Supplemental fibrinogen restores thrombus formation in cardiopulmonary bypass-induced platelet dysfunction ex vivo.

BACKGROUND: Major cardiac surgery related blood loss is associated with increased postoperative morbidity and mortality. Platelet dysfunction is believed to contribute to post-cardiopulmonary bypass (CPB)-induced microvascular bleeding. We hypothesised that moderately hypothermic CPB induces platelet dysfunction and that supplemental fibrinogen can restore in vitro thrombus formation. METHODS: Blood from 18 patients, undergoing first-time elective isolated aortic valve surgery was drawn before CPB, 30 min after initiation of CPB, and after CPB and protamine administration, respectively. Platelet aggregation was quantified by optical aggregometry, platelet activation by flow-cytometric detection of platelet surface expression of P-selectin, annexin V, and activated glycoprotein IIb/IIIa, thrombus formation under flow and effect of supplemental fibrinogen (4 mg ml-1) on in vitro thrombogenesis. RESULTS: Post-CPB adenosine-diphosphate and TRAP-6-induced aggregation decreased by 40% and 10% of pre-CPB levels, respectively (P<0.0001). Although CPB did not change glycoprotein IIb/IIIa receptor expression, it increased the percentage of unstimulated P-selectin (1.2% vs 7%, P<0.01) positive cells and annexin V mean fluorescence intensity (15.5 vs 17.2, P<0.05), but decreased percentage of stimulated P-selectin (52% vs 26%, P<0.01) positive cells and annexin V mean fluorescence intensity (508 vs 325, P<0.05). Thrombus area decreased from 6820 before CPB to 5230 after CPB (P<0.05, arbitrary units [a.u.]). Supplemental fibrinogen increased thrombus formation to 20 324 and 11 367 a.u. before CPB and after CPB, respectively (P<0.001), thereby restoring post-CPB thrombus area to levels comparable with or higher than pre-CPB baseline. CONCLUSIONS: Single valve surgery using moderately hypothermic CPB induces partial platelet dysfunction. Thrombus formation was restored in an experimental study design by ex vivo supplementation of fibrinogen.

Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far. METHODS: In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria. RESULTS: We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2-9.7) in the MAFP group and 17.5% (95% CI 9.6-31.4) in the group without MAFP (p = 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01-0.63; p = 0.017). CONCLUSION: In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.

Platelet inhibitor withdrawal and outcomes after coronary artery surgery: an individual patient data meta-analysis.

OBJECTIVES: To evaluate the association between guideline-conforming as compared to shorter than recommended withdrawal period of P2Y12 receptor inhibitors prior to isolated on-pump coronary artery bypass grafting (CABG) and the incidence of severe bleeding and ischaemic events. Randomized controlled trials are lacking in this field. METHODS: We searched PUBMED, Embase and other suitable databases for studies including patients on P2Y12 receptor inhibitors undergoing isolated CABG and reporting bleeding and postoperative ischaemic events from 2013 to March 2024. The primary outcome was incidence of Bleeding Academic Research Consortium type 4 (BARC-4) bleeding defined as any of the following: perioperative intracranial bleeding, reoperation for bleeding, transfusion of ≥5 units of red blood cells, chest tube output of ≥2 l. The secondary outcome was postoperative ischaemic events according to the Academic Research Consortium 2 Consensus Document. Patient-level data provided by each observational trial were synthesized into a single dataset and analysed using a 2-stage IPD-MA. RESULTS: Individual data of 4837 patients from 7 observational studies were synthesized. BARC-4 bleeding, 30-day mortality and postoperative ischaemic events occurred in 20%, 2.6% and 5.2% of patients. After adjusting for EuroSCORE II and cardiopulmonary bypass time, guideline-conforming withdrawal was associated with decreased BARC-4 bleeding risk in patients on clopidogrel [adjusted odds ratio (OR) 0.48; 95% confidence intervals (CI) 0.28-0.81; P = 0.006] and a trend towards decreased risk in patients on ticagrelor (adjusted OR 0.48; 95% CI 0.22-1.05; P = 0.067). Guideline-conforming withdrawal was not significantly associated with 30-day mortality risk (clopidogrel: adjusted OR 0.70; 95% CI 0.30-1.61; ticagrelor: adjusted OR 0.89; 95% CI 0.37-2.18) but with decreased risk of postoperative ischaemic events in patients on clopidogrel (clopidogrel: adjusted OR 0.50; 95% CI 0.30-0.82; ticagrelor: adjusted OR 0.78; 95% CI 0.45-1.37). BARC-4 bleeding was associated with 30-day mortality risk (adjusted OR 4.76; 95% CI 2.67-8.47; P < 0.001). CONCLUSIONS: Guideline-conforming preoperative withdrawal of ticagrelor and clopidogrel was associated with a 50% reduced BARC-4 bleeding risk when corrected for EuroSCORE II and cardiopulmonary bypass time but was not associated with increased risk of 30-day mortality or postoperative ischaemic events.

