Evidence map›Paper›PMID 39938570›Full record

ArticleThrombosis and haemostasis2026

Modifications of the Prothrombin Active Site S4 Subpocket Confer Resistance to Dabigatran.

Viola J F Strijbis, Ka Lei Cheung, Dejvid Veizaj, Tessa Rutten, Boris de Bruin, Pieter H Reitsma, Daniël Verhoef, Mettine H A Bos

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Thrombosis and haemostasis, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Viola J F Strijbis *Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0003-1530-0818
Ka Lei Cheung *Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Dejvid VeizajDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0003-1042-7211
Tessa RuttenDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Boris de BruinDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Pieter H ReitsmaDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Daniël VerhoefDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0002-1604-6965
Mettine H A BosDivision of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0002-8164-817X

Funding

Health~Holland, Top Sector Life Sciences & Health LSHM19064Health∼Holland, Top Sector Life Sciences & Health LSHM19064
6 · The paper itself

Abstract

Direct anticoagulants inhibit coagulation serine proteases by reversibly engaging their active site with high affinity. By modifying the S4 active site subpocket of factor (F)Xa, we introduced inhibitor resistance while preserving catalytic activity. Given the homology between FXa and thrombin in active site architecture and direct anticoagulant binding, we have targeted the S4 subsite to introduce inhibitor resistance in (pro)thrombin.Recombinant prothrombin variants were generated in which I174 was substituted or sequence R92-N98 was exchanged with that of human kallikrein-3.Specific prothrombin clotting activity of the variants was 6-fold (intrinsic clotting) to 10-fold (extrinsic clotting) reduced relative to wild-type prothrombin. Further analyses revealed that modification of the S4 subsite hampers fibrinogen and thrombomodulin-mediated protein C conversion by thrombin. Consistent with this, the thrombin variants displayed a reduced catalytic efficiency toward the peptidyl substrate used in thrombin generation assessments. The variants displayed a 2-fold reduced sensitivity for dabigatran relative to wild-type prothrombin, while argatroban inhibition was unaffected. Analyses using a purified component system revealed an up to 24-fold and 4-fold reduced IC

Indexed as

AntithrombinsDabigatranDrug ResistanceProthrombinBlood CoagulationCatalytic DomainHumansKallikreinsMolecular Dynamics SimulationRecombinant ProteinsThrombinAntithrombinsDabigatranKallikreinsProthrombinRecombinant ProteinsThrombin

Identifiers

PMID39938570
PMCPMC12758957

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.