A Multitrait Genetic Study of Hemostatic Factors and Hemorrhagic Transformation after Stroke Treatment

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\u27s prognosis. OBJECTIVES: to investigate the association between genetically determined natural hemostatic factors\u27 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 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

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

[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.This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. E.M. is supported by a Río Hortega Contract (CM18/00198) from the ISCIII. J.C.-M. is supported by an Agència de Gestió d’Ajuts Universitaris i de Recerca Contract (FI_DGR 2020, grant number 2020FI_B1 00157) cofinanced by the European Social Fund. C.G.-F. is supported by a Sara Borrell Contract (CD20/00043) from ISCIII and Fondo Europeo de Desarrollo Regional (ISCIII- FEDER). M.L. is supported by a Contratos Predoctorales de Formación en Investigación en Salud Contract from the ISCIII (FI19/00309).Peer reviewe

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

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. To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. 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. Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10. 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; rs1421067 (CHD9), P = 1.81 × 10; and rs34780449, near ROBO1 gene, P = 1.64 × 10. 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. 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). 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