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| ID | Type | Description | Link |
|---|---|---|---|
| Pending ethics committee aprov | Other Identifier | Ethics Committee of Fundacion Jimenez Diaz |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with prolonged activated partial thromboplastin time (APTT) | Patients with prolonged activated partial thromboplastin time (APTT) and normal prothrombin time undergoing routine laboratory evaluation. Clot waveform analysis (CWA) data and clinical information are collected prospectively as part of standard care and analyzed using the APTTO predictive models. No additional diagnostic or therapeutic procedures are performed. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clot waveform analysis-based risk stratification (APTTO models) | Other | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Discriminatory performance of the APTTO model | Discrimination of the APTTO1 and APTTO2 models for identifying the cause of prolonged activated partial thromboplastin time (APTT), assessed by the area under the receiver operating characteristic curve (AUC) in an independent multicenter cohort. | Baseline (at the time of prolonged APTT laboratory assessment) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline (at the time of prolonged APTT laboratory assessment) |
| Calibration slope of the APTTO model |
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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:
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:
Exclusion Criteria:
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.
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The study population includes pediatric and adult patients undergoing routine coagulation testing in clinical practice who present with isolated prolongation of activated partial thromboplastin time (APTT) and normal prothrombin time (PT). Patients may be evaluated in the preoperative setting or during routine clinical care for other indications.
All laboratory data, including clot waveform analysis (CWA), are generated as part of standard diagnostic procedures, without additional blood sampling or modification of clinical management. Patients receiving anticoagulant therapy that may prolong APTT are included, provided that PT remains within the normal range.
The study uses pseudonymized data obtained from electronic medical records and laboratory systems, with no direct patient contact and no anticipated risks beyond routine care.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Diego Velasco Rodríguez, MD, PhD | Contact | +34 669 98 04 32 | diego.velascor@quironsalud.es |
| Name | Affiliation | Role |
|---|---|---|
| Diego Velasco Rodríguez, MD, PhD | Hospital Universitario Fundación Jiménez Díaz / IIS-FJD | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitario Severo Ochoa | Recruiting | Leganés | Madrid | Spain |
Individual participant data will not be shared publicly. Data will be analyzed in aggregated and pseudonymized form exclusively for the objectives of the study, in accordance with applicable data protection regulations and ethics committee approval.
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|
Calibration slope of the APTTO1 and APTTO2 models, evaluating the relationship between predicted and observed risk across the probability spectrum. |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | During the preoperative evaluation period and up to 30 days after surgery. |
| Hospital de la Santa Creu i Sant Pau | Recruiting | Barcelona | Spain |
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| Hospital Universitario Arnau De Vilanova | Recruiting | Lleida | Spain |
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| Hospital Universitario 12 de Octubre | Recruiting | Madrid | Spain |
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| Hospital Universitario Clínico San Carlos | Not yet recruiting | Madrid | Spain |
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| Hospital Universitario Fundación Jiménez Díaz | Recruiting | Madrid | Spain |
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| Hospital Universitario Gregorio Marañón | Not yet recruiting | Madrid | Spain |
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| Hospital Universitario Puerta de Hierro | Not yet recruiting | Madrid | Spain |
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| Hospital Universitario Ramón y Cajal | Recruiting | Madrid | Spain |
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| Hospital Clínico Universitario Virgen de la Arrixaca | Not yet recruiting | Murcia | Spain |
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| Clínica Universidad de Navarra | Not yet recruiting | Pamplona | Spain |
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| Hospital Clínico Universitario de Salamanca | Not yet recruiting | Salamanca | Spain |
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| Complexo Hospitalario Universitario de Santiago | Not yet recruiting | Santiago de Compostela | Spain |
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| Hospital Clínico Universitario de Valladolid | Recruiting | Valladolid | Spain |
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| Complexo Hospitalario Universitario De Vigo | Not yet recruiting | Vigo | Spain |
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| Hospital Clínico Universitario Lozano Blesa | Not yet recruiting | Zaragoza | Spain |
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| ID | Term |
|---|---|
| D001778 | Blood Coagulation Disorders |
| D020141 | Hemostatic Disorders |
| D014842 | von Willebrand Diseases |
| ID | Term |
|---|---|
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006474 | Hemorrhagic Disorders |
| D025861 | Blood Coagulation Disorders, Inherited |
| D020147 | Coagulation Protein Disorders |
| D001791 | Blood Platelet Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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