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

This multicenter observational cohort study is designed to externally validate the APTTO predictive models in patients with prolonged APTT and normal prothrombin time evaluated in routine clinical practice across multiple hospitals, and to prospectively assess their perioperative clinical implementation and utility.

During the external-validation phase, the original APTTO model coefficients and predefined cut-offs are applied without recalibration, re-estimation, or modification of clinical management. Model discrimination, calibration, classification performance at the predefined cut-offs, decision-analytic performance, and robustness across clinical, analytical, and preanalytical conditions are evaluated.

At Hospital Universitario Fundación Jiménez Díaz, a prospective perioperative implementation phase begins on 1 October 2026. In eligible preoperative patients with isolated prolonged APTT, normal prothrombin time, and no clinically relevant bleeding history, APTTO is used as a clinical decision-support tool. In patients classified as low probability according to the prespecified pathway, hematological clearance for surgery may be issued without awaiting completion of deferred etiological testing, according to clinical judgment. The impact of implementation on time from Anesthesiology referral to hematological clearance, subsequent time to surgery, resource use, and perioperative safety is evaluated by comparison with the pre-implementation cohort.

From 1 January 2027, participating centers continue prospective recruitment restricted to a dedicated preoperative cohort using standardized perioperative pathway milestones and variables. Perioperative safety outcomes are assessed through 30 days after surgery.

No additional blood sampling or laboratory testing is required solely for research purposes.

The external-validation analyses are performed using the frozen APTTO models, without model updating or data-driven threshold optimization.

Inclusion criteria

• Patients of any age (pediatric and adult populations) undergoing coagulation testing with:

• Prolonged activated partial thromboplastin time (APTT), defined as an APTT ratio ≥ 1.25.

• Normal prothrombin time (PT), according to local laboratory reference ranges.
• Availability of clot waveform analysis (CWA) data obtained during routine APTT testing using:

• Optical coagulation analyzers (ACL TOP platform).
• Silica-based APTT reagent (SynthASil®).
• Completion of the standard laboratory evaluation for prolonged APTT as part of routine clinical care, when clinically indicated.
• Samples collected and processed in accordance with the standardized preanalytical protocol defined in the study SOP.
• Patients evaluated in either:

• Preoperative assessment, or
• Routine clinical practice (non-preoperative setting).

Exclusion criteria

• Prolonged prothrombin time (PT) or combined prolongation of PT and APTT.

2- Inadequate preanalytical conditions, defined as non-compliance with the study SOP, including but not limited to:

• Incorrect blood-to-anticoagulant ratio.
• Delayed plasma processing beyond protocol-defined time limits.
• Inadequate centrifugation or plasma quality.

• Absence of required CWA data or unavailable clot waveform images.

• Samples in which APTT values are outside the measurable range of the analyzer, preventing extraction of CWA-derived parameters.

5- Patients with missing essential clinical or laboratory data required for application of the APTTO models.