Ability of Coagulation Tests to Assess Hemotherapeutic Agent Response Testing
Bibliographic record
Abstract
Introduction: Hemotherapeutic agents (HA) administered in response to abnormal coagulation tests may not be optimal, for abnormal tests do not identify specific deficient coagulation factors. The Multiple Coagulation Test System (MCTS) (Coagulation Sciences, Riverdale, NY) is developed to perform Hemotherapeutic Agent Response Testing (HART) to compare ability of HA (blood products, factors and drugs) to normalize clotting. In MCTS, after HA added to blood, a steel ball moves through blood as a cartridge moves in a see-saw motion. As blood clots, changes in motion of the steel ball result in changes in voltage applied to a magnetic field. These changes indicate clot formation. The goal of the study is to compare coagulation tests and assess probabilities (PROB) of the tests to generate dose-response (DR) curves for high-dose HA vs. low-dose HA vs. coagulopathic samples, in four hemostatic states in five coagulopathic models. Methods: With IRB approval and informed consent 40 volunteers donated fresh whole blood (FWB) (Step A). Contrived whole blood samples of severe hemophilia, Von Willebrand Disease, dilution, hypofibrinogenemia and F:VII deficiency were created. FWB was centrifuged at 3000 g X 15 minutes. Platelet-deficient plasma (PDP) was pipetted avoiding the buffy coat. Factor-deficient diluents were added to RBC and buffy coat in volume equal to PDP removed, to create severely coagulopathic blood (Step B). Diluents that replaced PDP to create coagulopathies were: factor-VIII deficient plasma, George King Biomedical, Overland Park, KS (GKB) for hemophilia; type III VWD plasma, GKB, for VWD; 5% albumin, Grifols, Los Angeles, CA for dilution; fibrinogen-depleted plasma, Affinity Biologicals, Ancaster, ON, Canada for hypofibrinogenemia; F:VII-deficient plasma, GKB, for F:VII deficiency. HA were added to step B blood to treat coagulopathies in doses of 20% and 100% of factors, resulting in step B samples treated with low-dose HA (step C) and high-dose HA (step D). HA agents were Humate-P, CSL Behring (CSL), King of Prussia, PA for hemophilia and VWD; HemosIL normal assayed plasma, Instrumentation Laboratory, Bedford, MA for dilution; RiaSTAP, CSL for hypofibrinogenemia; reagent grade F:VIIa, Enzyme Research Laboratories, South Bend, IN for F:VII deficiency. At A, B, C and D tests performed included activated clotting time (ACT), thromboelastogram (TEG), ProTime (PT), activated partial thromboplastin time (APTT), MCTS Clotting Time (MCTS-CT), and factor levels appropriate for each coagulopathy. A random-intercept hierarchal mixed regression model assessed differences in tests at B, C, and D vs A. The model was recast into Bayesian form. Default priors and 4 chains of 50,000 iterations each were used to reach convergence. Predictive posterior distributions, by averaging over assumed new samples, were calculated for scenarios, e.g., probability ACT in high-dose HA would clot faster than low-dose HA. A DR curve was modeled, calculating PROB a high-dose HA would clot faster than low-dose and, simultaneously, that low-dose HA would clot faster than coagulopathic. The higher the PROB, the greater chance a DR exists. These are ordinary PROBS; not p-values or parameter estimates. i.e. chance that in new samples, high-dose HA would clot faster than low-dose. Sample size calculations based on paired differences of coagulopathic to normal MCTS-CT, with power of 90% and a test level of 0.05, assuming difference 200 seconds lower than the baseline 400 seconds, with a standard deviation of 100 seconds, indicated a sample size of n = 10. Results: Due to cost once a vial of HA was opened we performed as many experiments that day as possible, explaining n = 11 or 12 for some experiments. Factor levels confirmed coagulopathies were created and treated. Tests with 1st and 2nd highest PROB of demonstrating DR curve for hemophilia APTT (PROB 0.931) and MCTS (PROB 0.78); VWD, APTT (PROB 0.995) and MCTS (PROB 0.934); for hemodilution, APTT (PROB 0.997) and ACT (PROB 0.989); for hypofibrinogenemia, TEG-MA (PROB 0.996) and TEG-G (PROB 0.916); for F:VII deficiency, APTT (PROB 0.758) and MCTS (PROB 0.746). Conclusion: Different tests had greater PROB for different coagulopathic models. As other tests, MCTS differentiated between hemostatic states. Optimizing doses of HA may improve MCTS performance. If MCTS can perform automated HART, treatment truly targeted to each patient's unique coagulopathy may become a reality.
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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 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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".