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

Abstract

Summary. 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 wildtype 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.

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

“…These experiments demonstrate that SDF1a is a physiological substrate of CPB2 and that there is a bleeding diathesis in a model of chronic bleeding in Cpb2 À/À mice. Septicemia The observation that intraperitoneal E. coli administration caused less liver damage in Cpb2 À/À mice than in WT mice in a septicemia model [79] has been corroborated in a pneumococcal mouse model in which Cpb2 À/À mice were also protected, but its substrate was not identified [80]. A role for CPB2 in protection against sepsis is consistent with data showing that CPB2 levels in the cerebrospinal fluid correlate with the severity of disease and the levels of complement activators such as C3a, iC3b, and C5b-9 [80].…”

“…Septicemia The observation that intraperitoneal E. coli administration caused less liver damage in Cpb2 À/À mice than in WT mice in a septicemia model [79] has been corroborated in a pneumococcal mouse model in which Cpb2 À/À mice were also protected, but its substrate was not identified [80]. A role for CPB2 in protection against sepsis is consistent with data showing that CPB2 levels in the cerebrospinal fluid correlate with the severity of disease and the levels of complement activators such as C3a, iC3b, and C5b-9 [80]. In a polymicrobial sepsis model, Cpb2 À/À mice were protected and the relevant physiological substrate causing the phenotype was shown to be C3a, although both C5a and fibrin also played a role in the disease [51].…”

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood–brain barrier dysfunction

“…reported on brain‐derived full‐length CPB2 transcripts and shorter alternatively spliced transcripts without carboxypeptidase activity . Baseline levels of proCPU in CSF have been detected in controls and elevated levels were found in patients with traumatic brain injury and bacterial meningitis . Antovic et al .…”

“…Baseline levels of proCPU have been detected in cerebrospinal fluid (CSF) of controls but so far no information on proCPU and CPU levels in CSF of AIS patients and their potential relationship to stroke parameters is available. In the current study we investigate proCPU in undiluted CSF of patients with AIS and controls.…”

Endothelial protein C receptor polymorphisms and risk of sepsis in a Chinese population

“… 16 As a member of the protein C system, EPCR regulates protein C by activating it to play a role in many pathological processes such as anti-inflammatory and anti-apoptotic pathways and reduce the overall permeability of endothelial cells. 45 – 48 Mutations in the EPCR gene have been reported to be relevant to the occurrence and development of sepsis by regulating the cytoprotective and anticoagulant effects of APC to influence the expression of EPCR and sEPCR. 28 , 49 Plasma sEPCR competes with the membrane form of EPCR (mEPCR) to bind to PC/APC to inhibit the effect of mEPCR.…”