Coagulation Disorder, Blood, Prolonged APTT
Conditions
Keywords
Activated Partial Thromboplastin Time, Prolonged APTT, Clot Waveform Analysis, CWA, Preoperative Assessment, Predictive Model, Diagnostic Algorithm, Risk Stratification, Decision Support Systems, Hemostasis, Coagulation Disorders, Lupus Anticoagulant, Coagulation Factor Deficiency, von Willebrand Disease, Laboratory Automation, Clinical Decision-Making, Surgical Delay, Resource Utilization
Brief summary
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 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.
Interventions
OTHERClot 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.
Sponsors
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Availability of clot waveform analysis (CWA) data obtained during routine APTT testing using: * Optical coagulation analyzers (ACL TOP platform). * Silica-based APTT reagent (SynthASil®). 3. Completion of the standard laboratory evaluation for prolonged APTT as part of routine clinical care, when clinically indicated. 4. Samples collected and processed in accordance with the standardized preanalytical protocol defined in the study SOP. 5. Patients evaluated in either: * Preoperative assessment, or * Routine clinical practice (non-preoperative setting).
Exclusion criteria
1. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Discriminatory performance of the APTTO model | Baseline (at the time of prolonged APTT laboratory assessment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Calibration-in-the-large of the APTTO model | Baseline (at the time of prolonged APTT laboratory assessment) | Calibration-in-the-large of the APTTO1 and APTTO2 models assessing agreement between predicted and observed probabilities in an independent multicenter cohort. |
| Calibration slope of the APTTO model | Baseline (at the time of prolonged APTT laboratory assessment) | Calibration slope of the APTTO1 and APTTO2 models, evaluating the relationship between predicted and observed risk across the probability spectrum. |
| Overall prediction error of the APTTO model | Baseline (at the time of prolonged APTT laboratory assessment) | Overall prediction error of the APTTO1 and APTTO2 models, assessed using the Brier score. |
| Clinical utility of the APTTO model assessed by decision curve analysis | Baseline (at the time of prolonged APTT laboratory assessment) | 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. |
| Diagnostic accuracy of predefined APTTO cut-offs | Baseline (at the time of prolonged APTT laboratory assessment) | Sensitivity, specificity, positive predictive value, and negative predictive value of predefined APTTO cut-offs for identifying pathological causes of prolonged APTT. |
| Interobserver agreement in clot waveform morphology classification | Baseline (at the time of prolonged APTT laboratory assessment) | 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. |
| Estimated impact of the APTTO algorithm on preoperative workflow | Baseline (model-based estimation using timing data from index APTT laboratory assessment through surgical clearance) | Estimated potential reduction in time to surgical cleareance and avoidance of additional etiologic testing based on application of the APTTO algorithm. |
| Association between clot waveform morphology and severity of factor deficiency | During the preoperative evaluation period | 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. |
| Clinical impact of APTTO implementation in preoperative management | During the preoperative evaluation period and up to 30 days after surgery. | 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. |
Countries
Spain
Contacts
CONTACTDiego Velasco Rodríguez, MD, PhD
PRINCIPAL_INVESTIGATORDiego Velasco Rodríguez, MD, PhD
Hospital Universitario Fundación Jiménez Díaz / IIS-FJD
Outcome results
None listed