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Thrombin-activatable fibrinolysis inhibitor influences disease severity in humans and mice with pneumococcal meningitis

Mook-Kanamori, B. B., Valls Serón, M., Geldhoff, M., Havik, S. R., van der Ende, A., Baas, F., van der Poll, T., Meijers, J. C. M., Morgan, Bryan Paul, Brouwer, M. C. and van de Beek, D. 2015. Thrombin-activatable fibrinolysis inhibitor influences disease severity in humans and mice with pneumococcal meningitis. Journal of Thrombosis and Haemostatis 13 (11) , pp. 2076-2086. 10.1111/jth.13132

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Abstract

Background Mortality and morbidity in patients with bacterial meningitis result from the proinflammatory response and dysregulation of coagulation and fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by free thrombin or thrombin in complex with thrombomodulin, and plays an antifibrinolytic role during fibrin clot degradation, but also has an anti-inflammatory role by inactivating proinflammatory mediators, such as complement activation products. Objective To assess the role of TAFI in pneumococcal meningitis. Methods We performed a prospective nationwide genetic association study in patients with bacterial meningitis, determined TAFI and complement levels in cerebrospinal fluid (CSF), and assessed the function of TAFI in a pneumococcal meningitis mouse model by using Cpb2 (TAFI) knockout mice. Results Polymorphisms (reference sequences: rs1926447 and rs3742264) in the CPB2 gene, coding for TAFI, were related to the development of systemic complications in patients with pneumococcal meningitis. Higher protein levels of TAFI in CSF were significantly associated with CSF complement levels (C3a, iC3b, and C5b-9) and with more systemic complications in patients with bacterial meningitis. The risk allele of rs1926447 (TT) was associated with higher levels of TAFI in CSF. In the murine model, consistent with the human data, Cpb2-deficient mice had decreased disease severity, as reflected by lower mortality, and attenuated cytokine levels and bacterial outgrowth in the systemic compartment during disease, without differences in the brain compartment, as compared with wild-type mice. Conclusions These findings suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of systemic complications and inflammation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: blood coagulation; complement system proteins; pneumococcal meningitis; Streptococcus pneumoniae; thrombin-activatable fibrinolysis inhibitor
Publisher: Wiley-Blackwell
ISSN: 1538-7933
Date of Acceptance: 16 August 2015
Last Modified: 11 Jun 2019 08:38
URI: http://orca-mwe.cf.ac.uk/id/eprint/84585

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