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A novel prothrombin R533Q variant in patient with recurrent venous thrombosis

1Center for Molecular and Vascular Biology, University of Leuven; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 2Center for Molecular and Vascular Biology, University of Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 3Research Department of Haematology, University College London (UCL) – Cancer Institute, London, United-Kingdom, London, England, United Kingdom, 4University Hospitals Leuven, Leuven, Vlaams-Brabant, Belgium, 5Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Vascular Medicine and Hemostasis, University Hospitals Leuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium

Abstract Number: PB1111

Meeting: ISTH 2022 Congress

Theme: Diagnostics and OMICs » Laboratory Diagnostics

Background: Specific genetic variants in F2 gene coding for prothrombin are known to increase risk for venous thrombosis (VT). The most common is prothrombin c.G20210A UTR variant. More recently heterozygous gain-of-function missense variants Arg596Leu/Gln/Trp have been described in patients with VT by causing increased resistance towards antithrombin [Girolami et al, 2018].

Aims: We studied the potential prothrombotic effect of a novel heterozygous F2 variant Arg533Gln (R533Q) detected in a patient with recurrent VT.

Methods: A 66-year old male with recurrent pulmonary embolism and thrombophlebitis underwent screening using ThromboGenomics gene panel test [Downes et al, 2019]. This resulted in the detection of the common F2 c.G20210A variant and a second novel F2 variant R533Q. His 39-year old daughter only carries the R533Q variant and has no history of thrombosis. Recombinant FII (rFII) wild type (WT) and R533Q proteins were produced in HEK Expi293TM cells. Thrombin generation assays (TGA) were performed with plasma samples treated with DOAC-StopTM and with different dilutions of rFII in FII deficient plasma.

Results: The index patient and his daughter had normal FII activity levels of 96% and 100%, respectively. Plasma samples from both showed higher thrombin generation in comparison to a control plasma sample, which was however more pronounced for the index. TGA with rFII R533Q using a concentration of 100% FII activity showed a higher ETP, peak value and velocity index of 26%, 43% and 25%, respectively, compared to adding the same concentration of rFII WT (figure 1).

Different tests such as a FII activation assay by the prothrombinase complex, activation of FVIII by rFIIa and ecarin-based thrombin activity with rFII were carried out. None of these assays could explain the mechanism of the increased thrombin formation by the mutant.

Conclusion(s): The novel F2 R533Q variant is able to generate higher thrombin levels, which can be a risk factor for thrombosis.

image

Figure 1. Endogenous thrombin potential -ETP-, peak height and velocity index of rFII WT and R533Q using different dilutions in FII deficient plasma -unpaired t-test, ns P>0.05, * P≤0.05, ** P≤0.01 *** P≤0.001 **** P≤0.001-

To cite this abstract in AMA style:

Van Laer C, Freson K, Lavend'homme R, Muczynski V, Peerlinck K, Thys C, Jacquemin M. A novel prothrombin R533Q variant in patient with recurrent venous thrombosis [abstract]. https://abstracts.isth.org/abstract/a-novel-prothrombin-r533q-variant-in-patient-with-recurrent-venous-thrombosis/. Accessed December 6, 2023.

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