirudin) and a parenteral anti-platelet agent (cangrelor) may prove safe and effective in this scenario. From November 2019 to December 2021, 14 patients received at least one dose of cangrelor (starting dose: 0.125 μg/kg/min) plus bivalirudin, without background aspirin, in the context of PCI and VA-ECMO for ACS-related CS/CA, and were included in this study. Efficacy endpoint was occurrence of thrombotic events and safety endpoint was major bleeding occurrence. Median age was 58 years. The majority (64%) presented with refractory CA. A thrombotic event occurred in 14%, while major bleeding occurred in 21% patients. One patient experienced arterial thrombosis after VA-ECMO arterial cannula removal, another experienced ischemic cerebellar stroke without functional sequelae. Bleeding events were: 29% BARC 3a, 14% BARC 3b, and 7% BARC 5b. Overall in-hospital mortality was 50%. Cangrelor was continued for 5 (4-10) days; temporary discontinuation was necessary in 36%, either for VA-ECMO cannula removal or for bleeding events. A low dose of cangrelor, associated with standard-intensity anticoagulation with bivalirudin was a feasible anti-thrombotic strategy in patients undergoing PCI during VA-ECMO support for ACS-related CS/CA. Bleeding events rates outweighed thrombotic events rates in this critically-ill population, although the observed rates were lowest among available studies.

Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.

Introduction: Unfractionated heparin (UFH) has traditionally been the agent of choice in patients on extracorporeal membrane oxygenation (ECMO). However, direct thrombin inhibitors (DTI) have recently garnered more attention in ECMO because of their advantages over UFH. Given the heterogeneous results of multiple recent published studies, we performed a meta-analysis to describe pooled outcomes between bivalirudin and UFH anticoagulation in patients on ECMO. Methods: Relevant studies were identified from MEDLINE and Google Scholar database searches through April 23, 2022. The primary efficacy outcome was thromboembolism (TE), and secondary efficacy outcomes included all-cause mortality and circuit thrombosis. The primary safety outcome was major bleeding. Results: A total of 6 studies were included in the meta-analysis. Bivalirudin use was associated with significantly lower risk of TE (OR 0.61; 95% CI 0.38-.99; P = .05; I2 = 0%) and circuit thrombosis (OR 0.51; 95% CI .32-.80; P = .004; I2 = 0%) compared with UFH. There was no significant difference in all-cause mortality risk (OR 0.75; 95% CI .52-1.09; P = .13; I2 = 30%) between the bivalirudin and UFH groups. No significant difference in the risk of major bleeding between 2 groups was found (OR 0.67; 95% CI 0.25-1.81; P = .43; I2 = 80%). Conclusion: These data support that bivalirudin is a reasonable alternative to UFH in patients on ECMO. Randomized controlled trials are needed to confirm bivalirudin's efficacy and safety results compared with UFH.

Extracorporeal membrane oxygenation (ECMO) poses unique thrombotic and hemorrhagic risks, and the optimal anticoagulant choice is unknown. We systematically searched Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection for randomized-, crossover-, retrospective cohort-, or parallel-designed clinical studies of adult patients receiving ECMO that compared heparin recipients with bivalirudin recipients. Meta-analysis was performed with random-effects models. The ROBINS-I tool was used to assess the risk of bias. Six retrospective observational studies met the inclusion criteria for the qualitative summary. Five studies were suitable for meta-analysis. Those who received heparin were more likely to experience circuit-related thrombosis (odds ratio [OR] 2.05, 95% confidence interval [CI] 1.25-3.37, p = 0.005, I2 = 0%) and die (OR 1.62, 95% CI 1.19-2.21, p = 0.002, I2 = 0%) compared with those who received bivalirudin. There were no differences in major bleeding events between heparin and bivalirudin recipients (OR 1.83, 95% CI 0.55-6.09, p = 0.33, I2 = 82.7%). In retrospective settings compared with heparin anticoagulation, bivalirudin was associated with less circuit-related thrombotic events and greater survival in adults supported on ECMO, without contributing to more bleeding complications. Prospective controlled studies comparing heparin and bivalirudin in adult ECMO patients are warranted to corroborate these findings.

Previous randomised trials of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) have reported conflicting results, in part because of treatment with different pharmacological regimens. We designed a large-scale trial examining bivalirudin with a post-PCI high-dose infusion compared with heparin alone, the regimens that previous studies have shown to have the best balance of safety and efficacy.

(1) Background: In COVID-19 patients, the occurrence of thromboembolic complications contributes to disease progression and mortality. In patients at increased risk for thrombotic complications, therapeutic enoxaparin should be considered. However, critically ill COVID-19 patients could develop resistance to enoxaparin. Bivalirudin, a thrombin inhibitor, may be an alternative. This pilot multicenter randomized controlled trial aims to ascertain if bivalirudin may reduce the time spent under invasive mechanical ventilation, as compared to enoxaparin. (2) Methods: Intubated COVID-19 patients at risk for thrombo-embolic complications were randomized to receive therapeutic doses of enoxaparin or bivalirudin. We ascertained the time spent under invasive mechanical ventilation during the first 28 days from Intensive Care Unit (ICU) admission. A standardized weaning protocol was implemented in all centers. In addition, we assessed the occurrence of thromboembolic complications, the number of patients requiring percutaneous tracheostomy, the gas exchange, the reintubation rate, the ICU length of stay, the ICU and 28-days mortalities. (3) Results: We enrolled 58 consecutive patients. Bivalirudin did not reduce the time spent under invasive mechanical ventilation as compared to enoxaparin (12 [8; 13] vs. 13 [10; 15] days, respectively; p = 0.078). Thrombotic (p = 0.056) and embolic (p = 0.423) complications, need for tracheostomy (p = 0.423) or reintubation (p = 0.999), the ICU length of stay (p = 0.076) and mortality (p = 0.777) were also similar between treatments. Patients randomized to bivalirudin showed a higher oxygenation at day 7 and 15 after randomization, when compared to enoxaparin group. (4) Conclusions: In intubated COVID-19 patients at increased risk for thromboembolic complications, bivalirudin did not reduce the time spent under invasive mechanical ventilation, nor improved any other clinical outcomes.

