A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment
File(s)
Published version
Author(s)
Gallego-Fabrega, Cristina
Temprano-Sagrera, Gerard
Cárcel-Márquez, Jara
Muiño, Elena
Cullell, Natalia
Type
Journal Article
Abstract
BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
Date Issued
2024-04
Date Acceptance
2023-11-27
Citation
Journal of Thrombosis and Haemostasis, 2024, 22 (4), pp.936-950
ISSN
1538-7836
Publisher
Elsevier
Start Page
936
End Page
950
Journal / Book Title
Journal of Thrombosis and Haemostasis
Volume
22
Issue
4
Copyright Statement
© 2023 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38103737
Subjects
fibrinogen
hemorrhagic transformation
hemostatic factors
r-tPA treatment
von Willebrand factor
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2023-12-15