This was a retrospective, observational, multicenter study that identified patients treated at the Medical University of South Carolina, University of Kentucky HealthCare, University of Florida Health, and Indiana University Health Methodist Hospital between 2011 and 2021. The study was approved by the institutional review board at all study sites, with the data coordinating site being the University of South Carolina. Adult patients over 18 years of age who presented for major bleeding associated with oral factor Xa inhibitors were identified for inclusion. Major bleeding was defined as bleeding into a critical site, life-threatening bleeding requiring emergent surgery or an invasive procedure, or bleeding requiring a blood transfusion within 24 h of reversal [13]. Patients had to receive either 4F-PCC or 3F-PCC in order to be included. As 3F-PCC was used as the standard product at Indiana University Health Methodist Hospital during the study period, all patients receiving 3F-PCC were identified from this center, while patients receiving 4F-PCC identified from the remaining 3 centers. Exclusion criteria included pregnancy, incarceration, perioperative reversal unrelated to bleeding, intracranial hemorrhage (ICH) with an initial Glasgow Coma Scale (GCS) less than seven, death within 24 h of reversal, acute coronary syndrome or ischemic stroke within the last 30 days, initial presentation at outside hospital, surgery within 24 h of presentation, large blood vessel rupture (e.g. aortic dissection or ruptured aortic aneurysm), primary intraventricular hemorrhage, epidural hematoma, or if the patient underwent a craniotomy prior to repeat head imaging.

Data collection was performed by manual chart review of electronic medical records. Study data were collected and managed using REDCap (Research Electronic Data Capture). REDCap access was supported by the South Carolina Clinical & Translational Research Institute, with an academic home at the Medical University of South Carolina, through NIH—NCATS Grant Number UL1 TR001450 [14]. Interrater reliability (IRR) testing was conducted at all sites to ensure consistency with an IRR of 1. Baseline data collected included demographics, oral factor Xa inhibitor utilized, indication for the oral factor Xa inhibitor, use of antiplatelet agents, and type of bleeding noted. Laboratory parameters collected included markers of blood volume (e.g. hemoglobin, hematocrit), renal function (e.g. serum creatinine) as it can impact the clearance of certain anticoagulants, and coagulation (e.g. prothrombin time, activated partial thromboplastin time). Data on reversal strategies and blood products utilized were also collected. Patients were divided into cohorts based on the use of 4F-PCC and 3F-PCC. The primary outcome of interest was hemostatic effectiveness, which was assessed via previously validated criteria [13]. Secondary outcomes included thromboembolism, in-hospital mortality, and length of hospital and intensive care unit stay.

Data are presented as counts with percentage for categorical data and medians with interquartile ranges for continuous data. Chi square or Fisher’s Exact tests were used to compare categorical variables between cohorts, while Mann–Whitney U tests were utilized for continuous variables. To assess the primary outcome of hemostatic effectiveness in patients who received 4F-PCC versus 3F-PCC after adjusting for baseline factors, adjusted odds ratios and 95% confidence intervals were estimated using logistic regression. This multivariable analysis adjusted for race, total body weight greater than or equal to 85 kg, type of bleed (intracranial, gastrointestinal, or other), and use of any antiplatelet therapy at baseline. Statistical analyses were conducted using SPSS v29 (IBM Corp., Armonk, NY).