Argatroban Inhibits Human Factor Xa at Therapeutic Drug Levels: An Explanation for Its Prolongation of the INR.
Bibliographic record
Abstract
Abstract Three direct thrombin inhibitors (DTIs) differ in their ability to increase the International Normalized Ratio (INR) for a given prolongation of the activated partial thromboplastin time (APTT), as follows: argatroban > bivalirudin > lepirudin. This phenomenon is clinically-relevant, as it can complicate the transition to coumarin therapy (a risk factor for venous limb ischemia in patients with heparin-induced thrombocytopenia and deep-vein thrombosis, i.e., a clinical situation in which a DTI may be given). Since this observed order of INR prolongation by DTIs is the reverse of that expected based on their known relative affinities for human thrombin (see Table), we tested whether these DTIs (as well as the small-molecule thrombin inhibitor, D-Phe-Pro-ArgCH2Cl [PPACK]) also inhibit free and/or prothrombinase-bound factor Xa (FXa). Prothrombinase-bound FXa was assembled on rabbit brain phospholipids supplemented with human plasma factor X-depleted plasma, to which human FXa (0.5 nM, final) was added. We found that argatroban inhibited free human FXa, i.e., FXa in the fluid-phase (IC50 = 5 μM), whereas it inhibited bovine FXa much less effectively (IC50 = 110 μM). In contrast, only supratherapeutic concentrations of bivalirudin inhibited human and bovine FXa, whereas lepirudin had no effect (see Table). Neither therapeutic nor supratherapeutic concentrations of the three DTIs inhibited prothrombinase-bound FXa. Comparison of DTIs on INR, APTT, IIa, and Inhibition of Human and Bovine Fxa PPACK Argatroban Bivalirudin Lepirudin * published values Effect on INR N.D. Greatest Intermediate Least [DTI] doubling APTT N.D. 1 μM 0.25 μM 0.06 μM Ki for human thrombin* ~40 nM ~2 nM ~0.0001 nM IC50 human FXa 3 μM 5 μM 1,700 μM >10,000 μM IC50 bovine FXa 5 μM 110 μM 2,900 μM >10,000 μM CONCLUSION: Compared with the other two DTIs, argatroban effectively inhibits human FXa at concentrations (IC50 = 5 μM) within the order of magnitude of the usual therapeutic drug levels (about 1 to 2 μM). Inhibition of free FXa is a plausible reason why argatroban prolongs the INR more effectively than the other two DTIs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".