Inhibition of Fibrin-Bound Thrombin by a Covalent Antithrombin-Heparin Complex
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Bibliographic record
Abstract
Numerous studies have shown that fibrin-bound thrombin (IIa) is protected from inhibition by antithrombin (AT) + heparin (H) due to the formation of a ternary fibrin.IIa.H complex. We investigated factors affecting the inhibition of fibrin.IIa by a covalent complex of AT and H (ATH). The rate of IIa reaction with ATH was decreased 2-3-fold by fibrin monomer as compared to 57-fold for AT + heparin with high AT affinity. Furthermore, although the reaction of AT + H with a IIa mutant with decreased H binding (RA-IIa) was inhibited 2-3-fold in the presence of fibrin, reaction rates of ATH + RA-IIa were not reduced by fibrin. The relative difference in the effect of fibrin on the ATH reaction with RA-IIa compared to that for reactions of AT + H with RA-IIa is consistent with the fact that, in the absence of fibrin, the rate of the ATH reaction with RA-IIa relative to IIa was much less reduced (8-fold) compared to the corresponding reactions of AT + H (decreased 306 fold). Similarly, the addition of excess H in the absence of fibrin gave only a small decrease in rate of ATH + IIa reaction. However, in the presence of fibrin, the addition of 40-fold excess H decreased the rate of ATH inhibition of IIa by 1 order of magnitude. Experiments with ATH containing low molecular weight heparin chains with low AT affinity showed that IIa inhibition requires ATH with long chains that activate the AT moiety. Finally, electrophoresis of fibrin +/- ((125)I-)IIa +/- ((125)I-)ATH on native and denaturing gels showed that ATH forms ATH-IIa complexes that remain bound to fibrin through the ATH component. Thus, ATH is a potent inhibitor of fibrin-bound IIa, likely due to the formation of fibrin.ATH-IIa as opposed to fibrin.IIa.H ternary complexes.
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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 | 0.000 | 0.000 |
| 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) | 0.001 | 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 it