Abstract Number: PB0711
Meeting: ISTH 2022 Congress
Background: Prekallikrein deficiency is a rare autosomal disorder caused by variants in KLKB1. It is generally not associated with a bleeding phenotype so is probably under reported, usually detected incidentally following an abnormal coagulation screen. Detection of Prekallikrein deficiency, in the presence of a prolonged APTT, is beneficial as it gives definitive explanation excluding other potential causes.
Aims: Genetic confirmation of Prekallikrein deficiency and identification of causative variant.
Methods: A 52 year old woman with Primary Sjögren’s syndrome was referred for investigation of ‘unexplained bruising to limbs’. Coagulation assays were performed as standard on a Sysmex analyser. Prekallikrein was measured using an APTT-based factor assay, also on a Sysmex analyser. NGS analysis was performed for the R90 Bleeding and Platelet disorder panel. Analysis was performed using a Twist Bioscience custom design panel run on a NovaSeq and the data analysed using Congenica. Putative pathogenic variants were confirmed by Sanger sequencing.
Results: Initial coagulation studies showed a normal INR but raised APTT. This was initially considered to be ‘consistent with the presence of a lupus anticoagulant’. Factor analysis showed a severe Prekallikrein deficiency (PK < 1 IU/dL). NGS analysis showed her to be homozygous for a c.1739G>T; p.(Gly580Val) missense variant in KLKB1 that scores as ‘likely pathogenic’ using ACGS Guidelines.
Conclusion(s): The identification of the homozygous p.(Gly580Val) missense variant confirms a diagnosis of congenital Prekallikrein deficiency. This explains the prolonged APTT and excludes its being an inhibitory antibody effect, in a patient with an autoimmune condition. To date only 15 KLKB1 variants have been reported associated with Prekallikrein deficiency (HGMD Professional 2021.4), only 6 of which are missense variants. The identification of this novel missense variant adds to our knowledge of KLKB1 / Prekallikrein deficiency.
To cite this abstract in AMA style:Mitchell M, Wheeler R, Cutler J, Ling G. A novel homozygous KLKB1 missense variant causative of severe Prekallikrein deficiency. [abstract]. https://abstracts.isth.org/abstract/a-novel-homozygous-klkb1-missense-variant-causative-of-severe-prekallikrein-deficiency/. Accessed February 28, 2024.
« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-novel-homozygous-klkb1-missense-variant-causative-of-severe-prekallikrein-deficiency/