Background: Von Willebrand factor (VWF) is a glycoprotein that plays a critical role in haemostasis and thrombosis. The size of VWF multimers is regulated by ADAMTS13, which cleaves VWF at single peptide bond, Y1605-M1606, in the A2 domain. The VWF is encoded by a large and polymorphic gene in which many polymorphisms have been reported as thrombogenic.

Aims: This observational study investigated the presence of polymorphic variants in VWF gene in congenital Thrombotic Thrombocytopenic Purpura (cTTP).

Methods: DNA was extracted from EDTA samples of 63 cTTP patients from the UK TTP Registry. VWF exons from 28 to 32, and exon 45, were amplified by polymerase chain reaction (PCR), with corresponding introns primers. PCR products were sequenced by GENEWIZ and sequences data were analysed using Sequencher 5.4.6 (Gene Codes Corporation).

Results: The study population was composed by 75% (n=47) female and 25% (n=16) male, median age 34 years (range: 2-74). The investigated exons correspond to the A1, A2, A3 and C4 domains, where binding sites for GPIb, ADAMTS13, collagen and GPIIb/IIIa are respectively located. VWF polymorphisms were identified in 47.6% (n=30) cTTP patients: two missense variants in exon 28, both located in A1 domain, p.T1381A (rs216311) and p.D1472H (rs1800383) and one in exon 45, p.F2561Y (rs35335161). Sixteen percent of patients (n=10) T/T1381 homozygotes and 46% (n=29) A/T1381 heterozygotes were identified. The D1472H and F2561Y heterozygous variants were detected respectively in 28.6% (n=18) and 6% (n=4) of patients.

Conclusions: The homozygous T/T1381 variant has been already investigated to enhance the affinity of VWF for the platelet receptor GPIbα. Similarly, the F2561Y variant has been demonstrated to increase platelets aggregates size. The D1472H polymorphism has shown to decrease ADAMTS13 cleavage. In conclusion, VWF variants were a common finding in cTTP cases and may correlate with an increased thrombotic risk for cTTP patients.

« Back to ISTH 2020 Congress

ISTH Congress Abstracts - https://abstracts.isth.org/abstract/genetic-study-of-von-willebrand-factor-variants-in-congenital-thrombotic-thrombocytopenic-purpura-patients/