How do type of preoperative P2Y12 receptor inhibitor and withdrawal time affect bleeding? Protocol of a systematic review and individual patient data meta-analysis.

INTRODUCTION: In order to reduce the risk of bleeding in patients on P2Y12 receptor inhibitors presenting for non-emergent coronary artery bypass grafting (CABG), current guidelines recommend a preoperative discontinuation period of at least three, five and seven days for ticagrelor, clopidogrel and prasugrel, respectively, to allow for recovery of platelet function. However, there is still substantial interinstitutional variation in preoperative management and relevant covariates of CABG-related bleeding are largely elusive so far. METHODS AND ANALYSIS: We will search PubMed (July 2013 to November 2021) and EMBASE (January 2014 to November 2021) using the following terms, MeSH terms and their synonyms: clopidogrel, prasugrel, ticagrelor, dual antiplatelet, P2Y12 receptor inhibitor, CABG, bleeding, haemorrhage. Two independent reviewers will screen all abstracts and full papers for eligibility. Disagreements will be solved by consulting with a third reviewer.The primary outcome is the incidence of Bleeding Academic Research Consortium type-4 bleeding depending on type of P2Y12 receptor inhibitor and preoperative withdrawal period. The secondary outcomes are mortality and ischaemic events according to the Academic Research Consortium 2 Consensus Document. We will perform an individual patient data meta-analysis (IPD-MA) with drug-specific preoperative withdrawal time and adjust for demographic and procedural variables. Subgroup analyses will be performed for anaemic patients and patients undergoing non-emergent versus urgent/emergent surgery. ETHICS AND DISSEMINATION: This IPD-MA consists of secondary analyses of existing non-identifiable data and meets the criteria for waiver of ethics review by the local Research Ethics Committee. Data sharing and transfer will be subject to a confidentiality agreement and a data use agreement. Findings will be disseminated through peer-reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42022291946.

How Do Type of Preoperative P2Y12 Receptor Inhibitor and Withdrawal Time Affect Bleeding?

BACKGROUND: Despite recommendations for standardized preoperative waiting of at least 3, 5, and 7 days for ticagrelor, clopidogrel, and prasugrel, respectively, there is still substantial interinstitutional variation in preoperative discontinuation of dual antiplatelet therapy in patients needing coronary artery bypass grafting (CABG). METHODS: In 299 patients undergoing CABG with or without valve intervention less than 7 days after last P2Y12 receptor inhibition, this study evaluated calculated red blood cell loss and Bleeding Academic Research Consortium type 4 (BARC-4) bleeding. RESULTS: A total of 83% of patients underwent CABG less than 48 hours after last drug intake. Calculated blood loss was lower in patients taking clopidogrel as compared with prasugrel or ticagrelor (1063 mL [690 to 1394 mL] vs 1351 mL [876 to 1829 mL] vs 1330 mL [994 to 1691 mL]; P < .001). Overall, 135 (45%) patients sustained BARC-4 bleeding; the incidence differed among the groups (P = .015) and was significantly higher in prasugrel-treated patients, as compared with clopidogrel-treated patients. In multivariable linear regression analysis, European System for Cardiac Operative Risk Evaluation II (EuroSCORE II), aspirin dose, cardiopulmonary bypass time, drug withdrawal time, and type of P2Y12 receptor inhibitor were significantly associated with red blood cell loss. Compared with 0 to 24 hours, a period of more than 48 hours of preoperative discontinuation substantially reduced calculated blood loss by 37% to 48% and BARC-4 bleeding by 58% to 71%, depending on the P2Y12 receptor inhibitor. CONCLUSIONS: Exposure to prasugrel and ticagrelor 24 hours or less before CABG increases both calculated blood loss and BARC-4 bleeding as compared with clopidogrel. Although discontinuation for longer than 48 hours substantially reduced calculated blood loss and BARC-4 bleeding across all P2Y12 receptor inhibitors, our single-center data further support strict adherence to the 2017 guidelines whenever justified by stable hemodynamics and nonjeopardized myocardium.