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[Preprint]. 2025 Jul 8:rs.3.rs-5685318.
doi: 10.21203/rs.3.rs-5685318/v1.

Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13

A Inkeri Lokki  1 , Michael Triebwasser  2 , Emma Daly  3 , Mitja I Kurki  1 , Markus Perola  4 , Kirsi Auro  4 , Anuja Java  5 , Jane E Salmon  6 , Seppo Heinonen  7 , Eero Kajantie  8 , Juha Kere  9 , Riitta Lassila  10 , Mark Daly  1 , John P Atkinson  5 , Hannele Laivuori  11 , Seppo Meri  1
Affiliations

Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13

A Inkeri Lokki et al. Res Sq. .

Abstract

Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor (VWF) (OR=1.72, p-value=3.57E-4) and a low-frequency missense variant rs41314453 (Ala732Val) in the gene coding for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (OR=1.97, p-value=0.044) were associated with preeclampsia. rs41314453 is known to decrease ADAMTS13 expression and activity. Thus, the reduced enzyme activity could promote the formation of large vWF polymers on endothelial cells and platelets and thereby increase vascular prothrombotic activity in preeclampsia. Our results support a role for an impaired ability of ADAMTS13 to limit VWF polymerization in the pathogenesis of PE. Ultralarge multimers of VWF could mediate platelet accumulation in the turbulent intervillous spaces in preeclamptic placentae, calling upon novel therapeutics to control the VWF-ADAMTS13 axis in severe cases having low ADAMTS13 in the presence of high VWF levels and multimerization.

Keywords: ADAMTS13; coagulation cascade; genetic association; preeclampsia; pregnancy; von willebrand factor.

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Conflict of interest statement

Additional Declarations: Competing interest reported. RL is a member of an advisor board and given lectures for Sanofi and Takeda. AJ serves on the scientific advisory boards of Alexion, AstraZeneca Rare Disease, and Novartis International AG, and serves as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals. She has been a Principal Investigator for Apellis Pharmaceuticals and is a Principal Investigator for Novartis International AG. She also receives royalty from UptoDate. HL has received honoraria from Orion Corporation. JPA is in the Scientific Advisory Board of Complement Corporation and Kypha, Inc; Scientific Advisory Board. Furthermore, he serves as a consultant in Celldex Therapeutics, formerly Avant Immunotherapeutics, Inc., Biothera and Clinical Pharmacy Services, CDMI. SM has received honoraria from Alexion, AstraZeneca Rare Disease, Biogen, Merck, Pfizer and UCB, and research funding from Alexion. Other authors have no conflicts of interest to report.

Figures

Figure 1
Figure 1
Domain structure of von Willebrand factor and ADAMTS13 with associating variants indicated with black arrows. Panel (A) von Willebrand factor (VWF) protein consists of eight functional classes of domains (29 in total, not shown) encoded by 52 exons (not shown). The domains in the propeptide region consisting of 741 amino acids are marked with sharp-cornered boxes and the domains that produce the mature VWF consisting of 2050 amino acids are marked by round-cornered boxes. The cleavage site of ADAMTS13 in the A2 domain is indicated with a dashed vertical line. Panel (B). ADAMTS13 consists of 12 domains that are encoded by 29 exons. The domains of the ADAMTS13 are a signal peptide (S), a propeptide (P), a metalloprotease domain (MP), a disintegrin domain (DIS), 8 thrombospondin type 1 domains (1–8), a cysteine-rich region (CYS), a spacer domain and two CUB domains. The domains that bind VWF are marked with dashed outlines. The disintegrin and spacer domains cleave the VWF A2 domain. The thrombospondin type domains 5–8 and CUB domains bind D4 and CK domains of VWF.
Figure 2
Figure 2
Frequency of blood groups of preeclampsia patients with any predisposing VWF/ADAMTS13 allele (pe; N=80) and in the Finnish population (fin; N=5536, source: Finnish Red Cross Blood Service). *** indicates p<0.0001.
Figure 3
Figure 3
Schematic depiction of the proposed role of the ADAMTS13 Ala732Val variant in PE. In normal pregnancy (panel A), the cleavage of Weibel-Palade body-derived VWF from endothelial cells by ADAMTS13 prevents excessive VWF multimerization. In preeclampsia pregnancies (panel B) with rs41314453*T of ADAMTS13, the amount or enzymatic activity of ADAMTS13 is reduced thereby enhancing multimeric VWF and platelet aggregation. Created with BioRender.com.
See this image and copyright information in PMC

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