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

Official title

Multicenter External Validation of the APTTO Predictive Model Based on Clot Waveform Analysis for the Assessment of Prolonged Activated Partial Thromboplastin Time

Overview

Prolonged activated partial thromboplastin time (APTT) is a frequent laboratory finding that may reflect a broad spectrum of underlying conditions, ranging from benign laboratory abnormalities to clinically relevant hemostatic disorders. Clot waveform analysis (CWA), automatically generated during routine APTT testing by optical coagulation analyzers, provides additional quantitative and qualitative information on clot formation dynamics. The APTTO model is a previously developed two-step predictive algorithm based on CWA features designed to estimate the probability of a pathological cause of prolonged APTT and to differentiate lupus anticoagulant from intrinsic pathway factor deficiency or von Willebrand disease. Internal validation has demonstrated good discrimination and calibration. This multicenter observational study aims to perform an external validation of the APTTO model in independent patient cohorts, assessing its discrimination, calibration, and decision-analytic performance without model updating.

Detailed description

This multicenter observational cohort study is designed to externally validate the APTTO predictive model in patients with prolonged APTT and normal prothrombin time evaluated in routine clinical practice across multiple hospitals.

All laboratory data, including CWA parameters and waveform morphology, are generated as part of standard diagnostic workflows. No additional blood sampling, laboratory testing, or modifications to clinical management are introduced for research purposes.

The study focuses on evaluating model performance in independent cohorts by applying the original APTTO model coefficients and predefined cut-offs without recalibration or re-estimation. Model discrimination, calibration, and decision-analytic measures will be assessed. Secondary analyses will explore model performance across predefined subgroups and analytical robustness.

This study adheres to the TRIPOD statement for validation of prediction models.

Interventions

• Other Clot waveform analysis-based risk stratification (APTTO models)
  Application of the APTTO predictive models (APTTO1 and APTTO2) to clot waveform analysis parameters generated during routine activated partial thromboplastin time testing, for research purposes only. The model output does not influence clinical management or surgical decision-making during the study.

Primary outcome measures

• Discriminatory performance of the APTTO model [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]

Secondary outcome measures (9)

• Calibration-in-the-large of the APTTO model [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Calibration slope of the APTTO model [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Overall prediction error of the APTTO model [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Clinical utility of the APTTO model assessed by decision curve analysis [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Diagnostic accuracy of predefined APTTO cut-offs [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Interobserver agreement in clot waveform morphology classification [Time frame: Baseline (at the time of prolonged APTT laboratory assessment)]
• Estimated impact of the APTTO algorithm on preoperative workflow [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 [Time frame: During the preoperative evaluation period]
• Clinical impact of APTTO implementation in preoperative management [Time frame: During the preoperative evaluation period and up to 30 days after surgery.]

Eligibility criteria

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.

3\. Absence of required CWA data or unavailable clot waveform images.

4\. 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Spain · 16 centers

• Hospital Universitario Severo Ochoa — Leganés
• Hospital de la Santa Creu i Sant Pau — Barcelona
• Hospital Universitario Arnau De Vilanova — Lleida
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Clínico San Carlos — Madrid
• Hospital Universitario Fundación Jiménez Díaz — Madrid
• Hospital Universitario Gregorio Marañón — Madrid
• Hospital Universitario Puerta de Hierro — Madrid
• … and 8 more centers

Identifiers

NCT: NCT07418099 · APTTO-EXT-IISFJD-2026 · Pending ethics committee aprov

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