Bivalirudin offers several important advantages of relevance to the management of extracorporeal membrane oxygenation (ECMO) patients. This multicenter retrospective analysis evaluated the bivalirudin dosing in pediatric ECMO and correlated these doses with the severity of renal dysfunction. A total of 75 patients were included in this analyses: estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m 2 (n = 29), eGFR 30-60 (n = 18), eGFR < 30 (n = 28), and of those 23 were on renal replacement therapy (RRT). The initial bivalirudin dose used to reach therapeutic anticoagulation in patients with eGFR > 60 was significantly higher than the dose required in those with renal impairment (0.25 mg/kg/hr in patients with eGFR > 60 and 0.19 mg/kg/hr in patients on RRT, 0.18 mg/kg/hr in patients with eGFR 30-60 and 0.13 mg/kg/hr in patients with eGFR < 30 with no RRT). Progressive dose escalations (two to threefold increase) were required to maintain therapeutic range over the initial 4 days of ECMO that coincided with improving renal creatinine clearance during that same time period. Establishing an initial starting dose of bivalirudin contingent upon eGFR is essential for the rapid achievement of target anticoagulation intensity. Further dose adjustments guided by laboratory monitoring is necessary given the dynamic changes in creatinine clearance following ECMO initiation.

The effect and safety of bivalirudin compared with heparin in patients undergoing extracorporeal membrane oxygenation (ECMO) remains unclear. Therefore, we conducted a systematic review and meta-analysis to compare the effectiveness and safety of heparin and bivalirudin in patients who underwent ECMO. We searched Embase, the Cochrane Central Register of Controlled Trials, and MEDLINE. Inclusion criteria included patients (1) undergoing ECMO and (2) receiving bivalirudin or heparin. We excluded studies where the majority of patients switched heparin to bivalirudin or vice versa during the clinical course. The primary outcome was short-term mortality. We presented the results of all analyses with the use of random-effects models. Eleven studies reported short-term mortality. The use of bivalirudin was associated with significantly lower short-term mortality, compared with heparin (odds ratio: 0.71, 95% confidence interval, 0.55-0.92; p = 0.01, I2 = 7%). In this meta-analysis of observational studies, the use of bivalirudin was associated with significantly lower short-term mortality, compared with heparin. Further prospective studies are warranted to clarify this finding.

Bivalirudin is a medication used to manage and treat patients undergoing percutaneous coronary intervention for acute myocardial infarction. It is in the direct thrombin inhibitor class of drugs. This activity reviews the indications, action, and contraindications for bivalirudin as a valuable agent in the therapy of acute myocardial infarction, in addition to its broader applications in thromboembolic disease, cardiopulmonary bypass, and extracorporeal membrane oxygenation. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for the management team members of the patients, as previously mentioned.

Background: Patients with diabetes mellitus (DM) are considered to increase the risk of thrombosis and bleeding. However, whether DM is an independent risk factor for events in patients anticoagulated with bivalirudin during elective percutaneous coronary intervention (PCI) is not clear. Methods: Patients anticoagulated with bivalirudin during elective PCI from January 2017 to August 2018 in 3 centers were enrolled. The primary endpoint of thrombotic events was major adverse cardiac and cerebrovascular events (MACCE, including all-cause death, myocardial infarction, ischemic revascularization, stent thrombosis, and stroke); the primary endpoint of bleeding events was Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Results: 1152 patients were finally enrolled. After one-year follow-up, 89 (7.7%) MACCE and 21 (1.8%) BARC 2, 3 or 5 bleeding occurred. Multivariate Cox regression analysis showed DM was not an independent risk factor for MACCE (hazard ratio [HR]: 1.029, 95% confidence interval [CI]: 0.674-1.573, P = .893), but peripheral artery disease (PAD) history (HR: 2.200, 95%CI: 1.290-3.751, P = .004) was an independent risk factor for MACCE. DM was not an independent risk factor for BARC 2, 3 or 5 bleeding (HR: 0.732, 95%CI: 0.293-1.831, P = .505), but PAD history (HR: 3.029, 95%CI: 1.102-8.332, P = .032) and low hemoglobin level (HR = 0.972, 95%CI: 0.947-0.998, P = .036) were independent risk factors for BARC 2, 3 or 5 bleeding. Conclusions: DM was not an independent risk factor for one-year thrombotic and bleeding events in patients anticoagulated with bivalirudin during elective PCI. More attention should be paid to PAD history and hemoglobin level to identify high-risk patients.