Interference of lupus anticoagulant causing antiprothrombin and anti-beta-2-glycoprotein I antibodies on international normalized ratio measurements: comparative analysis of international normalized ratio methods

Rachel Gehlen; Roxanne G Moesbergen; CuiCui Bai; Philip G de Groot; A J Gerard Jansen; Joost C M Meijers; Bas de Laat; Jasper A Remijn

doi:10.1016/j.rpth.2024.102470

Interference of lupus anticoagulant causing antiprothrombin and anti-beta-2-glycoprotein I antibodies on international normalized ratio measurements: comparative analysis of international normalized ratio methods

Res Pract Thromb Haemost. 2024 Jun 8;8(5):102470. doi: 10.1016/j.rpth.2024.102470. eCollection 2024 Jul.

Authors

Rachel Gehlen¹, Roxanne G Moesbergen², CuiCui Bai³, Philip G de Groot¹, A J Gerard Jansen⁴, Joost C M Meijers^{5

6}, Bas de Laat¹, Jasper A Remijn²

Affiliations

¹ Department of Functional Coagulation, Synapse Research Institute, Maastricht, the Netherlands.
² Department of Clinical Chemistry, Meander Medical Centre, Amersfoort, the Netherlands.
³ Department of Protein Engineering, Synapse Research Institute, Maastricht, the Netherlands.
⁴ Department of Haematology, Erasmus Medical Center, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
⁵ Department of Molecular Haematology, Sanquin Research, Amsterdam, the Netherlands.
⁶ Department of Experimental Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Abstract

Background: Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements.

Objectives: Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements.

Methods: Pooled normal plasma and control plasma from patients on VKA (without LA) were incubated with monoclonal and isolated patient immunoglobulin G antiprothrombin and anti-beta-2-glycoprotein I antibodies that express LA activity. INR was determined before and after addition using 3 laboratory assays (Owren STA-Hepato Prest, Quick STA-NeoPTimal, and Quick STA-Neoplastine R) and 1 point-of-care test device (CoaguChek Pro II).

Results: Antiprothrombin and anti-beta-2-glycoprotein I antibodies with LA activity interfered with recombinant human thromboplastin reagents (Quick STA-Neoplastine R and CoaguChek Pro II), particularly when added to plasma of VKA-treated controls. This effect was most evident on point-of-care test INR measurements, while the recombinant Quick reagent exhibited a lesser degree of interference. In contrast, tissue-derived thromboplastin reagents (Owren STA-Hepato Prest and Quick STA-NeoPTimal) remained largely unaffected by these antibodies, both in pooled normal plasma and VKA anticoagulated control plasma. Among these reagents, the Owren INR reagent exhibited the lowest sensitivity to the influence of LA antibodies. This observed difference in sensitivity is independent of the plasma dilution factor or the presence of factor V or fibrinogen in Owren reagent.

Conclusion: INR reagents that utilize recombinant human thromboplastin are more sensitive to the presence of monoclonal and patient-derived antibodies with LA activity. Consequently, APS patients positive for LA should be monitored using tissue-derived thromboplastin reagents, given its reduced susceptibility to interference by LA-causing antibodies.

Keywords: anticoagulants; antiphospholipid syndrome; international normalized ratio; lupus coagulation inhibitor; warfarin.