GLOBAL COMPARATIVE ANTITHROMBIN-FIELD STUDY: IMPACT OF LABORATORY ASSAY VARIABILITY ON THE ASSESSMENT OF ANTITHROMBIN ACTIVITY MEASUREMENT
Bibliographic record
Abstract
Fitusiran is an investigational, subcutaneous small interfering RNA therapeutic in development for hemophilia A and B, with and without inhibitors that aims to rebalance hemostasis by targeting antithrombin (AT) mRNA to lower AT levels and restore sufficient thrombin generation. To further enhance the benefit-risk profile of fitusiran, the revised AT-based dosing regimen was designed to target AT activity levels of 15-35%. The objective of this study was to evaluate and compare AT activity measurements in hemostasis laboratories using commercially available in vitro diagnostic AT activity assays across countries. AT immunodepleted and normal pooled plasma were mixed to generate 100%, 36%, 14% and 9% (IU/dL) AT activity levels, based on the Siemens Innovance® AT activity assay. Forty-eight Hemostasis Laboratories in 16 countries, blinded to AT activity levels, tested plasma samples in triplicates on three different days. Labs used their routine chromogenic AT activity assays, which evaluate the effectiveness of AT in inhibiting human or bovine factor IIa or Xa. Pre-defined acceptable recovery criteria was set at ± 20% of assigned value with intra-assay coefficient of variation (CV) < 20%. Siemens Innovance® AT (human FXa based) assay can reliably measure antithrombin across all activity levels (CV 20%) with the highest reproducibility at 14% and 36% (CV 10%). Siemens Berichrom® and STA® -Stachrom® (bovine IIa based) assays could reliably measure 100% and 36% samples but showed lab-to-lab variability for ≤ 15% AT activity. Siemens Berichrom® had a CV > 20% for 14% and 9% samples. For Stachrom®, only 8/12 labs reported a value for the 14% sample and all labs failed to measure the 9% sample. The HemosIL® (bovine FXa based) assay significantly underestimated AT activity levels ≤ 36%. Most labs using HemosIL® failed to report any values for 14% and 9% AT samples. Clear inference regarding rarely used AT assays (each N < 4) could not be made. This study provides important data regarding the performance of commercially available, regulatory cleared AT activity assays across a range of AT activity levels. Siemens Innovance® AT (human FXa) assay can reliably measure AT activity at clinical decision points of 15%–35% (CV 10%) and is recommended for fitusiran monitoring. This assay was used for all fitusiran phase 1,2,3 clinical trials for measuring AT activity. Berichrom® and Stachrom® (bovine FIIa) assays can only be used for fitusiran monitoring after extra validation for ≤ 15% AT (CV < 20%). HemosIL® (bovine FXa) assay significantly underestimates AT activity ≤ 36% and should not be recommended for fitusiran patient management.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".