External Multicenter Validation of the APTTO Model for Prolonged APTT Using Clot Waveform Analysis

Calibration-in-the-large of the APTTO model

Calibration-in-the-large of the APTTO1 and APTTO2 models assessing agreement between predicted and observed probabilities in an independent multicenter cohort.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Calibration slope of the APTTO model

Calibration slope of the APTTO1 and APTTO2 models, evaluating the relationship between predicted and observed risk across the probability spectrum.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Overall prediction error of the APTTO model

Overall prediction error of the APTTO1 and APTTO2 models, assessed using the Brier score.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Clinical utility of the APTTO model assessed by decision curve analysis

Net clinical benefit of the APTTO models compared with investigate-all and investigate-none strategies, assessed by decision curve analysis across clinically plausible threshold probabilities.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Diagnostic accuracy of predefined APTTO cut-offs

Sensitivity, specificity, positive predictive value, and negative predictive value of predefined APTTO cut-offs for identifying pathological causes of prolonged APTT.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Interobserver agreement in clot waveform morphology classification

Agreement between local investigators and central reader (blinded to clinical data) for qualitative clot waveform morphology classification, assessed using Cohen´s kappa or Fleiss´kappa statistics, as appropriate.

Time frame: Baseline (at the time of prolonged APTT laboratory assessment)

Estimated impact of the APTTO algorithm on preoperative workflow

Estimated potential reduction in time to surgical cleareance and avoidance of additional etiologic testing based on application of the APTTO algorithm.

Time frame: Baseline (model-based estimation using timing data from index APTT laboratory assessment through surgical clearance)

Association between clot waveform morphology and severity of factor deficiency

Assessment of the association between clot waveform morphology, particularly strictly normal waveform patterns, and the severity of intrinsic pathway factor deficiencies in patients with prolonged activated partial thromboplastin time (APTT). This analysis aims to determine whether a normal waveform is associated with higher residual factor levels and a lower likelihood of clinically relevant deficiency. During the course of the study, additional exploratory objectives were incorporated to further investigate the clinical and physiological implications of clot waveform analysis. In particular, the relationship between strictly normal waveform morphology and the severity of factor deficiency will be evaluated prospectively in the remaining study cohort.

Time frame: During the preoperative evaluation period

Clinical impact of APTTO implementation in preoperative management

Evaluation of the clinical impact of implementing a clot waveform analysis-based diagnostic strategy (APTTO) in the preoperative management of prolonged activated partial thromboplastin time (APTT). This analysis will compare patients managed before and after implementation of APTTO at the development center, time to surgical clearance, and perioperative outcomes. This objective was incorporated during the course of the study to further assess the clinical implications of APTTO in routine practice and will be evaluated prospectively in the remaining study cohort.

Time frame: During the preoperative evaluation period and up to 30 days after surgery.