Abstract Number: PB0541
Meeting: ISTH 2021 Congress
Background: Warfarin remains an essential anticoagulant for some patients with high thrombotic risk and requires meticulous dose monitoring.
Aims: We performed a snapshot survey of 2,093 patients in the warfarin clinics at two UK hospitals in January 2021 to investigate the prevalence and aetiology of high warfarin dose requirement.
Methods: In both clinics, venous blood INRs were determined using Innovin thromboplastin and Sysmex CA1500 coagulometers. Warfarin dosing was based on RAID or DAWN algorithms.
Results: The median daily warfarin dose was 4.9 mg (range 0.64-100mg). Five (0.24%) patients had warfarin resistance (WR; warfarin dose >25 mg/day). Four of these cases (recurrent thrombosis n=3; mechanical heart valve=1) initially achieved stable therapeutic anticoagulation with warfarin <10mg/day but then required escalating doses to achieve target INR. Plasma warfarin levels were all within therapeutic range of 0.7-2.3 mg/l indicating acquired pharmacokinetic WR. In two cases, this could be linked to established interacting co-medications.
The remaining case was a 43-year-old male who required anticoagulation after mitral valve repair. INR-guided warfarin dosing rapidly escalated to 35 mg/day at which point the INR was 1.3. Despite this sub-therapeutic INR, the plasma warfarin level was 3.03 mg/l indicating pharmacodynamic WR. Analysis of VKORC1 that encodes the warfarin target Vitamin K epoxide reductase subunit 1 (VKORC1) revealed the heterozygous missense c.85G>T variant predictive of a p.Val29Leu substitution. This likely disrupts VKORC1 warfarin binding interface I (Leu22-Val29) and was shown by others in a cell line model to increase the warfarin IC50 by more than five-fold. c.85G>T is one of 26 missense variants in VKORC1 previously associated with WR in humans, but which do not diminish VKORC1 function in the Vitamin K pathway.
Conclusions: Our findings indicate that WR remains a rare phenotype but has heterogeneous origin. We highlight the utility of measuring plasma warfarin level and VKORC1 genetic testing to assist diagnosis.
To cite this abstract in AMA style:Peck R, Burley K, FitzGibbon L, Doherty C, Bacon S, Thorne R, Mumford A. Warfarin Resistance Is Rare but Has Heterogeneous Origin in an Anticoagulation Clinic Population [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/warfarin-resistance-is-rare-but-has-heterogeneous-origin-in-an-anticoagulation-clinic-population/. Accessed December 7, 2021.
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